14,839 Matching Annotations
  1. Jul 2018
    1. On 2014 Oct 12, George Ntoumenopoulos commented:

      I completely concur with these authors. In addition the potential impact of ventilatory and patient positioning strategy on the movement of airway secretions also deserves attention. Our recent case report (Physiother Res Int. 2014 Jun;19(2):126-8. doi: 10.1002/pri.1563. Epub 2013 Aug 17. Justification for chest physiotherapy during ultra-protective lung ventilation and extra-corporeal membrane oxygenation: a case study.Cork G1, Barrett N, Ntoumenopoulos G.) highlights the potential failings of current recommendations for secretion clearance. The ultra protective ventilator settings combined with head of bed upright positioning may predispose to secretion retention and warrants further investigation.


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    1. On 2016 Apr 02, Daniel Tsin commented:

      I will like to mention that : Historically Dr. D.O. Ott performed a ventroscopy appendectomy during vaginal hysterectomy on April 26, 1906 and was published in 1908 : Ott D.O. (1908). Results achieved by the use of direct illumination of the abdominal cavity, colon and urinary bladder during operations and for examination. Russky Vrach 43: 3-11.

      Besides our team performed transvaginal appendectomies under the name of Culdolaparoscopy without hysterectomy : Tsin DA, Colombero LT, Mahmood D, Padouvas J, Manolas P.Operative culdolaparoscopy: a new approach combining operative culdoscopy and minilaparoscopy.J Am Assoc Gynecol Laparosc. 2001 Aug;8(3):438-41 .

      https://www.ncbi.nlm.nih.gov/pubmed/11509789?dopt=Abstract


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    1. On 2016 Aug 08, Christopher Southan commented:

      Seems a shame if the 10yr momentum has stalled. Any prospect of updating from the declared 2013 statistics?


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    1. On 2014 Oct 31, R Y Seedat commented:

      Thank you for the positive comments regarding the study.

      Lesotho is a different country, with different demographics and burden of disease and a different healthcare system with differences in accessibility, availability of services and referral protocols. It would thus not make sense to combine the data.

      I don't think that the calculation of confidence intervals would be a valid statistical test since the study was not based on a population samples but on entire populations. While the incidences calculated are an underestimate, the calculation of confidence intervals would not assist in determining the degree to which the incidence is underestimated.


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    2. On 2014 Oct 29, Farrel Buchinsky commented:

      Nicely done study and well reported. I have seen several incidence reports but almost always from North America, or Denmark (or another developed country) and never from anywhere in Africa. The best-done North American studies show incidence of about 1 per 100000 or below (around 0.2-1). As the author states, The data described in the Free State and Lesotho is probably an underestimate since pediatric hoarseness (sans dyspnea or stridor) may not be diagnosed amongst those with less access to health care.

      • If all the cases from Lesotho are referred to Bloemfontein why not combine the statistics?<br>
      • Also, one could provide 95% confidence intervals (Poisson model probably) around the best estimates and see where the estimates from other reports fall within that range.


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    1. On 2014 Oct 21, Bertie Gottgens commented:

      One point worth making may be that the studies reported here were presumably done under pathogen-free conditions, and in the absence of predators or any other environmental stresses. "Normal" hemaopoiesis in the real world may therefore have to call on blood production from the traditional 'transplantation HSCs' more often than is suggested here.


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    1. On 2016 Jun 14, Christopher Uhde commented:

      This study was commented on as the principle subject of two Correspondence articles in Development:

      Transcriptional interpretation of Shh morphogen signaling: computational modeling validates empirically established models. Uhde CW, Ericson J. Development. 2016 May 15;143(10):1638-40. doi: 10.1242/dev.120972. No abstract available. PMID: 27190032

      and

      Mathematical models help explain experimental data. Response to 'Transcriptional interpretation of Shh morphogen signaling: computational modeling validates empirically established models'. Cohen M, Page KM, Perez-Carrasco R, Barnes CP, Briscoe J. Development. 2016 May 15;143(10):1640-3. doi: 10.1242/dev.138461. No abstract available. PMID: 27190033


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    1. On 2014 Oct 14, Jonathan Eisen commented:

      I would like to point out that I and multiple coauthors published a paper on pooling mitochondrial genomes and shotgun sequencing them for biodiversity analysis in 2000. I believe our paper should have been cited and discussed in this paper. See A case for evolutionary genomics and the comprehensive examination of sequence biodiversity. Pollock DD, Eisen JA, Doggett NA, Cummings MP. Mol Biol Evol. 2000 Dec;17(12):1776-88..

      Abstract is pasted below:

      Comparative analysis is one of the most powerful methods available for understanding the diverse and complex systems found in biology, but it is often limited by a lack of comprehensive taxonomic sampling. Despite the recent development of powerful genome technologies capable of producing sequence data in large quantities (witness the recently completed first draft of the human genome), there has been relatively little change in how evolutionary studies are conducted. The application of genomic methods to evolutionary biology is a challenge, in part because gene segments from different organisms are manipulated separately, requiring individual purification, cloning, and sequencing. We suggest that a feasible approach to collecting genome-scale data sets for evolutionary biology (i.e., evolutionary genomics) may consist of combination of DNA samples prior to cloning and sequencing, followed by computational reconstruction of the original sequences. This approach will allow the full benefit of automated protocols developed by genome projects to be realized; taxon sampling levels can easily increase to thousands for targeted genomes and genomic regions. Sequence diversity at this level will dramatically improve the quality and accuracy of phylogenetic inference, as well as the accuracy and resolution of comparative evolutionary studies. In particular, it will be possible to make accurate estimates of normal evolution in the context of constant structural and functional constraints (i.e., site-specific substitution probabilities), along with accurate estimates of changes in evolutionary patterns, including pairwise coevolution between sites, adaptive bursts, and changes in selective constraints. These estimates can then be used to understand and predict the effects of protein structure and function on sequence evolution and to predict unknown details of protein structure, function, and functional divergence. In order to demonstrate the practicality of these ideas and the potential benefit for functional genomic analysis, we describe a pilot project we are conducting to simultaneously sequence large numbers of vertebrate mitochondrial genomes.


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    1. On 2014 Dec 02, Helen E Benson commented:

      The IUPHAR/BPS Guide to PHARMACOLOGY contains curated information on ENaC and ASICs.


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    1. On 2015 Mar 27, KLAUS KAESTNER commented:

      Dear Dr. Tarlow We are well aware of the fact that a CreER is required for genetic lineage tracing. We tried many times to derive a Foxl1-CreER line. Unfortunately, none of our six founders showed any expression. We will keep trying!

      In the case of Foxl1 expression in the liver, there is an additional difficulty to consider. There are no Foxl1 expressing cell in the healthy, uninjured liver. Thus, even a Foxl1-CreER does not help, as it will not label any cell! The Foxl1 promoter becomes activated only AFTER specific types of liver injury.

      Note that additional evidence for the bi-lineage potential of Foxl1-Cre marked cells comes from the fact that one can establish clones of cells from a SINGLE Foxl1-Cre/RosaYFP labelled cell, and these can be expanded indefinitely. Thus, these cells are clonogenic. In vitro, these cells can be differentiated towards both the cholangiocyte and hepatocyte lineage.

      Note also that we acknowledge the limitations of our current model in the discussion of this paper. Klaus Kaestner


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    2. On 2014 Dec 23, Branden David Tarlow commented:

      It's unclear why this group has not replicated their results with the Foxl1-Cre with a CreERT2 allele since the original 2009 publication. I agree with a recent review that stated "Experiments using non-inducible Cre lines do not constitute bona fide lineage tracing tools..." (see Lemaigre Hepatology 2014; doi: 10.1002/hep.27659)


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    1. On 2015 Dec 30, Vatsalya Vatsalya commented:

      SOCIAL SECURITY Fact Sheet: For persons born in 1938 or later, their Social Security benefit may be affected by a provision that raises the age at which full Social Security benefits are payable.

      The age for collecting full Social Security retirement benefits will gradually increase from 65 to 67 over a 22-year period beginning in 2000 for those retiring at 62.

      Web-link: https://www.ssa.gov/pressoffice/IncRetAge.html


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    1. On 2014 Oct 08, Elizabeth Moylan commented:

      Thank you for raising this, we are investigating in accordance with COPE guidelines (http://publicationethics.org/).

      Elizabeth Moylan, Biology Editor, BioMed Central.


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    2. On 2014 Oct 08, Neil Saunders commented:

      A substantial fraction of the text in this article has been copied verbatim from an earlier article which it cites. This can be demonstrated by entering the article URLs - http://genomebiology.com/2010/11/3/r25 and http://www.biodatamining.org/content/7/1/15 - into this online tool. Also, the first 10 or so references are identical and in the same order.

      Discussion at this Twitter thread includes images which make the similarity very apparent.


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    1. On 2015 Jan 29, CREBP Journal Club commented:

      This is a very informative and interesting paper, which highlights the utilities and caveats in the use of multiple-indication reviews. The coherent methodology of this article is admirable and we acknowledge that there is a lack of coherent terminology. The term “multiple-indication review” is unambiguous and should be used in future studies. We agree that producers of systematic reviews should consider using this kind of reviews instead of, or in addition to, reviews focusing on a single indication. Important information that we cannot get with traditional methods (single-indication reviews) can be achieved if this methodology is followed. For example, multiple-indication reviews are very useful in the fight against antibiotic resistance. Providing Health Care Professionals and patients with comprehensive information about the risk of adverse effects and the benefit-harm trade-off may reduce their desire for use of antibiotics. Chen et al identified three uses of multiple-indication reviews. However, we propose that the use of this kind of review can be broadly categorised as either:

      ● To get a better estimate of the effectiveness or harms e.g., 'What are the adverse effects of amoxicillin?' (P* I C H1, H2, …)

      ● To examine heterogeneity across indications or interventions e.g., 'When are prophylactic antibiotics effective?' (P1, P2, P3, … I C O1), or 'What is the optimum timing of prophylactic antibiotics before any surgery?' (P* I1 I2 I3, … C O1)

      (PICO notation: P* = any disease; P1 P2 P3 = set of disease, I1 I2 I3 = set of interventions, C = comparison, O1 = outcome, H = harm)

      When undertaking a multiple-indication review much attention has to be paid to the methodologically caveats such as ‘overlapping’ of included reviews; the extra level of complexity (potential heterogeneity in the contributing systematic reviews, in addition to heterogeneity in the primary trials); potential confounders (e.g. methodological quality of included studies and reviews) and risk of bias (e.g. different duration or dose of tested treatment or different control groups). Some of these methodological challenges can be dealt with in the designing of the review and some should be taken into account in the analytical approach. ‘Overlapping’ can be circumvented if only the data from the originals trials are included in the multiple-indication review. However, if the multiple-indication review is based on results from systematic reviews one need to take account of the potential ‘overlapping’ of included studies and we would be very interested in software routines to conduct these reviews - especially in a 2-step frequentist approach. See CREBP Journal Club for more information


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    1. On 2014 Dec 08, George Parris commented:

      Between 2004 and 2009 I developed a hypothesis for the origin of HIV-1M based on the idea that anti-malarial drugs may have steered the evolution of HIV-1 along a unique trajectory Parris GE, 2004 Parris GE, 2007 Parris GE, 2007. My model deviates substantially from the widely accepted zoonosis model advocated by Sharp and Hahn (2008, 2011). Now, Faria et al. have independently proposed a model of HIV spread based on a detailed conventional analysis of the evolution of the HIV-1M sequence, which is consistent with my model:

      Clearly the transfer of SIV to humans in SE Cameroon (about 1876 according to recent analysis Wertheim JO, 2009) substantially predates the MRCA of HIV-1M (1920s). Thus, the original SIV infection in humans lingered for as much as 50 years (1876-1926) and mutated without producing a pandemic while evolving into the HIV-1 clade. Through the 1920s many persons from SE Cameroon with HIV-1 likely visited Leopoldville (Kinshasa) via the Sangha River (see the reports of Louise Pearce concerning African sleeping sickness dating from 1921). The MRCA of HIV-1M subsequently arose in Leopoldville as a result of some unique mutations (not shared with HIV-1O or other HIV-1 groups). The date of this unique transformation has been the subject of several studies and according to Faria et al. (page 60) if subtypes B and C (which obviously evolved later) are eliminated from the dataset, the molecular clock is more appropriately calibrated and the date of the MRCA of HIV-1M settles at 1926. They point out that neither population growth nor genital ulcer disease can explain the "starburst" pattern of divergence of the numerous HIV-1M lines (i.e., few subtypes in the period 1926-1950 followed by many subtypes and sublines in the 1950s and beyond). Finally, they conclude that their findings are consistent with "iatrogenic interventions in Kinshasa...were critical for the emergence of group M." In my papers I describe a specific (well-documented) iatrogenic event in early 1927 in Leopoldville/Kinshasa, which involved a child associated by name and disease (she had sleeping sickness) with SE Cameroon and the Sangha River. It is documented that after being treated with a powerful anti-malarial (pamaquine that affects the white blood cells) she and two other young girls were tested for malaria (blood drawn by syringe) at the same place and same day in sequence.

      The substantial delay in the spread of HIV-1M from Leopoldville (from 1927-1937)clarified by Faria et al. is consistent with the virus being in the bodies of children (under 10-years old in 1927). Had the virus been in the adult population (1926-onward) it undoubtedly would have spread geographically much earlier via rail and boat; moreover as a result of commercial sex workers and screening for sleeping sickness (e.g., by Jamot in Cameroon), there would have been many more unique subtypes generated in the period 1926-1940.

      It is incredible to me that in spite of the fact that anti-malaria drugs (e.g., chloroquine) are known to affect the replication of HIV (see papers by Savarino A starting in 2001 Savarino A, 2001) that this effect has been universally ignored in analysis of the evolution of HIV. Chloroquine became a daily fact of life in the Congo Basin in the late 1950s, just when the starburst is observed. Moreover, suppression of HIV by chloroquine can explain why HIV was first detected in the US in the 1980s (where chloroquine was not being widely used).


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    1. On 2014 Dec 11, Ibrahim Masoodi commented:

      This interesting case brings to the fore the multiple complications of SLE, a clinical scenario due to the generation of multiple autoantibodies directed towards the pancreas and the hemopoietic system. Acute vasculitis with its varied clinical presentation is often the commonest cause of abdominal pain in SLE, but acute pancreatitis and acute autoimmune hemolytic anemia, with its consequences, should be kept in mind in a given case of SLE. Further, this case emphasizes the need for close follow-up and proper health education in an SLE patient in order to circumvent any complication.


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    1. On 2015 Feb 24, Jonathan S Hausmann commented:

      We read with great interest this article by Lukens JR, 2014 on the role of diet in the development of inflammatory bone disease in Pstpip2<sup>cmo</sup> mice. They report that mice fed a low-fat diet had elevated levels of pro-IL-1B and developed inflammatory bone disease, a disease which resembles the human autoinflammatory disease chronic multifocal osteomyelitis. However, mice fed a high-fat diet had lower pro-IL-1B levels and did not develop osteomyelitis, despite their genetic predisposition.

      The authors conclude that the different outcomes are due to differences in the composition of the diets. However, the diets differed in more than fat content—notably in gluten content. The low fat diet, LabDiet 5013 has wheat as a main ingredient, whereas the high-fat diet, Research Diets Incorporated D12107 contains no wheat and is gluten-free.

      Pro-inflammatory effects of gluten have previously been demonstrated in mice. Non-obese diabetic (NOD) mice fed a standard wheat-containing diet had increased levels of inflammatory cytokines, as compared to those maintained on a gluten-free diet during gestation and early life (Hansen CH, 2014). Furthermore, those on gluten-free diets showed changes in the microbiome which conferred protection against the development of diabetes despite their genetic susceptibility.

      In patients with familial Mediterranean fever (FMF), another autoinflammatory disease, attempts to modulate the frequency and severity of attacks based on the fat content of the diet have been largely unsuccessful (SOHAR E, 1962). It is now known that the microbiome of patients with FMF differs from that of healthy controls (Ktsoyan ZA, 2013). What has yet to be determined is how diet affects this altered microbiome, and whether a gluten-free diet can promote an anti-inflammatory microbiome and modulate the clinical course of FMF and other autoinflammatory diseases.

      The question whether fat or gluten were responsible for the observed changes does not change the remarkable findings by Lukens JR, 2014 that diet can change the expression of this genetic autoinflammatory disease in mice by modulating the microbiome. However, when considering these results in developing possible treatments, it will be important to clearly determine the ingredients that changed the microbiome for the better.


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    1. On 2016 Feb 24, Lily Chu commented:

      Above link is broken. See here for new link:

      http://iacfsme.org/ME-CFS-Primer-Education/Bulletins/2009/Severe-ME-CFS-in-Adults-A-report-from-the-CH-(1).aspx


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    2. On 2014 Oct 21, Lily Chu commented:

      The results of this study confirm those of an earlier study by Pheby et al. in 2009. That study also noted two onset peaks, one from ages 11-20 and another from 31-40.

      Pheby's article can be accessed online here: http://www.iacfsme.org/BULLETINWINTER200910/Winter0910PhebySneddonHeinrichCHROMEReport/tabid/413/Default.aspx


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    1. On 2015 May 02, Arthur Yin Fan commented:

      The original trial by Hinman's has many methodology flaws, please read the comments under the original trial report.


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    2. On 2014 Nov 08, Qin-hong Zhang commented:

      None


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    1. On 2014 Oct 04, Ryan Radecki commented:

      Post-publication commentary:

      "ARISE, and Cast Off the Shackles of EGDT"

      The sound you hear is a sigh of relief from Emergency Physicians and intensivists regarding the outcomes of the Australasian Resuscitation in Sepsis Evaluation (ARISE).

      As ProCESS suggested, and as many have suspected all along, it seemed the critical intervention from Early Goal-Directed Therapy was the early part – and less the SCO2 monitoring and active management of physiologic parameters using dobutamine and blood transfusion. Now, we have a second study, in addition to ProCESS, supporting the same general conclusions....

      http://www.emlitofnote.com/2014/10/arise-and-cast-off-shackles-of-egdt.html


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    1. On 2016 Jun 07, Arthur Yin Fan commented:

      Acupuncture is Effective for Chronic Knee Pain: A Reanalysis of the Australian Acupuncture Trial. Altern Ther Health Med. 2016 Mar;22(3):32-6. Yin Fan A, Zhou K, Gu S, Ming Li Y. Abstract Context • In the October 2014 issue of the Journal of the American Medical Association (JAMA), Hinman et al published the results of an Australian clinical trial on acupuncture in a paper entitled "Acupuncture for Chronic Knee Pain: A Randomized Clinical Trial" (JAMA report), in which they concluded that neither acupuncture nor laser acupuncture had any greater effects than sham laser acupuncture for pain or function for patients aged 50 y and older with moderate-to-severe knee pain. That study has been criticized extensively by international scholars for its validity because serious methodological flaws existed throughout the study's design, implementation, and conclusions. Objective • The current study intended to re-examine the prior study's conclusions about the efficacy of acupuncture for chronic knee pain. Design • The current research team performed a reanalysis of relevant data from the JAMA report. Intervention • The original study included 4 groups: (1) an acupuncture group, which received needle acupuncture, inferred by the current authors to have been set up to be a positive control in the original study; (2) a laser acupuncture group, which received laser acupuncture; (3) a sham laser acupuncture group, which received sham laser acupuncture and acted as the negative controls for the laser acupuncture intervention; and (4) a control group, which received conventional care but no acupuncture or laser treatments. The study lasted 12 wk. Outcome Measures • The measures included evaluations in the following areas: (1) poststudy modifications-an evaluation of the consistency of the JAMA report with the study's intentions as identified for a grant that was originally approved and funded by the Australian National Health and Medical Research Council (NHMRC) in 2009, as indicated in the study's trial registration, and as compared with the published protocols and to the study's originally stated objectives; (2) high heterogeneity-an assessment of the heterogeneity among the 4 groups for the overall outcome related to pain; (3) ineffectiveness of laser acupuncture-an analysis of laser acupuncture's efficacy for chronic knee pain as stated in the JAMA report, using effect size (ES); (4) effectiveness of acupuncture-a reanalysis of acupuncture's efficacy for chronic knee pain in comparison with the original analysis in the JAMA report, using ES; and (5) acupuncture after data adjustment-a new analysis of acupuncture's efficacy for chronic knee pain using data from the original study that was discussed in the JAMA report, using ES, with an estimation after data adjustment and elimination of the dilution effect of the Zelen design. Results • Contrary to a general impression that acupuncture was the focus, laser acupuncture was the primary intervention tested in the actual study, "Laser Acupuncture in Patients With Chronic Knee Pain: A Randomized, Placebo Controlled Trial." The study discussed in the JAMA report was neither a truly randomized, controlled trial (RCT) for acupuncture nor was it an appropriately designed, randomized study in general. High heterogeneity was found among its groups in the evaluation of overall pain in patients. Both the ES of 0.60 that had been set by Hinman et al for the minimal clinically important difference (MCID) and the resulting interpretation of results in the JAMA report were not appropriate. Using the original study's criteria of efficacy, the reanalysis has confirmed that the laser acupuncture was not effective, whereas the acupuncture was found to be moderately effective for chronic knee pain (P < .05) for both overall pain and function at 12 wk, with an ES of 0.58, or after the adjustment of the data, with an ES of 0.67. Conclusions • The JAMA study was neither a conventional RCT nor an appropriately randomized trial, and its results are probably invalid. The ES of 0.60 for the MCID that was used in the JAMA study and the resulting explanation were not appropriate. Even with an ES of 0.60 for the MCID, acupuncture remained effective after data adjustment. Consequently, compared with conventional care, acupuncture treatment was found to be moderately effective for chronic knee pain in patients aged 50 y and older. PMID: 27228270 [PubMed - in process]


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    2. On 2015 May 30, Arthur Yin Fan commented:

      The sample size calculation is inaccurate in this study. http://www.jcimjournal.com/articles/publishArticles/pdf/S2095-4964(15)60184-4.pdf

      It should be 773, instead of 282. Hinman described she considered the factors of multiple groups' comparison, intra-therapies,however, she did not.

      See the step by step sample size calculation detail in: The methodology flaws in Hinman’s acupuncture clinical trial, Part III: Sample size calculation. http://www.jcimjournal.com/articles/publishArticles/pdf/S2095-4964(15)60184-4.pdf


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    3. On 2015 May 29, Hongjian He commented:

      One our main criticisms of this publication was that there was no detailed reporting of number of needles used per treatment, acupuncture sites targeted per treatment, and specific treatment duration and electric stimulation for each patient. Dr. Hinman responded by stating:

      "Dr. He suggests lack of acupuncture standardization, treatment infrequency, and no electrical stimulation may explain our findings. However, when comparing acupuncture with sham treatment, a meta-analysis1 found no evidence that needle number or placement; use of electrical stimulation; or number, frequency, or duration of treatments influence acupuncture outcomes"

      We looked at the article Dr. Hinman cited (MacPherson et al., PLoS 2013) and she did not do a good job of reading it. They showed that number of needles used per treatment was statistically significantly correlated with effect size. The electrical stimulation had a significantly stronger effect. She incorrectly summarized the study results. Therefore, Dr. Hinman’s statement that needle numbers, length of treatment and electric stimulation have no effect on acupuncture outcomes is incorrect. We still await a sufficient explanation for why these specifics were not reported in her study.


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    4. On 2016 Apr 09, Leigh Jackson commented:

      Wit et al. conducted a pragmatic trial whose design had glaring weaknesses.

      There was no sham control. There was no blinding. Control was usual care inviting negative bias. The non-randomized self-selecting cohort invited positive bias. Consort was not followed. Patients had individualised treatment creating a chaotic heterogeneity of data.

      Wit et al. to Hinman et al. is as chalk to cheese. The difference in their results might be due to low dosage levels in Hinman et al. It might be due to high levels of bias in Wit et al.


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    5. On 2015 Apr 27, Qin-hong Zhang commented:

      Acupuncture treatment for chronic knee pain: study by Hinman et al underestimates acupuncture efficacy

      http://aim.bmj.com/content/33/2/170.full.pdf+html

      Dr Hinman and colleagues [1] completed a Zelen-design clinical trial for acupuncture for chronic knee pain patients and concluded that neither laser nor needle acupuncture conferred benefit over sham for pain or function in patients older than 50 years with moderate or severe chronic knee pain. We disagree with authors because they failed to use the most effective acupuncture regimen in their trial.

      We consider that their treatment regimen is inferior for the following reasons. First, the dosage of acupuncture is far from adequate. The protocol specified the acupuncture intervention as a twenty minute treatment once or twice weekly for 12 weeks, with 8 to 12 sessions in total permitted [1]. Treatment compliance was not reported. Even with an assumption of full compliance, the study participants received only 0.67 to 1.0 session weekly with a total 160 to 240 minutes in 12 weeks. This was below the treatment regimen in the trial by Witt, et al. [2], in which participants received 12 sessions of 30 min duration, administered over 8 weeks, i.e., average 1.5 sessions weekly, and 360 minutes in total for only 8 weeks. It is worthwhile to point out that Witt, et al. had opposite conclusions. Second, the study protocol did not require deqi (a renowned acupuncture sensation), which is profoundly regarded as a prerequisite of a preferable acupuncture treatment efficacy [3]. Third, the paper did not follow the CONSORT statement of acupuncture [4] that requires details of needling, such as needle manipulation, depth of needle insertion, and points selected unilateral, bilateral or both. Fourth, the dose of laser acupuncture was 0.2J per acupuncture point, which was considered too low to achieve a clinical effect [5]. Previous study suggested that the minimum dose should probably be 0.5 J/point [5] . Thus it is difficult to evaluate if effective treatment regimen was compared against the Sham.

      Because the efficacy of acupuncture therapy depends on the dose and deqi of acupuncture intervention, it is premature to us to reach the conclusion that acupuncture is not effective to treatment osteoarthritis pain of the knee.

      REFERENCES

      1. Hinman RS, McCrory P, Pirotta M, et al. Acupuncture for Chronic Knee Pain A Randomized Clinical Trial. JAMA. 2014;312(13):1313-1322.

      2. Witt C, Brinkhaus B, Jena S, et al. Acupuncture in patients with osteoarthritis of the knee: a randomised trial. Lancet. 2005;366(9480):136-143.

      3. Shi GX, Yang XM, Liu CZ, et al. Factors contributing to therapeutic effects evaluated in acupuncture clinical trials. Trials. 2012; 13:42.

      4. MacPherson H, Altman DG, Hammerschlag R, et al; STRICTA Revision Group. Revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA): extending the CONSORT statement. PLoS Med. 2010;7(6):e1000261.

      5. Baxter GD. Laser acupuncture: effectiveness depends upon dosage. Acupunct Med. 2009;27(3): 92.


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    6. On 2015 Apr 16, Arthur Yin Fan commented:

      The methodology flaws in Hinman’s acupuncture clinical trial, Part II: Zelen design and effectiveness dilutions: http://www.jcimjournal.com/articles/publishArticles/pdf/S2095-4964(15)60172-8.pdf

      Hinman and colleagues concluded that “in patients older than 50 years with moderate or severe chronic knee pain, neither laser nor needle acupuncture conferred benefit over sham for pain or function. Our findings do not support acupuncture for these patients.” As pointed out in my former article (The methodology flaws in Hinman’s acupuncture clinical trial, Part I: Design and results interpretation. J Integr Med. 2015; 13(2): 65–68.), there were serious flaws in the trial design and statistics, as well as in the interpretation of the results. In here I address problems in the Zelen design used by them -Using Zelen design in this study does cause biases.

      1 High drop-out rate:

      The drop-out rates were 2.82% (2/71) in the control group; 22.86% (16/70) in the acupuncture group; 18.31% (13/71) in the laser acupuncture group; and 22.86% (16/70) for the sham laser acupuncture group. According to the acceptable standards for an RCT, dropout rates less than 10% are acceptable, drop-out rates between 10% and 20% mean that the resulting data quality is poor, and drop-out rates of more than 20% mean that the data quality is considered very poor and should not be used in analysis. In this trial analysis, the data quality in the acupuncture and sham laser acupuncture groups are very poor as the drop-out rates are over 20%; the authors should not have directly used them in any statistical analysis, unless they had re-adjusted and re-balanced the sample among the groups during the study. As outlined by the National Institutes of Health, if there is a differential drop-out rate of 15% or higher between study arms, such as between the control group and the treatment group in this clinical trial, then there is a very high potential for bias. This is a flaw that can decrease the quality of the study results.

      2 The effectiveness in intervention groups was diluted by various factors

      The dilution rates should then be 21.87% in the laser acupuncture group, 13.80% in the sham laser acupuncture group, and 31.27% in the acupuncture group (the dilution rate calculations were shown in Tables 1–3). The dilution rate was very significant in the acupuncture group, which causes the effectiveness to be undervalued in the acupuncture group, by almost 1/3.

      The effective significance was masked by limited sample size due to the Zelen design of this study.

      3.The sample size calculation in this study is questionable.Too small.

      4 Conclusion

      The effectiveness of the acupuncture group was diluted 31.27%, and its drop-out rate was 22.86%, much higher than that of the other groups in Hinman’s clinical trial, which constitutes major flaws in how this study is analyzed and interpreted[8]. Based on the bias of Zelen design used in the study, and incorrect sample size calculation, the conclusions drawn from this study are of poor quality, inaccurate, and invalid.

      http://www.jcimjournal.com/articles/publishArticles/pdf/S2095-4964(15)60172-8.pdf


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    7. On 2015 Apr 11, Arthur Yin Fan commented:

      The sham laser acupuncture is not a valid negative control for acupuncture

      I agree acupuncture should have a real sham control in a vigorous RCT; however, in Hinman's acupuncture RCT, the sham laser acupuncture is only fit to the laser acupuncture, not to real acupuncture. Because Acupuncture and Sham laser acupuncture, these two interventions do not have comparability in both characteristics and form (i.e., not matched). Furthermore, there was no blinding method performed between these two groups-both the patients and the administrators who performed the interventions knew the difference between the groups, such as needling acupuncture and sham laser acupuncture.


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    8. On 2015 Apr 11, Arthur Yin Fan commented:

      There is a crucial mistake in interpreting the Hypothesis testing - What means? if P>0.05.

      Hinman said :"in......chronic knee pain, neither laser nor needle acupuncture conferred benefit over sham for pain or function (Dr. Fan notes: Her statement was based on P>0.05). Our findings do not support acupuncture for these patients”

      From the perspective of hypothesis testing in Statistics, if acupuncture has better results and with significant difference over the primary control (no-treatment group), p<0.05, we can conclude that “acupuncture is effective”- no matter what the result get from the comparing to the secondary control, such as “sham laser acupuncture”, but Hinman intentionally does not report this effectiveness in her conclusion; if acupuncture has better results over “laser acupuncture” and “sham laser acupuncture”, without significant in statistics, p>0.05, we can conclude that “acupuncture is better than the laser acupuncture, and sham laser acupuncture, but need more studies to confirm”. We can’t conclude that “acupuncture is not effective” because that there are no significant difference in statistics between acupuncture and “laser acupuncture”, or between acupuncture and “sham acupuncture” does not mean there is no difference between these treatments clinically. Hinman et al mis-interprets the results and violates the basic principle of Statistics.


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    9. On 2015 Apr 11, Arthur Yin Fan commented:

      Hinman's acupuncture RCT has too many methodology flaws and misleading

      As an independent researcher and practitioner in Acupuncture and Chinese medicine for thirty years, I strongly disagrees with Hinman's conclusion, as there were serious flaws in the trial design, the statistical analysis of the data and in the interpretation of the results of this study. I published a commentary recently [Fan A. The methodology flaws in Hinman’s acupuncture clinical trial, Part I: Design and results interpretation. J Integr Med. 2015; 13(2): 65–68.] http://www.jcimjournal.com/articles/publishArticles/pdf/S2095-4964(15)60170-4.pdf

      The major concerns are:

      (1)There is a major mistake in the primary testing factor in this RCT: the laser acupuncture should be the primary testing factor, not the needle acupuncture;

      (2)The interpretation of the results was misleading;

      (3)The “under-dosed” acupuncture treatments diluted the potential real effectiveness of acupuncture;

      (4)Laser acupuncture and acupuncture would be effective in Hinman’s RCT, if the statistics were re-analyzed after re-adjusting the data.

      (5)It is improper to test two different testing factors in one RCT with so small sample size;

      (6)Laser acupuncture is not one kind of acupuncture, the author intentionally mixes it with acupuncture;

      (7)Acupuncture did have significant effectiveness (p<0.05 in week 12), compared to the control (this is a primary control). However, the author intentionally does not interpreter this important result into the conclusion, instead, she concludes acupuncture is not effective and says her findings do not support acupuncture for patients.

      I feel the author, somehow, intentionally misleads readers by testing acupuncture as a major intervention in this RCT-There was no significance between the positive control and the naïve control (i.e., acupuncture and control groups). Therefore, we can only conclude that the positive control, acupuncture was under-dosed or the study was otherwise flawed. That the positive control shows significance is a basic sign of the success of a clinical trial. From this perspective, Hinman’s trial was a failed clinical trial for laser acupuncture. As it would be unethical to publish an astonishing article, with a group of almost scrapped data and confusing logic, that misleads the readers, including the general public, medical society and policy makers, the researchers should have re-adjusted or re-designed their study instead of publishing it.


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    10. On 2015 Jun 14, Arthur Yin Fan commented:

      Meridians could be tested by physics method, they are low electric resistance lines.


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    11. On 2015 Jun 11, David Keller commented:

      It is no longer accurate to label evidence-based science as "Western"

      The scientific method is the most powerful tool ever developed for the advancement of humanity, and science has, in turn, been advanced by humans from all cultural backgrounds.

      Ancient societies all developed superstition-based pseudo-sciences, which are incapable of predicting natural phenomena or truly understanding them. Astrology was a vain attempt to rationalize the movements of the planets, utterly useless until it was replaced by the science of astronomy. Similarly, alchemy led nowhere until it was transmuted by the scientific method into chemistry. Homeopathy is based on false concepts involving dilution, and yields "medicines" which are nearly pure placebo. Chiropractic medicine, in addition to being based on disproved concepts, can be downright dangerous. PubMed has documented many cases of carotid and vertebral artery dissections caused by chiropractic neck manipulations (search on "artery dissection chiropractor").

      The National Institutes of Health were founded to advance the scientific method in pursuing solutions to the health problems which plague mankind. Superstition-based folk remedies should be investigated when there is a chance that ancient peoples may have stumbled on a real medicine - such as aspirin from willow bark or digitalis from the foxglove plant. The active ingredient should be isolated, synthesized, tested and meta-analyzed until it is thoroughly understood, using the scientific method.

      Where in the human body can we find anatomical evidence of a meridian, or "chee"? Acupuncture is based on complex and detailed theories, but theories must be tested and proved in the material world, in a reproducible fashion. If acupuncture is incapable of demonstrating significant pain relief in a carefully conducted clinical study, perhaps its adherents should reexamine their beliefs rather than invoking ever more arcane and obscure objections to the study design.


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    12. On 2015 May 30, Arthur Yin Fan commented:

      Western medicine more focuses on structure, and Eastern medicine more on function. So, when explaining a specific issue, for example, a disc hernia induced lower back pain, even sciatica, western medicine will say the nerve gets pinched, however, eastern medicine will says the Bladder meridian Qi stagnant. Both are correct. Just because using different perspective, and using different language.

      What is the meridian? just a functional manifestation of the never. Nerve is the structure, the meridian is the function.

      Quite simple.


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    13. On 2014 Nov 13, David Keller commented:

      Should medical doctors recommend acupuncture to patients with chronic knee pain?

      Here is a brief description of acupuncture: "In traditional Chinese medicine, certain body systems, called meridians, are thought to regulate body function through the normal flow of energy [this energy is spelled "qi" but pronounced "chee"] from one part to another. Disturbances in this flow are thought to cause disease. Acupressure and acupuncture techniques are believed by practitioners of traditional Chinese medicine to cure disease by restoring this flow."(1) Without physiological or anatomical evidence of the existence of meridians or qi, acupuncture should be viewed as similar to chiropractic or homeopathic therapies, which lack scientifically credible theoretical mechanisms of action. This study found no significant clinical benefit of acupuncture for chronic knee pain. Therefore, I will not begin referring patients with chronic knee pain for acupuncture. I would like to see this study repeated for chronic pain syndromes of other body regions. If the null result is confirmed in all such regions, acupuncture will have to be classified as an expensive and complex placebo. Funding for research on debunked alternative therapies should be diverted to investigators conducting basic or clinical research of a more scientific nature.

      Reference

      1: Wang W and Wu S. Treating Pain With Acupuncture. JAMA 2014;312(13):1365.


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    14. On 2014 Nov 07, Qin-hong Zhang commented:

      None


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    15. On 2016 Apr 03, Leigh Jackson commented:

      Laser acupuncture provides a means for double blinding. This is a useful methodology for acupuncture trials where double blinding has always been the weakest link.


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    16. On 2015 May 30, Arthur Yin Fan commented:

      This study used a wrong sham for acupuncture, so the conclusion is not reliable.


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    17. On 2014 Oct 08, David Keller commented:

      Acupuncture trials have difficulty addressing the placebo effect and blinding

      Acupuncture has been challenging to test in a true double-blinded and placebo-controlled fashion. Skilled practitioners of acupuncture have invested years in their training and licensing, and may unintentionally transmit signals of their own strong belief in its purported beneficial effects, augmenting the placebo effect. Simply poking needles into a patient at randomly chosen points could have a strong placebo effect if done with an air of compassion and clinical authority.

      It has been argued that sham acupuncture performed as placebo therapy in clinical trials may accidentally stimulate a true acupuncture point, and thereby reduce the apparent benefit of acupuncture in the intervention subjects compared to controls. The use of sham laser acupuncture seems to address that objection.

      The arguments and criticisms of acupuncture trials will continue. More good evidence, such as the findings of this study, will be required before we can conclude that acupuncture is of no more benefit for relieving pain than placebo. Better understanding of the biological basis of pain is needed, to develop new and truly effective analgesic therapies.


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    1. On 2014 Oct 13, David Keller commented:

      Will mapping of all neural circuits increase understanding of the brain in meaningful ways?

      The Human Brain Mapping Initiative (HBMI) is a government-mandated research program with the goal of systematically mapping the neural circuitry of the entire human brain. Will this large-scale fiat-funded project result in commensurate advances in neuroscience, or will it divert scarce funds away from smaller, innovative research projects with the potential for breakthroughs in diverse realms? Are we trading away the prospect of new fundamental discoveries, in order to accumulate terabytes of minimally meaningful mapping data in a routine and mechanistic fashion? The brain circuit mapping study by Fox et al provides interesting and relevant findings, much to the credit of the overall Brain Initiative.

      The Human Brain Mapping Initiative recalls prior large-scale government-mandated projects, such as the effort to put a man on the moon, and the Human Genome Sequencing Project. The moon shots consumed funding which could have driven great progress in more crucial areas of discovery than lunar geology and micro-gravity ant farming. And, while the Genome Project did yield important information quickly, it has been criticized for amassing huge amounts of expensive data before they were needed, when the same information would have accumulated naturally over the years during the course of other investigations, and at less expense. Supporters have replied that the Genome Project itself drove down the cost of DNA mapping, due to the large market for sequencing equipment it created and funded. Similar arguments can probably be made both to attack and to defend the Brain Mapping Project. Only time, and further results, will settle these questions.


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    1. On 2015 Sep 17, Ghassan El-Baalbaki commented:

      authors of this comment are: Loose, T.<sup>1,3</sup> , Ashrah, L.<sup>1,</sup> Romero, M.<sup>1,</sup> Bégin, J.<sup>1</sup> and El-Baalbaki, G.<sup>1,2</sup> Affiliations, Université du Québec À Montréal<sup>1,</sup> McGill University<sup>2,</sup> Université de Nantes<sup>3</sup> .

      In this study, the authors examine the efficacy of Acceptance and Commitment Therapy (ACT) in treating partner aggression. After entering into communication with the first author, she confirmed that this study corresponds to her doctoral thesis (Zarling, 2013). We read her thesis in order to gain further knowledge about the published study, and we found two important aspects of the work that need to be brought into light: 1) we find it difficult to conclude that partner aggression was specifically reduced, because of threats to internal validity. 2) There seems to be inaccuracies in their statistical calculations.

      The primary objective was to demonstrate that ACT reduces intimate partner aggression better than the placebo control group. The authors strongly suggest that ACT was indeed able to do so. However, several points call this statement into question.

      First of all, it is worth noting that partner aggression is never specifically assessed. One may think that the Conflict Tactics Scales-2-Physical Assault Scale (CTS-2) did assess this construct (Straus, Hamby, Boney-McCoy & Sugarman, 1996), but when taking into account the exact content of the administered questionnaire that was figured in her thesis, it can be seen that the instructions were modified in order to include aggression towards “people we care about” (Zarling, 2013, p.132) instead of specifically towards a partner. This modification is not mentioned in the published article. Hence, participants could have hypothetically committed aggressive acts exclusively towards a non-partner, such as a child or a friend. It is thus hard to conclude that aggressive behavior, specifically among couples, decreased as a result of therapy.

      Furthermore, after modifying the instructions, one of the items even became incoherent. More specifically, when taking into the modified instructions of the questionnaire, the item stated “When upset or in a disagreement with someone you care about … have you became angry enough to frighten your partner?” (italics added)(Zarling, 2013, p. 132). It seems that this question was destined to ask if the participant became angry enough to frighten someone that they « care about » and not their « partner ». For example, if the participants were (or became) single, they could have interpreted this question as if they were angry enough to frighten someone that is not necessarily their partner. It is unclear how the authors wanted the participants to interpret this item. The way that the construct of partner aggression was assessed calls into question the internal validity of the study.

      It remains questionable why the authors neglected to assess attrition of couples during the study. Over the course of the study, it is possible that aggressive behavior decreased more in the ACT group as a result of more couples breaking up in this treatment condition than in the placebo control group. Even if the authors carried out both completer analysis and intent to treat analysis and the results did not differ on measured variables, the attrition of couples was not measured. Hence, it is impossible to know if the groups differed on partner attrition. It remains possible that participants continued to aggress former partners, but again this cannot be asserted simply because it was not measured. Assessing partner attrition would have helped neutralize a pertinent threat to internal validity. Hence, internal validity was limited by not taking into account partner attrition.

      Lastly, it is worth bringing up that the first author and two other investigators co-led all administered interventions (p. 201). Even if the authors state this in their article, after looking at the detailed explanation of the recruitment process of investigators, this choice does not seem to be justified. It seems that the first author was able to recruit investigators at no extra cost and it is questionable as to why she did not recruit three instead of two, thus avoiding a potential threat to internal validity. The explanation provided in her thesis, but not the article, also states that all the manipulation checks were carried out by the first author and supervised by the second and third authors (Zarling, 2013, p.61). Because of the implication of the authors in the experimental procedure, the results are potentially attributable to the experimenter expectancy effect. This is another threat to internal validity that evokes the tendency for researchers to unintentionally bias the results of their investigations in accord with their hypotheses. In taking into account the previously stated points, it seems difficult to conclude that this study shows that ACT specifically reduces partner aggression better than a placebo control group.

      On another note, the statistical validity of the study can be questioned:

      Throughout the results section of the paper (pp. 205–207), the authors report many beta values (β) for intercepts and slopes. If these are indeed beta values, they should vary between approximately 1 and -1 (Cohen, Cohen, West & Aiken, 2002). However in many cases, reported values are outside of this range. For example the authors state “The ACT participants also reported significantly less psychological aggression, β = 2.05, SE = 0.71, t(97) = 8.33, p < .001, and physical aggression, β = 2.21, SE = 0.65, t(97) = 8.19, p < .001, at the 6-month follow-up assessment” (p. 8). This leads us to think that the authors are actually reporting non-standardized coefficients (B) because B values can vary outside of this range. However, if this is the case, then the t values reported become incoherent. t values should equal B/(2SE) (we retained the value of 2 after rounding up from 1.96 which corresponds to 95% of a normal distribution (Christensen, 1986)), but reported t values do not correspond to this calculation. For example, let’s take another look at the previous citation and assume that it actually refers to B values. According to our calculations, t = B/(2SE) = 2.05/(2*0.71)=1.44, but the authors report that t = 8.33, p < .001. More simply stated,if the authors are indeed reporting β values, then many of the β values seem to be impossible (outside of the ± 1 range), but if they are reporting B values, the t values seem to be impossible according to our calculations. We were wondering how these seemingly paradoxical results could be explained.

      In conclusion, even if this research topic is of great interest, two main points should to be taken into account. First of all, it is hard to state that ACT is an effective treatment to reduce partner aggression because 1) partner aggression was never specifically assessed 2) partner attrition was not measured 3) of potential bias due to the experimenter expectancy effect. Secondly, it is hard to draw conclusions from the statistics figured in the study because 1) if β values were indeed being reported, then they lie outside of the ± 1 range and 2) if B values were actually reported, then the t values become incoherent.

      References

      Christensen, H. B. (1986). La statistique: démarche pédagogique programmée. Boucherville: Gaëtan Morin.

      Cohen, J., Cohen P., West, S. G. et Aiken, L. S. (2002). Applied multiple regression/correlation analysis for the behavioral sciences. New York: Routledge.

      Straus, M. A., Hamby, S. L., Boney-McCoy, S., & Sugarman, D. B. (1996). The revised conflict tactics scales (CTS2): Development and preliminary psychometric data. Journal of Family Issues, 17, 283–316.

      Zarling, A. (2013). A preliminary trial of ACT skills training for aggressive behavior. University of Iowa.


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    1. On 2014 Oct 02, David Keller commented:

      Quicker-and-sicker discharges inevitably result in increased hospital re-admissions

      Medicare and many private insurers pay hospitals a fixed amount to treat a given diagnosis, regardless of length of stay, which creates a financial incentive to discharge patients as soon as possible. Targets for shorter lengths of stay are set by hospital managements and are incorporated into the performance reviews of employed hospitalist physicians. With hospitalists pushing the envelope to get patients discharged quicker, an increase in the number of "bounce-back" re-admissions is inevitable, due to inadequate treatment, recrudescence of illness, or the lack of resources or support needed to complete recovery at home. To discourage premature discharges, financial penalties for "bounce-back" re-admissions were created by Medicare and other payers. Of course, these penalties are also incorporated into the performance reviews of employed physicians, and create a disincentive to readmit patients who were recently discharged. But, if the patient presents for treatment at a different hospital, the readmission penalty applies against the first hospital to treat and discharge the patient, not the second hospital. Thus, recently-discharged patients who are still too sick to complete their recovery at home may find it easier to be readmitted at a new hospital for inpatient treatment, where they will be evaluated by physicians who do not have a disincentive to re-admit them. Switching hospitals can make it easier for a still-sick patient to get re-hospitalized, but it also results in discontinuities of care and resulting inefficiencies, because records need to be transferred, new doctors need to learn about the patient, etc. This all just demonstrates that for every action to reduce costs by penalizing providers, there are unintended consequences which can harm patients.


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    1. On 2014 Oct 12, Amanda Capes-Davis commented:

      Cell lines derived from ductal carcinoma in situ are certainly needed. Many thanks to the authors for including an STR profile for ETCC001 as part of their work. Did the authors test the other derivatives that were transfected with hTERT? It would be worthwhile testing all derivatives, just to confirm that they come from the same donor.


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    1. On 2014 Oct 18, stephane burtey commented:

      It is interesting to remind that pioglitazone the drug use in the experiments is associated with an increased risk of bladder cancer (http://onlinelibrary.wiley.com/doi/10.1111/bcp.12306/abstract;jsessionid=0BF19A6B1135280E0C6DAAB5F9A2BF21.f02t03) and was withdrawn in France for this reason. It could be very interesting that the authors discuss this strange fact. Why imagine to use a drug known to cause be associated with an increase risk of cancer to treat cancer?


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    1. On 2016 Apr 15, Amanda Capes-Davis commented:

      This article has now been retracted. See http://www.ncbi.nlm.nih.gov/pubmed/26909548 for the retraction notice and further comment.


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    2. On 2014 Oct 15, Amanda Capes-Davis commented:

      KB is not an OSCC cell line - KB cells are actually HeLa, from cervical adenocarcinoma. Cross-contamination of KB was discovered by Stanley Gartler back in 1967. Unfortunately, KB is still widely used as a model for oral cancer. Cross-contaminated cell lines are extensively used in the scientific literature, with many scientists not aware of this important problem.

      A list of cross-contaminated or otherwise misidentified cell lines can be found at http://iclac.org/databases/cross-contaminations/.


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    1. On 2015 Aug 01, James C Coyne commented:

      Discussion of recovery patterns and schizophrenia will be facilitated when these authors finally published the overdue results of Klingberg, S., Wittorf, A., Meisner, C., Wölwer, W., Wiedemann, G., Herrlich, J., ... & Buchkremer, G. (2010). Cognitive behavioural therapy versus supportive therapy for persistent positive symptoms in psychotic disorders: The POSITIVE Study, a multicenter, prospective, single-blind, randomised controlled clinical trial. Trials, 11(1), 123. <pubmed/21190574>. This represents the largest clinical trial of cognitive behavior therapy for psychosis ever undertaken.


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    1. On 2016 Jun 03, Ewen Gallagher commented:

      This work analyses the MEKK1 (encoded by Map3k1) PHD motif genetically and by protein array substrate screening. Shows an important role for the MEKK1 PHD motif in TGF-β cytokine signaling and demonstrates how PHD ubiquitination can influence TAK1 signal transduction. Shows genetically by knockin mutation (Map3k1<sup>mPHD</sup> allele) that MEKK1 is important for stem cell MAPK signaling, differentiation and tumorigenesis. Reports phenotypes of Map3k1<sup>mPHD/+</sup> mice. A review is also published for this work (1). Other recent works looking at MEKK1 activation by cytokines and hyperosmotic stress (2-3). A short review is available relating to this work (4).

      Related work. (1). Suddason T, Gallagher E. A RING to rule them all? Insights into the Map3k1 PHD motif provide a new mechanistic understanding into the diverse roles of Map3k1. Cell Death Differ 2015. (2). Matsuzawa A, Tseng PH, Vallabhapurapu S, Luo JL, Zhang W, Wang H, Vignali DA, Gallagher E, Karin M. Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex. Science 2008; 321:663-8. (3). Steed E, Elbediwy A, Vacca B, Dupasquier S, Hemkemeyer SA, Suddason T, Costa AC, Beaudry JB, Zihni C, Gallagher E, et al. MarvelD3 couples tight junctions to the MEKK1-JNK pathway to regulate cell behavior and survival. The Journal of cell biology 2014; 204:821-38. (4). Gallagher E, Suddason T. The PHD motif of Map3k1 activates cytokine-dependent MAPK signaling. Molecular & cellular oncology 2015; 2:e980659.


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    1. On 2014 Dec 18, DAVID ALLISON commented:

      Regression to the mean is a concept that does not seem to be known by or intuitive to many scientists. This paper by Love-Osborne et al. provides an example of that. Specifically, the authors state “For the power calculation, we estimated that 50% of the participants in the IG [intervention group] would either decrease or maintain their BMI z-score and that only 25% of the participants in the CG [control group] would.” Yet, given that the subjects studied were “adolescents with BMI ≥ 85%” (i.e., above the 85 percentile) and who had baseline BMI z-scores nearly two standard deviations above the mean, by regression to the mean alone, we would expect subjects’ BMI z-scores to decrease on average and that more than 50% of subjects would have decreased BMI z-scores even without any intervention. Despite this, the randomization makes their study internally valid, but by not considering regression to the mean, the authors’ power analysis makes little sense.


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    1. On 2016 Aug 24, Ben Goldacre commented:

      This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT0172340. We believe the correct ID, which we have found by hand searching, is NCT01723540.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , an open database threading together all publicly accessible documents and data on each trial, globally. In the course of creating the database, and matching documents and data sources about trials from different locations, we have identified various anomalies in datasets such as PubMed, and in published papers. Alongside documenting the prevalence of problems, we are also attempting to correct these errors and anomalies wherever possible, by feeding back to the originators. We have corrected this data in the OpenTrials.net database; we hope that this trial’s text and metadata can also be corrected at source, in PubMed and in the accompanying paper.

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

      [1] Goldacre, B., Gray, J., 2016. OpenTrials: towards a collaborative open database of all available information on all clinical trials. Trials 17. doi:10.1186/s13063-016-1290-8 PMID: 27056367

      * Dr Ben Goldacre BA MA MSc MBBS MRCPsych<br> Senior Clinical Research Fellow<br> ben.goldacre@phc.ox.ac.uk<br> www.ebmDataLab.net<br> Centre for Evidence Based Medicine<br> Department of Primary Care Health Sciences<br> University of Oxford<br> Radcliffe Observatory Quarter<br> Woodstock Road<br> Oxford OX2 6GG


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    1. On 2014 Nov 02, Swapnil Hiremath commented:

      This is a nice, and elegant study which reiterates the potential effects of the av fistula creation on cardiac remodeling. However, given the survival benefit with AVF (as compared to central venous catheters) these results should be interpreted with caution. Another confounding factor perhaps not considered in this study is the effect of worsening kidney function over time: over the 6 months of study, the kidney function of some of these patients would have worsened, and in some cases accompanied by salt and water retention - or worsening hypertension. It would have been helpful to present these details (and/or control for them). Indeed, the absence of controls (i.e. patients who may not have had an AVF created) is a significant limitation. Lastly, the authors do not cite previous work from our group which used echocardiograms (and not CMR), with slightly greater numbers and longer follow up.


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    1. On 2015 Jan 05, Peter Gøtzsche commented:

      Antidepressant drugs should not be used in old people

      Warren D. Taylor mentioned that people with late-onset depression are at higher risk for subsequent dementia.1 However, none of the references he provided lend support to the idea that it is the disease that causes the dementia. It is more likely that it is the antidepressant drugs that cause the dementia, e.g. benzodiazepines double the risk for dementia.2

      Taylor also noted that depressed older adults are at increased risk for suicide and he recommends SSRIs. However, it has never been shown in reliable studies that SSRIs protect against suicide, but it has been shown that they cause suicide.3 Further, as Taylor noted, SSRI cause falls, which is detrimental in old people, as 20-25% die when they get a hip fracture. A meticulous cohort study of depressed people over 65 years of age, in which the patients were their own controls, showed that for every 28 people treated for 1 year with an SSRI, there was one additional death, compared to no treatment. A further reason why antidepressants should not be used in old people is that their effect on the depression is doubtful.4

      1. Taylor WD. Depression in the elderly N Engl J Med 2014;371:1228-36.

      2. Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer's disease: case-control study. BMJ 2014;349:g5205.

      3. Gunnell D, Saperia J, Ashby D. Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA’s safety review. BMJ 2005;330:385.

      4. Gøtzsche PC. Why I think antidepressants cause more harm than good. Lancet Psychiatry 2014;1:104-6.


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    2. On 2014 Nov 19, Peter Gøtzsche commented:

      Antidepressant drugs should not be used in old people

      Warren D. Taylor mentioned that people with late-onset depression are at higher risk for subsequent dementia.1 However, none of the references he provided lend support to the idea that it is the disease that causes the dementia. It is more likely that it is the antidepressant drugs that cause the dementia, e.g. benzodiazepines can cause dementia.2

      Taylor also noted that depressed older adults are at increased risk for suicide and he recommends SSRIs. However, it has never been shown in reliable studies that SSRIs protect against suicide, in fact they cause suicide.3 Further, as Taylor noted, SSRI cause falls, which is detrimental in old people, as many die when they get a hip fracture. A meticulous cohort study of depressed people over 65 years of age, in which the patients were their own controls, showed that for every 28 people treated for 1 year with an SSRI, there was one additional death, compared to no treatment. Antidepressants should not be used in old people, also because their effect on the depression is doubtful.4

      1. Taylor WD. Depression in the elderly N Engl J Med 2014;371:1228-36.

      2. Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer's disease: case-control study. BMJ 2014;349:g5205.

      3. Gunnell D, Saperia J, Ashby D. Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA’s safety review. BMJ 2005;330:385.

      4. Gøtzsche PC. Why I think antidepressants cause more harm than good. Lancet Psychiatry 2014;1:104-6


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    1. On 2015 Feb 09, Andrey Petrenko commented:

      Dr. Junfeng Zhang and colleagues have demonstrated that postoperative deterioration of rat cognitive performance in the Barnes maze could be prevented by amantadine. Amantadine also increased GDNF production in hippocampus and pretreatment with anti-GDNF antibody could abolish cognitive improvement attained by this drug. Since both amantadine and GDNF also inhibited interleukin 1β production, the authors concluded that the observed beneficial effect of amantadine on cognition is essentially an anti-neuroinflammatory effect mediated through GDNF. These are novel and interesting findings suggesting possible therapeutic potential of amantadine in treating postoperative cognitive dysfunction in humans. While we do not doubt the overall authors’ conclusion, we believe that there may be another mechanism underlying the reported cognition-preserving effect of amantadine. It is based on the fact that amantadine is a noncompetitive NMDA receptor antagonist (Blanpied TA, 1997; Blanpied TA, 2005) that may have analgesic properties. Although Dr. Zhang and colleagues believe that by performing learning and memory tests one week after surgery they have avoided the influence of pain on their results, this might not be the case. Actual pain levels in operated animals were not assessed in this study, and it is possible that rats given amantadine could have experienced significantly less pain compared to those operated but not receiving the drug. Such a possibility is further supported by the regimen of amantadine administration chosen by the authors, which was similar to preventive analgesia (first dose of analgesic being administered before surgery) often employed to alleviate postoperative pain. In elderly patients postoperative pain can confound performance on cognitive tests (Heyer EJ, 2000) and also predicts decline in their mental status (Duggleby W, 1994). In aged rats postoperative pain impairs cognitive function and preventive administration of analgesics (including those with no anti-inflammatory effect) can prevent this cognitive decline (Chi H, 2013; Kawano T, 2014). The extent of postoperative cognitive decline positively correlates with the level of expression of the NMDA receptor GluN2 subunits in rat hippocampus (Chi H, 2013), further supporting the notion that the NMDA receptor inhibiting properties of amantadine should have not be discarded when interpreting the results of the study in question. In adult spinal nerve ligated rats preventive administration of memantine (a derivate of amantadine and also a noncompetitive NMDA receptor antagonist) inhibits the phosphorylation of the NMDA receptor GluN2 subunits in the spinal cord and hippocampus, causes antinociception and, as a consequence, preserves their cognitive function (Morel V, 2013).<br> Finally, several reports indicate the involvement of NMDA receptors in brain expression of neurotrophic factors (including GDNF) (Al-Amin H, 2011; Ranju V, 2015) and in the mechanisms of neuroinflammation (Liu CH, 2011; Yan J, 2014) with documented beneficial effects of NMDA receptor antagonists. Thus, there is a possibility that the NMDA receptor-inhibiting properties of amantadine could also have contributed to its beneficial effect on neuroinflammation observed by Dr. Zhang and colleagues.


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    1. On 2014 Sep 30, Ryan Radecki commented:

      Post-publication commentary:

      "The 2014 AHA NSTE-ACS Guidelines"

      One of the best things about Emergency Medicine is the preponderance of guidelines imposed upon our management of patients by non-Emergency Medicine clinicians. One of the most glorious offenders is the American Heart Association, dictating our care of Stroke and Acute Coronary Syndrome.

      But, actually, this most recent update – despite the continued absence of Emergency Medicine from the Writing Committee – contains some interesting subtle shifts. Out of its 150-odd pages of content and evidence, most of the Emergency Medicine-relevant content is in Section 3: Initial Evaluation and Management. Many of the guidelines are not controversial – send patients with suspected ACS to the Emergency Department, give aspirin, obtain an ECG, etc....

      http://www.emlitofnote.com/2014/09/the-2014-aha-nste-acs-guidelines.html


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    1. On 2015 Dec 11, Mark Johnston commented:

      An interactive protocol from this article is freely available at protocols.io.


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    1. On 2016 Aug 30, Ben Goldacre commented:

      This trial has the wrong trial registry link associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID in the link provided is NCT0102727. We believe the correct link, as found elsewhere in the text, is NCT01027273.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , an open database threading together all publicly accessible documents and data on each trial, globally. In the course of creating the database, and matching documents and data sources about trials from different locations, we have identified various anomalies in datasets such as PubMed, and in published papers. Alongside documenting the prevalence of problems, we are also attempting to correct these errors and anomalies wherever possible, by feeding back to the originators. We have corrected this data in the OpenTrials.net database; we hope that this trial’s text and metadata can also be corrected at source, in PubMed and in the accompanying paper.

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

      [1] Goldacre, B., Gray, J., 2016. OpenTrials: towards a collaborative open database of all available information on all clinical trials. Trials 17. doi:10.1186/s13063-016-1290-8 PMID: 27056367

      * Dr Ben Goldacre BA MA MSc MBBS MRCPsych<br> Senior Clinical Research Fellow<br> ben.goldacre@phc.ox.ac.uk<br> www.ebmDataLab.net<br> Centre for Evidence Based Medicine<br> Department of Primary Care Health Sciences<br> University of Oxford<br> Radcliffe Observatory Quarter<br> Woodstock Road<br> Oxford OX2 6GG


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    1. On 2014 Oct 16, Jongpil Kim commented:

      To Whom It May Concern:

      We have reviewed the concerns regarding some of the images presented in our study brought up by Paul Brookes on PubMed and Derek Lowe on his blog. In the wake of numerous controversial studies in the stem cell field, we appreciate the scrutiny of our results as skepticism plays a critical role in the progression of scientific research.

      We have addressed all of the concerns raised on the internet regarding duplication of images and cropping of western blots and detail these responses separately.

      First, regarding the similar radial contrast patterns in Figure 1C and 2D when black images are overexposed, we now provide high magnification versions of these images showing that while the radial contrast is similar between images (as would be expected when taking images from an essentially blank field on the same microscope with the same detector), there are clear differences observable upon higher magnification, demonstrating that these blank images were acquired independently.

      Also, we have now provided all of the original western blots to the Journal that can be published in an erratum if the Journal deems this necessary. There were no sign of splicing or cropping of these original western data in Figure 4C, and we cut out the unnecessary part of images for the display on the limited area of paper in Figure 4F.

      Finally, with regard to the image duplication of the brightfield micrograph of proliferating fibroblasts in Figure 2b: Yes, these are the same image, because this is the Time 0 timepoint of the experiment, prior to induction of EMF and factor infection. This began as a single culture at Time 0, after which half of the culture was exposed to EMF and the other half (control) was not (all in the presence of the Yamanaka factors). It is unclear to us why this is a concern for Paul Brookes, as he asserts this image was used to ‘represent different conditions’, however at Time 0, prior to the induction of EMF, these are in fact the same condition.

      We are more than happy to provide all original images and discussion regarding these points in an erratum to the manuscript if the Journal deems it to be necessary.

      On another note, we would like to point out significant errors made by Paul Brookes and Derek Lowe in their respective blogs in their interpretation of our study. Brookes states “in the wake of the STAP stem cell controversy, a paper claiming that iPSCs can be made using magnetic fields deserves special scrutiny”, and Lowe states “Yep, this paper says that stem cells can be produced from ordinary somatic cells by exposure to electromagnetic fields”. To us this suggests that neither Brookes nor Lowe actually read our manuscript, and rather just began altering contrast of images in the paper to find what they perceive as discrepancies.

      Nowhere in our manuscript do we claim “iPSCs can be made using magnetic fields”. This would be highly suspect indeed. Rather, we demonstrate that in the context of highly reproducible and well-established reprogramming to pluripotency with the Yamanaka factors (Oct4, Sox2, Klf4, and cMyc/or Oct4 alone), EMF influences the efficiency of this process. Such a result is, to us, not surprising given that EMF has long been noted to have effects on biological system(Adey 1993, Del Vecchio et al. 2009, Juutilainen 2005)(There are a thousand of papers for biological effects of EMF on Pubmed) and given that numerous other environmental parameters are well-known to influence reprogramming by the Yamanaka factors, including Oxygen tension (Yoshida et al. 2009), the presence of Vitamin C (Esteban et al. 2010), among countless other examples.

      For individuals such as Brookes and Lowe to immediately discount the validity of the findings without actually attempting to reproduce the central experimental finding is not only non-scientific, but borders on slanderous. We suggest that these individuals take their skepticism to the laboratory bench so that something productive can result from the time they invest prior to their criticizing the work of others.

      “Often those that criticize others reveal what he himself lacks.” ― Shannon L. Alder

      http://i.imgur.com/XgKBX47.jpg?1

      http://i.imgur.com/gvZdZAQ.jpg

      http://i.imgur.com/ljqPnxU.jpg

      http://i.imgur.com/dEB1aoX.jpg

      JP Kim

      JONGPIL KIM, Ph.D. Assistant Professor Dept of Biomedical Engineering Dongguk University Seoul, Korea Tel: 82-02-2260-3371 Fax: 82-02-2260-8726 Email: jpkim153@dongguk.edu, jk2316@gmail.com


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    2. On 2014 Oct 14, Paul Brookes commented:

      Cross-posted from PubPeer (https://pubpeer.com/publications/A730F960943331E553B54335FE8877)

      This paper came up on Derek Lowe's "In the Pipeline" blog... http://pipeline.corante.com/archives/2014/10/14/electromagnetic_production_of_stem_cells_really.php

      In the wake of the STAP stem cell controversy, a paper claiming that iPSCs can be made using magnetic fields deserves special scrutiny. Not surprisingly, there are a few problems with this paper...

      Figure 2B - image re-use to represent different conditions http://i.imgur.com/Tu0kA52.jpg

      Figures 4C & 4F - undisclosed splicing together of blots revealed at high contrast http://i.imgur.com/YREpQeF.jpg

      Figures 1C & 4D - background fluo' images in some controls are "more similar than would be anticipated by pure coincidence" http://i.imgur.com/VKfgNIx.jpg http://i.imgur.com/2FfvvpH.jpg

      There is another minor issue regarding the phase contrast images that are provided for numerous fluorescence images, including in the supplemental data. In short, it does not seem feasible that the fluorescent images shown could have originated from the cells shown in the phase contrast image. This probably means they just used different cells for the phase and the fluo' imaging, but this was not clearly stated anywhere, and is certainly not standard practice.


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    1. On 2016 Feb 03, Jahan Khalili commented:

      Mutations that result in cancer-specific peptides with enhanced HLA affinity based on anchor residue preferences was first published in 2012. See "In silico prediction of tumor antigens derived from functional missense mutations of the cancer gene census", Results section "Mutation-mediated alteration in HLA-binding affinity" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518500/


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    1. On 2014 Oct 14, Xiang Hu commented:

      Liang Cao and Xiang Hu are listed as Co-corresponding author


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    1. On 2014 Nov 21, Swapnil Hiremath commented:

      This study was discussed on Nov 4th 2014 in the open online nephrology journal club, #NephJC, on twitter. Introductory explanatory comments, written by Dr Susan Steigerwalt, are available at the NephJC website. It was an interesting discussion, which served partly to explain the experiments to the non-scientists in the chat, and partly to critique the study itself. It had more than 20 participants, including nephrologists, physiologists, basic scientists and nephrology fellows. A transcript and a curated (i.e. Storified) version of the tweetchat are available from the NephJC website. The highlights of the tweetchat were:

      • The investigators have been pursuing this research area (the immune systems and hypertension) over many years, and report here exhaustive and meticulous experiments, including multiple animal models and human data.

      • This group identified a novel connection between the production of isoketals (or isolevuglandins) in dendritic cells leading to isoketal-modified proteins which in turn activate T cells and promote hypertension.

      • Though these findings were greeted with a lot of interest, the results do need to be independently replicated; additionally, the exact biological mechanisms, including the mechanism of T cell activation and resultant alteration in either vascular function or sodium homeostasis, need to be elucidated further. However, these results could lead to novel therapies exploiting the immune system for therapeutic benefit in hypertension and resultant end organ damage.

      Interested individuals can track and join in the conversation by following @NephJC or #NephJC, or visit the webpage at NephJC.com.


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    1. On 2014 Dec 17, Sean Ekins commented:

      Some slides describing this work http://www.slideshare.net/ekinssean/medicinal-chemistry-due-diligence-computational-predictions-of-an-experts-evaluation-of-the-nih-chemical-probes


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    2. On 2014 Dec 17, Sean Ekins commented:

      Another link to a post where we mention this paper https://www.collaborativedrug.com/buzz/2014/12/16/beware-researchers-challenges-navigating-commercial-and-public-databases/


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    3. On 2014 Dec 15, Sean Ekins commented:

      Also added in my roundup of 2014 papers http://www.collabchem.com/2014/12/15/a-year-in-publications-2014/


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    4. On 2014 Dec 04, Sean Ekins commented:

      Here is a link to a discussion of the peer review of this paper and it includes all reviewer comments http://www.collabchem.com/2014/12/04/chemical-probes-and-parallel-database-worlds-who-wants-to-know-more-publishing-fun/


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    5. On 2014 Dec 02, Nadia Litterman commented:

      For a description of the process of gathering information on the probes, and a discussion of navigating between public and private data: http://www.ncbi.nlm.nih.gov/pubmed/25415348


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    6. On 2014 Dec 02, Nadia Litterman commented:

      The NIH Probe structures, associated bioactivity data, and expert evaluations can be found here: https://www.collaborativedrug.com/pages/public_access


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    7. On 2014 Dec 02, Sean Ekins commented:

      This article was mentioned here http://www.collabchem.com/2014/10/07/the-most-expensive-data-set-i-have-modeled-dont-blink-over-500m/


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    1. On 2015 Feb 06, Ryan Radecki commented:

      Post-publication commentary: "Just Poop, It Doesn’t Matter How"

      Hepatic encephalopathy, a consequence of bacterial overgrowth and impaired ammonia metabolism, contributes to (as these authors say) nearly $2B in healthcare costs due to hospitalization in the United States alone. Typical, goal-oriented, modern therapy? Lactulose, a non-digestible sugar, resulting in increased bowel movement frequency.

      These authors, appropriately, challenge established dogma – noting, perhaps, there are more effective strategies for clearing the bowels....

      http://www.emlitofnote.com/2014/12/just-poop-it-doesnt-matter-how.html


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    1. On 2015 Feb 27, Geriatric Medicine Journal Club commented:

      This is study looks at the effect of using the STOPP/START criteria in the chronic geriatric facility setting and was discussed at the December 2014 Geriatric Medicine Journal Club (follow #GeriMedJC on Twitter). The full discussion can be found at: http://gerimedjc.blogspot.com/2014/12/gerimedjc-december-19-2014.html?spref=tw One point of discussion was whether 20 minutes was a reasonable time frame for the intervention given the outcomes.


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    1. On 2016 Sep 12, Cicely Saunders Institute Journal Club commented:

      The Cicely Saunders Institute journal club discussed this paper on Wednesday 7th September 2016.

      We felt this is an important study that is opening the ‘black box’ of an intervention based on the habit formation model. The title itself stimulated discussion and reflection on the challenges of reducing sedentary behaviour.

      We enjoyed discussing the development of the habit–based intervention for older adults and the protocol for the randomised controlled trial. The paper is presented as a study protocol, yet the first few pages actually describe the developmental stage of the intervention. We felt the development phase warranted being presented more fully in a separate paper. Questions arose in our discussion related to the nature of the adverse health consequences associated with sedentary behaviour and physical inactivity.

      We commented on the pros and cons of publishing a protocol for a feasibility trial, including the need to publish amendments one year later. It was not clear how the behaviour change techniques utilised in the usual care fact sheet differed from those in the intervention booklet. Whilst we acknowledged there may be practical reasons for not presenting both the booklet and the control fact sheet in the protocol paper, we agreed that it would have been interesting to be able to see and compare these two documents.

      We noted the authors acknowledgement of the difficulty of attributing a behaviour change effect to the habit formation elements in the booklet. We also discussed the possible contextual factors that might contribute to any effect and were interested in how the long term impact of habit-based interventions could be evaluated.

      Commentary by Joanne Bayly and Roxana Vanderstay


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    1. On 2014 Sep 23, Samir Ounzain commented:

      Very nice editorial distilling the main points from our recent study and highlighting some very interesting concepts for future consideration. I would just like to briefly address a couple of the main points.

      Hofmann and Boon rightly point out ''it would be interesting to see if exogenous overexpression of one of these transcripts could have increased the mRNA levels of their putative target genes or whether genomic context is the main determininant for enhancer activity of lncRNAs''

      This is a fascinating point that we are indeed trying to address,, and one that could have implications for future potential cardiac ''enhancer'' therapies. What we can say is it appears that the majority of enhancer templated lncRNAs, at least their -cis activity is dependant on the nascent endogenously produced transcript recruiting and activating in a ''proximity-transfer'' manner chromatin remodelling complexes. This tends to mean that exogenous over-expression is not sufficient. However examples exist of exogenous over-expression impacting upon endogenous -cis loci. A recent study specifically addressed this issue and provides an excellent experimental framework for how such experiments to test these ideas should be conducted. This group mechanistically characterised an enhancer associated lncRNA named CCAT1-L.

      1: Xiang JF, Yin QF, Chen T, Zhang Y, Zhang XO, Wu Z, Zhang S, Wang HB, Ge J, Lu X, Yang L, Chen LL. Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res. 2014 Sep;24(9):1150. doi: 10.1038/cr.2014.117. PubMed PMID: 25174407; PubMed Central PMCID: PMC4152739.

      Finally Hofmann and Boon ask whether ''enhancer RNAs functionally affects the response to cardiac stress in a disease model like acute myocardial infarction''. This is a major questions ourselves and others in the community are trying to address using various strategies. We do suspect that considering the unique context and tissue specific expression profiles of enhancer associated lncRNAs, they would represent ideal specific therapeutic targets for ''enhancer-therapy'' type approaches post acute cardiac stress. We look forward to see how these concepts will emerge and evolve in the coming years.

      Finally it is worth noting that many adult heart specific lncRNAs are also associated with adult heart specific active enhancer sequences. Furthermore, heart specific lncRNAs associated with such enhancers are preferentially modulated post myocardial infarction in the mouse, implicating them in the global enhancer reprogramming that underpins maladaptive cardiac remodelling. More on this can be found ...

      Ounzain S, Micheletti R, Beckmann T, Schroen B, Alexanian M, Pezzuto I, Crippa S, Nemir M, Sarre A, Johnson R, Dauvillier J, Burdet F, Ibberson M, Guigó R, Xenarios I, Heymans S, Pedrazzini T. Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. Eur Heart J. 2014 Apr 30. [Epub ahead of print] PubMed PMID: 24786300.


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    1. On 2016 Apr 30, Morten Oksvold commented:

      Please be aware that this article represents one of eleven publications which were found to contain false data, after an investigation led by ORI in 2015:

      https://ori.hhs.gov/content/case-summary-dasmahapatra-girija


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    1. On 2015 Apr 22, Clyde Francks commented:

      Study authors Tulio Guadalupe and Clyde Francks reply to comment by Dorothy Bishop:

      We thank Dorothy Bishop for insightful comments. We considered the HO measurement of PT grey matter volume as a region-of-interest index 'within and around the human planum temporale', rather than a direct measurement of its neuroanatomical definition. The HO measurement was weighted on the voxels that most probably belonged to the PT, based on 37 brains used in constructing the atlas. The HO definition of PT is lateralized to the left and the measurement of PT regional asymmetry in our datasets reflected this. We agree that this spatial restriction probably contributed to the lower inter-subject variability measured with the HO approach compared to FreeSurfer's parcellations. However, because of the large variability in landmarks in the superior temporal lobe, these regions are among the least reliable in Freesurfer parcellations, and also the Freesurfer-Destrieux definition of the planum temporale includes the planum parietale which is not usually recognized as part of its extent. Reassuringly, we found PT regional lateralization to be sexually dimorphic with both approaches (PT region was the most sexually dimorphic of all 44 regions using the HO atlas and the third most dimorphic of 74 regions using the FreeSurfer-Destrieux atlas). We agree that the measurement issues do not obviously explain the sex effect.

      Because of the normalization pre-processing of the GM maps to the MNI template, subjects with departures from average PT lateralization are already somewhat 'pre-fitted' for the HO probabilistic atlas before it is applied (and we saw no major departures based on the random thirty normalized subjects we visually inspected, which would have been expected to contain three or four subjects with rightward PT lateralization). If normalization was perfect, someone with a larger-than-average right PT in relation to that hemisphere would have their right PT morphed into an equivalent normalized space as someone with a smaller than average right PT, prior to atlas application.

      Our additional requirement with our HO PT lateralization index was to support genome-wide association meta-analysis across multiple datasets, for which a single and comparable index was required across datasets, after which individual genetic associations would be further interrogated in a voxel-based-morphometry context without use of the HO atlas. We argued that, for measuring group and individual differences, regional identification was likely to be more accurate with an asymmetrical atlas than with a left-right symmetrized atlas, for structures that were asymmetrical both in the atlas and, on average, in our datasets. Using a symmetrized atlas would affect the mean and range of lateralization in the dataset, and probably allow some individuals to be measured with rightward lateralization, but then the fit would be worse for people with leftward lateralization (the majority) than for the un-symmetrized HO atlas.

      Genomewide association analysis requires thousands of participants to achieve sufficient statistical power to detect the effects of individual polymorphisms that are individually expected to account for a fraction of 1% of trait variation. Even the sex difference that we found only explained 1.2-1.6% of trait variance. The use of large and multiple datasets was required within a single collaborative study, and the creation of dataset-specific atlases, based on large numbers of participants, by each of the contributing teams matched to their particular scanning setup and population demographic, was not practical. We agree that there is an urgent need for manually created brain atlases based on larger numbers of participants, together with improved methods of automated application that are robust to dataset heterogeneities and flexible for the full range of individual differences.


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    2. On 2015 Apr 18, Dorothy V M Bishop commented:

      The literature on sex differences in cerebral asymmetry does appear to be very confusing, and this paper does a thorough job in attempting to address the inconsistencies. I'm not sure it completely resolves the issue, but it sets a high methodological standard by using much larger sample sizes than previous studies and including two replication samples. It also includes a genetic analysis, which I won't discuss here.

      Structural asymmetry of the planum temporale, with larger PT on the left, was described 47 years ago by Geschwind and Levitsky. Since that time it has become clear that the proportion of the population showing asymmetry varies substantially according to how it is measured. There have been claims of sex differences in PT asymmetry, but, as noted by Guadalupe et al, there have also been counterclaims, and a recent meta-analysis concluded that there is no sex difference, and the impression of one arose because of publication bias.

      Guadalupe et al, however, found a reliable sex difference in PT asymmetry that replicates across three samples. However, their method of measurement does have one characteristic that I found puzzling: in a sample of 2337 adults they found nobody with reversed asymmetry (i.e., R>L planum). This contrasts with the original sample of Geschwind and Levitsky, where 11% had reversed asymmetry, and 24% had equal size PT on left and right. G&L's study was based on examination of post mortem specimens, but Watkins et al (2001) found similar proportions in a voxel-based analysis of grey matter from 142 MRI scans.

      I assume the finding of universal left-biased PT in the current study had to do with the method by which this was defined: this was different from the method used by Watkins et al.

      In the current study, grey matter was quantified in cortical regions based on a template taken from a average brain, then weighting each voxel by the probability that it belonged to that specific cortical region. The authors note that there are regional asymmetries in the atlas they used that will necessarily influence the mean – presumably, the left planum map is bigger than the right planum map, and so there are more voxels to count on the left. The authors argue that we already know that the left and right perisylvian regions differ systematically in their anatomy on average, and the interest here is in individual differences. They argued therefore that an averaged left-right template would not capture the systematic differences between the two sides.

      I have trouble understanding how the template they used could adequately capture cases where someone had a larger than average PT. If the template represents the PT from an average brain, there will be variation around that average, with some people have larger and others having smaller PTs. If voxels were counted if they were within the template and not otherwise, anyone who had a PT that actually extended beyond the template would not have all their voxels counted. I appreciate that in practice, a more sophisticated probabilistic approach was used, but I'm not sure this would solve the problem. The template is based on 37 brains; we know that around 11% of people have R>L planum temporale, so around 3-4 contributors to the template would have that pattern. So, if I understand it correctly, voxels in the outskirts of a core region would have a low weighting, because in only a small proportion of the template subjects would this region be included in PT. But this means that for a new subject who genuinely had PT in that region, the amuont of grey matter in PT would be underestimated, because the weighting would be low. And there may be some people with rare PT configurations who may have parts of their PT not represented at all in the template. In this regard, given the known individual variation in PT, 37 people seems rather small a number on which to base probabilistic weightings.

      I wondered whether this aspects of methodology explained why the volume measures for the Freesurfer analysis had standard deviations that were about 1.7 times as large as the standard deviations for the HO atlas analysis – is the HO atlas analysis in effect minimising or excluding values for those whose PTs are more extensive than the average?

      I can't see an obvious reason why this should generate spurious sex differences, but I wondered if it could explain the absence of cases of reversed asymmetry in this sample.

      Overall, I thank the authors for providing such comprehensive data on this vexed topic; it is remarkable how the measurement of asymmetry, which looks on the surface like such a simple issue, is exceedingly complex, with specific analytic choices leading to different patterns of findings. It is good to see examples like this where alternative approaches are used to give one the opportunity to observe their effects.

      Geschwind, N., & Levitsky, W. (1968). Human brain: left-right asymmetries in temporal speech region. Science, 161, 186-187. Watkins, K. E., Paus, T., Lerch, J. P., Zijdenbos, A., Collins, D. L., Neelin, P., . . . Evans, A. C. (2001). Structural asymmetries in the human brain: a voxel-based statistical analysis of 142 MRI scans. Cerebral Cortex, 11, 868-877.


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    1. On 2015 Mar 08, David Keller commented:

      Arguments against the use of cannabidiol or other cannabis derivatives to treat Parkinson's disease

      Arguments against the use of cannabidiol to treat Parkinson's disease patients:

      1) Persistent cannabis users show neuropsychological decline from childhood to midlife [1], which is abnormal and worrisome.

      2) Cannabidiol (CBD) is a "major constituent of cannabis" [2]

      3) We do not know which one, or which combination of cannabis constituents, contributes to the neuropsychological decline observed in persistent users. The possible culprits include CBD, THC, and other compounds present in cannabis.

      4) The study by Chagas and colleagues [3] did not prove that long-term chronic CBD use does not contribute to neuropsychological decline.

      5) The alleged benefit demonstrated by CBD was a minor improvement in PDQ-39 score of borderline statistical significance. CBD use did not affect the 3 other reported outcomes significantly.

      6) The borderline improvement in PDQ-39 score observed with CBD use [3] does not justify the risk of neuropsychological decline which CBD, as a major constituent of cannabis, may cause [1].

      7) Researchers who work with cannabis, CBD, THC or any combination of cannabis derivatives, should declare whether they currently use any such substances, as should those who comment, review or editorialize about these substances, because such use constitutes a source of potential bias, which I shall designate as "Cannabis Derivatives User Bias".

      8) I do not use cannabis or any of its derivatives. I request that Dr. Kevin McKernan and all other commenters make similar disclosures.

      References

      1: Meier MH, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):E2657-64. PubMed PMID: 22927402

      2: Gallily R, Yekhtin Z, Hanuš LO. Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol. Pharmacology & Pharmacy,2015,6,75-85

      3: Chagas MH, Zuardi AW, Tumas V, Pena-Pereira MA, Sobreira ET, Bergamaschi MM, dos Santos AC, Teixeira AL, Hallak JE, Crippa JA. Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial. J Psychopharmacol. 2014 Nov;28(11):1088-98. doi: 10.1177/0269881114550355. Epub 2014 Sep 18. PubMed PMID: 25237116.


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    2. On 2015 Mar 05, David Keller commented:

      The first reference given by Kevin McKernan contradicts him, and also contradicts itself

      The first sentence of Dr. McKernan's first reference is: "Cannabidiol (CBD), a major constituent of Cannabis, has been shown to be a powerful anti-inflammatory and anti-anxiety drug, without exerting a psychotropic effect."[1] This sentence starts out by contradicting McKernan's assertion that "marijuana and Cannabidiol (CBD) are very rarely related", given that cannabis and marijuana are synonymous, and CBD is "a major constituent of Cannabis". Moreover, this sentence goes on to contradict itself by stating that CBD has been shown to be an "anti-anxiety drug" but "without exerting a psychotropic effect". It is clearly contradictory to state that an anti-anxiety drug has no psychotropic effect.

      My main point is that it is perfectly acceptable for a basic scientist, like Dr. McKernan, to explore the properties of "cocktails of cannabinoids" in his laboratory. However, before exposing human subjects suffering from Parkinson's disease to cannabidiol, or any other "major constituent of cannabis", the neurological safety of these cannabinoids must be established. I see nothing "controversial" about the study conducted by Meier and colleagues (2); rather, it confirms the widely-held perception that chronic users of cannibis (marijuana) suffer neuropsychological degeneration. Until this worrisome safety signal is addressed, I do not consider it ethical to test CBD, THC or any other major constituent of cannabis on patients with Parkinson's disease, Alzheimer's disease, or any other neurodegenerative condition. The borderline-insignificant gain in the PDQ-39 score observed in this study is simply not worth the risk, even if the benefit had been statistically significant.

      The amount of research into the beneficial effects of cannabidiol and other chemicals found in marijuana seems excessive, given the scant benefits demonstrated in this study, and others like it. How much of this zeal to promote the benefits of marijuana-derived compounds is driven by the wish for full legalization of this drug? I propose the following experiment: legalize marijuana in all 50 states and also by the Federal government. Once its advocates are free to grow, smoke, and consume this plant in any form or fashion without restrictions of any kind, I predict that the amount of research into the benefits of marijuana-derived chemicals will drop significantly.

      Lastly, it is reasonable to expect that a regular user of cannabis or any of its derivatives might exhibit bias when reporting results of a trial, or when commenting on them ("user bias"). For this reason, use of cannabis or any of its derivatives should be disclosed in the same fashion as a financial bias. Full disclosure: I do not use any of these substances, and I call on Dr. McKernan to make a similar disclosure.

      References

      1: Gallily R, Yekhtin Z, Hanuš LO. Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol. Pharmacology & Pharmacy,2015,6,75-85

      2: Meier MH, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):E2657-64. PubMed PMID: 22927402


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    3. On 2015 Feb 26, Kevin McKernan commented:

      Marijuana must not be conflated with Cannabidiol

      David Keller highlights a few controversial studies pointing out the adverse effects of "marijuana". This is known as a straw man argument as marijuana and Cannabidiol (CBD) are very rarely related. Most Marijuana is THC enriched and lacking CBD as a direct result. Pathways in the plant that synthesize THCA are in competition for GPP required to make CBDA (CBD's carboxylated precursor). Most "Marijuana" is devoid of CBD as a result. Likewise, most recreational "Marijuana" is consumed with a route of administration via smoking and cannot deliver 300mg/day via the hepatic portal system which is known to metabolize many cannabinoids into other active molecules not experienced with smoking "marijuana". Likewise, THC is pharmaceutically very different than CBD such that any reference to studies investigating the non descriptive 'Marijuana' are obsolete and irrelevant. The investigator bias on display here is clearly in the camp of Dr. Keller not understanding some of the basics of Cannabidiol research. For reference I would point to the following references highlighting the very distinct nature of CBD compared to THC. Any attempt to conflate these two molecules has already been thoroughly established as foolhardy in the endocannabinoid sciences. For instance, CBD does not get patients 'stoned' and its mechanism of action is not related to the CB1 receptor. Some of the most exciting work in this field is exploring cocktails of cannabinoids found in more raw forms of the plant as these cocktails appear to widen the dose response curve. The above studies p-value will likely improve utilizing the methods recently published by Gallily et al.

      In summary, the Parkinsons genetic pathways continue to highlight the relevance of Parkin, LRRK2 and mitochondrial dysfunction. These genes are involved in the ROS pathway and lipid soluble antioxidants with very tolerant therapeutic indexes are a perfectly rational approach for Parkinsons disease. Future studies stratifying the genetics of the disease and widening the dose response curve with work like Gallily et al are likely to be very productive for the field.

      References

      Gallily- http://www.scirp.org/journal/PaperDownload.aspx?paperID=53912 http://www.sciencedirect.com/science/article/pii/S0006899306034718 https://www.google.com/patents/US6630507 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942876/ http://onlinelibrary.wiley.com/doi/10.1002/jat.2828/abstract;jsessionid=33248CFFF91EA20AE26A6C2EFE120DEE.f04t03?deniedAccessCustomisedMessage=&userIsAuthenticated=false http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797438/ http://www.pnas.org/content/95/14/8268.short http://jop.sagepub.com/content/early/2008/11/21/0269881108096519.short


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    4. On 2014 Sep 26, David Keller commented:

      The cognitive adverse effects of cannabidiol must be discussed

      Chronic cannabis use causes irreversible cognitive impairment, and is considered neurotoxic for that reason (1). Many marijuana addicts cite acute cognitive dysfunction as their intended goal; in street terms, this is known as being "stoned". Any proposal to treat Parkinson disease with cannabidiol, cannabis or marijuana itself which fails to assess and report cognitive impairment raises the question of investigator bias.

      Lastly, the results of a clinical trial are commonly deemed statistically significant when the probability that the findings are the result of chance is less than 5% (2). A p-value equal to 0.05 is usually described as being of borderline or marginal statistical significance.

      References

      1: Meier MH, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):E2657-64. PubMed PMID: 22927402;

      2: Higgins JPT and Green S. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0, revised March, 2011


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    1. On 2015 Apr 22, Fillip Port commented:

      I would like to add that inadvertent integration of a bi-cistronic plasmid, such as the one reported here, into the gRNA target site would create an autonomous gene drive. Genomic integration in the absence of homology arms is expected to be a rare event, but has been reported before. I would therefore suggest to take such a possibility into account. Further reading: PMID:25035423; http://biorxiv.org/content/early/2015/04/01/017384; http://www.sciencemag.org/content/early/2015/03/18/science.aaa5945.abstract.


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    2. On 2014 Oct 29, Fillip Port commented:

      The following comment was initially posted on the technology blog igtrcn.org

      As is the case for many other organisms, CRISPR has rapidly become the method of choice for targeted genome modification in insects. Much of the method development has been taking place in the model organism Drosophila melanogaster, where, in little over a year, 17 publications have demonstrated various ways to harness the CRISPR system for fly genome editing.

      However, this flurry of papers has not resulted in a consensus about which protocol is best suited to modify the fly genome, not least because each method comes with certain strengths and weaknesses. CRISPR components – i.e. the Cas9 endonuclease and short gRNAs - can be delivered into fly embryos by microinjection of either plasmid DNA, in-vitro transcribed RNA or purified protein. Microinjection is the most rapid way to introduce CRISPR components into flies and is independent of genetic background, but often suffers from a high degree of variability that leads to overall reduced efficiency. In contrast, transgenic CRISPR in which both Cas9 and gRNAs are expressed from previously integrated transgenes results in reproducible gene targeting at very high rates, but generating the transgenes in the first place is a time consuming process that makes this approach rather slow. Since all gene targeting experiments require Cas9, a popular compromise is to inject gRNA into cas9 expressing transgenic embryos. This approach benefits from good success rates due to the reliable source of Cas9, and is as rapid as microinjection of both components once a lab has acquired one of the publically available cas9 lines.

      Now Peter Duchek and colleagues (Gokcezade et al. 2014) present a new protocol for microinjection-based CRISPR in Drosophila melanogaster. The method uses microinjection of DNA plasmids, but rather than injecting a mix of two plasmids encoding Cas9 and gRNA as was done previously, they combine both components on a single plasmid. This small change proves an effective one. In their paper Gokcezade et al. present data from targeting five genes and achieve efficiencies of around 10% mutant offspring when monitoring random InDel mutations and around 5% for precise genome modifications by homology directed repair.

      Efficiencies of that range start to make it practical to screen for mutations by PCR based assays, a requirement for scarless genome engineering without the use of visible markers. If such high efficiencies can be routinely achieved on more target genes and in different laboratories then the method presented by Duchek and colleagues will present an attractive alternative to gRNA injections into transgenic cas9 embryos. This is particularly good news for researchers working on insects where transgenic cas9 strains are not available or for those who want to modify a specific genetic background of D. melanogaster. However, in another recent paper Frank Schnorrer and colleagues use the bi-cistronic plasmid presented in Gokcezade et al. to knock-in a RFP selection cassette into the Drosophila genome and achieve efficiencies that are substantially lower than the ones reported in Gokcezade et al. (Zhang et al., 2014, G3, PMID:25324299). This might be because of the larger size of the integration cassette, different target genes and gRNAs or differences in the microinjection procedure.

      Like with all other CRISPR protocols proposed today, it will be interesting to see how the bi-cistronic cas9/gRNA plasmid fares in the hands of other insect genome engineers. To aid this Gokcezade et al. have made their plasmids available from the non-profit repository Addgene (Plasmid number 59984 and 59985).


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    1. On 2015 Dec 27, Gwinyai Masukume commented:

      In the Introduction it is written, "Currently, health expenditure accounts for 4.6% of the Gross Domestic Product."

      South Africa spent between 8.5 - 9% of Gross Domestic Product on health expenditure, 2001 - 2015. THE WORLD BANK - Health expenditure, total (% of GDP)


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    1. On 2014 Sep 24, Jim Woodgett commented:

      Interesting study and raises a number of questions. I wonder if MVB sequestration is a rescue/escape mechanism in cells to deal with constant signalling (since the initial studies used a constitutively active LRP6 variant)? I always wondered why so much (80+%) GSK-3 was reported to be sequestered when we could only ever find 5% of the entire cellular content of this kinase associated with Axin.

      P.S. GSK-3alpha plays an equal role in Wnt signalling in mammals, although there is no equivalent in Drosophila. No small molecule inhibitor is able to discriminate between the GSK-3 isoforms (despite extensive literature).


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    1. On 2016 Sep 14, Kevin Hall commented:

      An Erratum for this article was published 10 AUG 2016 DOI: 10.1002/oby.21634.

      We recently identified an error in the measured resting metabolic rate (RMR) data in participants of “The Biggest Loser” competition (BLC) at 7 months. In Table 1, the corrected RMR at 7 months in BLC is (mean ± SD) 1967 ± 331 kcal/d such that there was a significant metabolic adaptation of −308 ± 165 kcal/d (P<0.0001) that was not significantly different from metabolic adaptation in Roux-en-Y gastric bypass surgery (RYBG) patients at 6 months (P=0.118). The corrected RMR at 7 months in BLC was significantly different from measured RMR in RYGB at 6 months (P<0.05). Figure 2 was corrected in the published Erratum.

      Metabolic adaptation was significantly correlated with energy imbalance (r=0.72, P<0.0001), rate of weight loss (r=0.67, P=0.0002), and percent change in leptin (r=0.52, P=0.006) in combined BLC at 7 months and RYGB at 1 year. Similarly, when including RYGB data at 6 months, metabolic adaptation was significantly correlated with energy imbalance (r=0.62, P=0.0001), rate of weight loss (r=0.61, P=0.0001), and percent change in leptin (r=0.38, P=0.02). Figure 3 was corrected in the published Erratum. Finally, the authors previously reported a non-significant association between metabolic adaptation and changes in T3; however, the corrected data demonstrate a trend for a positive association between metabolic adaptation and changes in T3 (r=0.48, P=0.06). The authors regret this error.


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    1. On 2016 Aug 24, Ben Goldacre commented:

      This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT0192052. We believe the correct ID, which we have found by hand searching, is NCT01920529.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , an open database threading together all publicly accessible documents and data on each trial, globally. In the course of creating the database, and matching documents and data sources about trials from different locations, we have identified various anomalies in datasets such as PubMed, and in published papers. Alongside documenting the prevalence of problems, we are also attempting to correct these errors and anomalies wherever possible, by feeding back to the originators. We have corrected this data in the OpenTrials.net database; we hope that this trial’s text and metadata can also be corrected at source, in PubMed and in the accompanying paper.

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

      [1] Goldacre, B., Gray, J., 2016. OpenTrials: towards a collaborative open database of all available information on all clinical trials. Trials 17. doi:10.1186/s13063-016-1290-8 PMID: 27056367

      * Dr Ben Goldacre BA MA MSc MBBS MRCPsych<br> Senior Clinical Research Fellow<br> ben.goldacre@phc.ox.ac.uk<br> www.ebmDataLab.net<br> Centre for Evidence Based Medicine<br> Department of Primary Care Health Sciences<br> University of Oxford<br> Radcliffe Observatory Quarter<br> Woodstock Road<br> Oxford OX2 6GG


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    1. On 2015 Mar 24, Michelle Lin commented:

      Video interview with first author, Dr. Rebecca Smith-Bindman (UCSF Department of Radiology), and co-author Dr. Ralph Wang (UCSF Department of Emergency Medicine) hosted at the Academic Life in Emergency Medicine website. In this video, questions and nuances in this landmark paper were addressed.

      http://www.aliem.com/author-insight-ultrasonography-versus-ct-for-suspected-nephrolithiasis-nejm/

      Four questions were posed:

      • Q1: About 1/3 of patients in the ultrasound study arms eventually went on to get CT’s in the same ED stay. What would you recommend to clinicians about when that should be?

      • Q2: Can you address generalizability issues in this 15-center study whereby the cohort has 40% with a history of previous kidney stones and only 60% demonstrating microscopic hematuria. Also what are your recommendations for obese patients (men >280 lb, women >250 lb) who were excluded from your study? CT them all?

      • Q3: What has been the feedback from urologists since the paper was published? What are the drivers of CT ordering?

      • Q4: What’s next? What’s NOT in your paper?

      Ultimately, this paper advocates for bedside ultrasonography over CT as the first-line diagnostic modality for patients with suspected kidney stones. In this 15-center study, the ~1800 ultrasounded patients had good primary and secondary outcomes despite the fact that 2/3 did NOT undergo a CT in the first ED visit.


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    2. On 2014 Nov 02, Swapnil Hiremath commented:

      This study was discussed on Oct 7th 2014 in the open online nephrology journal club, #NephJC, on twitter. Introductory comments are available at the NephJC website and cross-posted at the eAJKD blog. It was a great discussion, with more than 20 participants, including nephrologists, urologists and emergency medicine physicians. A transcript and a curated (i.e. Storified) version of the tweetchat are available from the NephJC website. A summary is also posted on the eAJKD blog. The highlights of the tweetchat were:

      • The investigators and the funding agency (AHRQ) should be commended for designing and funding this pragmatic trial to answer a key diagnostic question

      • There was broad agreement about the validity of the results, suggesting that an ultrasound should be performed first in case of suspected kidney stones; however, many participants look forward to more data being published, on patient characteristics that predicted subsequent CT scan use and details of the economic analysis

      • A concern was raised about the availability of point-of-care ultrasound in emergency departments, and the expertise and/or experience necessary to do these. It was recognized that this expertise is indeed rapidly becoming the standard for emergency room physicians

      Interested individuals can track and join in the conversation by following @NephJC or #NephJC, or visit the webpage at NephJC.com.


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    3. On 2014 Sep 30, Ryan Radecki commented:

      Post-publication commentary:

      "Farewell, CT Stone Protocol"

      Ureterolthiasis has become a poster child for over-utilization of advanced imaging. Despite the relative level of distress kidney stones cause our patients, the use of computed tomography has never been associated with improved outcomes – yet, CT is widespread for its diagnostic utility, contributing substantially to $2 billion in annual healthcare expenditures for this condition in the U.S. alone.

      This, however, is a comparative effectiveness evaluation promoting ultrasound for the diagnosis of ureterolithiasis in the Emergency Department, a three-pronged evaluation comparing CT, formal ultrasonography by radiology technicians, and bedside Emergency Department ultrasonography. Essentially, the objective of this study was to compare safety – regarding, in a sense, whether the additional information supplied by CT was valuable for the detection of life-threatening alternative diagnoses. And, with respect to this outcome all strategies had, essentially, the same number of “misses” during the follow-up period – mostly acute cholecystitis, one case of appendicitis, and a smattering of other thoracoabdominal diagnoses. And so – ultrasonography, even our amateur sort in the ED, is "just as good"....

      http://www.emlitofnote.com/2014/09/farewell-ct-stone-protocol.html


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    1. On 2016 Aug 24, Ben Goldacre commented:

      This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT10528605. We believe the correct ID, which we have found by hand searching, is NCT01528605.

      This comment is being posted as part of the OpenTrials.net project<sup>[1]</sup> , an open database threading together all publicly accessible documents and data on each trial, globally. In the course of creating the database, and matching documents and data sources about trials from different locations, we have identified various anomalies in datasets such as PubMed, and in published papers. Alongside documenting the prevalence of problems, we are also attempting to correct these errors and anomalies wherever possible, by feeding back to the originators. We have corrected this data in the OpenTrials.net database; we hope that this trial’s text and metadata can also be corrected at source, in PubMed and in the accompanying paper.

      Many thanks,

      Jessica Fleminger, Ben Goldacre*

      [1] Goldacre, B., Gray, J., 2016. OpenTrials: towards a collaborative open database of all available information on all clinical trials. Trials 17. doi:10.1186/s13063-016-1290-8 PMID: 27056367

      * Dr Ben Goldacre BA MA MSc MBBS MRCPsych<br> Senior Clinical Research Fellow<br> ben.goldacre@phc.ox.ac.uk<br> www.ebmDataLab.net<br> Centre for Evidence Based Medicine<br> Department of Primary Care Health Sciences<br> University of Oxford<br> Radcliffe Observatory Quarter<br> Woodstock Road<br> Oxford OX2 6GG


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    1. On 2014 Sep 21, David Keller commented:

      Was the ulcerative colitis patient status post colectomy, or taking corticosteroids during treatment with ipilimumab?

      In the case of the ulcerative colitis patient who tolerated ipilimumab and achieved partial remission of metastatic melanoma, this abstract does not indicate whether this patient was status post colectomy, or taking corticosteroids while being treated with ipilimumab. Ipilimumab treatment is associated with a high risk of autoimmune enterocolitis. This is important information for other patients with autoimmune diseases contemplating treatment with ipilimumab for metastatic melanoma.


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    1. On 2014 Oct 09, Arturo Casadevall commented:

      We thank Joshua L. Cherry for the additional comments. We also feel that our original response applies to much of the new comments but will try again to clarify our answers. As we have done previously, we copy Joshua L. Cherry’s comments and respond below.

      Joshua L. Cherry states “We have all encountered writing that refers to science or its subfields and uses scientific language but lacks scientific content. The editorial does something similar with respect to philosophy. It defines epistemology and makes use of its vocabulary, but the arguments that it makes are not epistemological. The only general principle about knowledge that it invokes is the Faberite notion that knowledge is good. This is not an epistemological proposition or a philosophical insight, nor a revelation to scientists”.

      We feel that Joshua L. Cherry misses the point in continuing to argue that our essay is not about philosophy and its branch epistemology. GOF experiments are the gold standard for acquiring certain times of information including the capacity of a virus to become mammalian transmissible. GOF experiments are accepted methodology in the field and commenting on their power and their standing within the normative standards of the field of molecular microbiology clearly constitutes epistemological content for scientific methodology is part of the epistemology of science. These experiments provide information with the highest standard of rigor that is unobtainable in any other way.

      Joshua L. Cherry states that “The benefits of GOF experiments commonly discussed are indeed benefits of the resulting knowledge. (What else would they be? The economic benefits of creating employment for laboratory personnel?) These have mostly been supposed direct practical applications of this knowledge for preventing human H5N1 infections. The response above suggests that the authors intended to emphasize “the many other possible future uses of that knowledge, some of them practical, but some of them purely theoretical”. As I stated, most or all scientific knowledge has many possible future uses, and it is common knowledge, not a philosophical insight, that science works this way.”

      We have no disagreement with this paragraph although we note that if this is indeed ‘common knowledge’ then we have trouble understanding why it is necessary for us to point this out in the context of weighing the epistemic value of GOF experiments.

      Joshua L. Cherry states that “Exceptional risks demand exceptional benefits. Satisfaction of normative standards does not imply exceptional benefits. The authors indeed make a logical leap in concluding that GOF experiments must be powerful because they share certain formal properties with experiments that proved to be powerful. The literature is filled with results of experiments that meet these normative standards, with importance ranging from great to nearly nil. Thus, we must consider the value of these particular experiments, using scientific reasoning and judgment. That is exactly what most of the debate has been concerned with.”

      We see several problems with this paragraph. First, there is no evidence that the experiments done carry ‘exceptional risks’. These have been done in laboratories with rigorous biosafety protocols and high level bio-containment capabilities. Furthermore, we do not know whether transmissibility in Ferrets confers transmissibility in humans. Second, we never argued that GOF experiments yielded "exceptional benefits," alone capable of balancing exceptional risks. Instead, we merely argued that the epistemological value of GOF experiments must be part of the bookkeeping, and we questioned the objectivity of the claimed exception character of the risk. These experiments have already provided important information regarding the biological potential of highly pathogenic avian influenza virus to acquire the capacity for mammalian transmissibility. We did not assign a specific value to this epistemic gain: we simply argued that it needed to be part of the risk-benefit analysis. We have no problem with the comment that “we must consider the value of these particular experiments, using scientific reasoning and judgment” and if Joshua L. Cherry feels that this “is exactly what most of the debate has been concerned with” then we are mostly on the same page.


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    2. On 2014 Oct 02, Joshua L Cherry commented:

      I thank the author(s) for responding. My original comment applies to much of the response, but a few points should be clarified.

      We have all encountered writing that refers to science or its subfields and uses scientific language but lacks scientific content. The editorial does something similar with respect to philosophy. It defines epistemology and makes use of its vocabulary, but the arguments that it makes are not epistemological. The only general principle about knowledge that it invokes is the Faberite notion that knowledge is good. This is not an epistemological proposition or a philosophical insight, nor a revelation to scientists.

      The benefits of GOF experiments commonly discussed are indeed benefits of the resulting knowledge. (What else would they be? The economic benefits of creating employment for laboratory personnel?) These have mostly been supposed direct practical applications of this knowledge for preventing human H5N1 infections. The response above suggests that the authors intended to emphasize “the many other possible future uses of that knowledge, some of them practical, but some of them purely theoretical”. As I stated, most or all scientific knowledge has many possible future uses, and it is common knowledge, not a philosophical insight, that science works this way.

      Exceptional risks demand exceptional benefits. Satisfaction of normative standards does not imply exceptional benefits. The authors indeed make a logical leap in concluding that GOF experiments must be powerful because they share certain formal properties with experiments that proved to be powerful. The literature is filled with results of experiments that meet these normative standards, with importance ranging from great to nearly nil. Thus, we must consider the value of these particular experiments, using scientific reasoning and judgment. That is exactly what most of the debate has been concerned with.


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    3. On 2014 Oct 01, Arturo Casadevall commented:

      We thank the writer for his comments. The writer is critical of several of the statements in our editorial. We respond to each individually:

      Joshua L Cherry states that: ‘The arguments are framed in philosophical terms, but there is no philosophical content, and the underlying question is one of scientific judgment.’

      We found this comment puzzling. Our paper includes discussion on two of the branches of philosophy: epistemology and ethics (by the writer’s own admission). Framing the GOF experiments within the normative standards of the field microbiology explores how we seek knowledge in the area. This together with discussion of ethical issues constitutes philosophical content.

      Joshua L Cherry states that: “[W]hen one does a risk-benefit analysis of this issue, the epistemic gain from GOF experiments should be included in the bookkeeping: if one does that, the benefits of GOF experiments are potentially so great as to warrant our risking more than we otherwise might.” This is a puzzling assertion. All of the benefits that have been considered are benefits of the resulting knowledge (“epistemic gain”). Perhaps the authors mean to refer to an intrinsic good of having knowledge, independent of any practical applications. If so, it is possible, and helpful, to state this more plainly, as I have just done. If there is a philosophical issue here, it is one of ethics, not epistemology. Perhaps the authors are referring to the practical value of the knowledge beyond its direct applicability to the case at hand. In either case the argument is weak. These are common properties of experiments, not special properties of potentially dangerous GOF experiments. The resources used for such experiments could be reallocated to other experiments that lack the serious safety concerns yet also have epistemic value (on any meaning), and quite possibly more of it.’

      The writer states that ‘all the benefits that have been considered are benefits of the resulting knowledge’. This is not the case. A reading of our paragraph describing the knowledge gained from GOF experiments considers the information that highly pathogenic avian influenza viruses can become mammalian transmissible useful because it provides a warning that these viruses have the biological potential to acquire this property. Prior to these experiments there was debate as to whether these viruses could become transmissible. Now we know that they can and that is a clear epistemic gain. But that epistemic gain goes beyond the utilitarian gain from any immediate application of this new knowledge, in part because of the many other possible future uses of that knowledge, some of them practical, but some of them purely theoretical. We have no disagreement with the notion that the subject of ethics is interwoven into considerations for GOF experiments. However, the idea that we should reallocate resources away from this type of work would accomplish nothing in helping us prepare against an influenza pandemic. As the currently developing Ebola epidemic in West Africa shows us we must continue research into highly dangerous pathogens for it is knowledge in medicine and science that provide the defenses against new threats from nature.

      Joshua L. Cherry states that: ‘The authors make much of the claim that the GOF experiments meet the “normative standards of the fields of microbiology and infectious diseases”. This is faint praise for experiments that, many fear, might cause pandemics. We might question the merits of these standards, despite their being normative, and might ask whether they are sufficient conditions for value, or merely necessary. Even putting those questions aside, at best this point establishes that the experiments have nonzero value, not that they are exceptionally powerful, as must be the case to justify exceptional danger. Again, there are plenty of other experiments that also satisfy these standards without posing the same threat.’

      Meeting the normative standards of the fields of infectious diseases and microbiology is high praise for GOF experiments for these fields have delivered some of the greatest successes in medicine. The writer appears to be mixing two issues that are very different: the fear and the power of GOF experiments. Fear can be minimized with strict laboratory safeguards that greatly reduce the likelihood of accidents. With regards to the power of GOF experiments, these have already taught us that highly pathogenic avian influenza virus has the capacity for mammalian transmission, as noted above. Since mammalian transmission is necessary for a pandemic this information is incredibly important. Humanity now stands warned that with a few sequence changes H5N1 influenza virus can acquire the property of mammalian transmissibility. The writer states that ‘there are plenty of other experiments that also satisfy these demands without posing the same threat’ but provides no examples. In fact, we counter that there is no other technology or mechanism short of waiting for epidemic to occur that could have provided this information. If there were, it is likely that a scientist would have pursued it by now. Hence, we stand by the words that these experiments are exceptionally powerful and that we lack alternatives if we are to seek certain types of knowledge.

      Joshua L. Cherry states that: The editorial seems to suggest such fallacious reasoning as this: The discovery that HIV causes AIDS established a cause-and-effect relationship about a pathogen and was very powerful; GOF experiments have established cause-and-effect relationships concerning pathogens; therefore, GOF experiments are very powerful.

      The key word here is “seems”: it is unclear how the writer infers this from what we wrote. GOF experiments trace their ancestry to the powerful scientific techniques that that have been responsible for some of the greatest successes in medicine including establishing disease causation and intervening against such diseases with vaccines and drugs. GOF experiments are fully within the normative standards of microbiology and molecular biology and as such they are incredibly powerful investigative tools that humanity can use to learn about microbial threats. As noted above GOF experiments have already produced highly valuable information that is not available from any other source.


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    4. On 2014 Sep 23, Joshua L Cherry commented:

      This editorial purports to offer new considerations that favor the continuation of potentially dangerous “gain of function” (GOF) experiments with pathogens with pandemic potential. The arguments are framed in philosophical terms, but there is no philosophical content, and the underlying question is one of scientific judgment. The philosophical language serves only to obscure and to create the illusion that a new consideration is being introduced.

      The authors state that

      “[W]hen one does a risk-benefit analysis of this issue, the epistemic gain from GOF experiments should be included in the bookkeeping: if one does that, the benefits of GOF experiments are potentially so great as to warrant our risking more than we otherwise might.”

      This is a puzzling assertion. All of the benefits that have been considered are benefits of the resulting knowledge (“epistemic gain”). Perhaps the authors mean to refer to an intrinsic good of having knowledge, independent of any practical applications. If so, it is possible, and helpful, to state this more plainly, as I have just done. If there is a philosophical issue here, it is one of ethics, not epistemology. Perhaps the authors are referring to the practical value of the knowledge beyond its direct applicability to the case at hand. In either case the argument is weak. These are common properties of experiments, not special properties of potentially dangerous GOF experiments. The resources used for such experiments could be reallocated to other experiments that lack the serious safety concerns yet also have epistemic value (on any meaning), and quite possibly more of it.

      The authors make much of the claim that the GOF experiments meet the “normative standards of the fields of microbiology and infectious diseases”. This is faint praise for experiments that, many fear, might cause pandemics. We might question the merits of these standards, despite their being normative, and might ask whether they are sufficient conditions for value, or merely necessary. Even putting those question aside, at best this point establishes that the experiments have nonzero value, not that they are exceptionally powerful, as must be the case to justify exceptional danger. Again, there are plenty of other experiments that also satisfy these standards without posing the same threat.

      Through reference to “normative standards”, the authors make an unjustified connection between GOF experiments and such important findings as the discovery that HIV causes AIDS. They tell us that “GOF experiments are very powerful because such experiments can give direct information on cause-and-effect relationships” about infectious agents. In reality, not all experiments that provide such information are “very powerful”. The editorial seems to suggest such fallacious reasoning as this: The discovery that HIV causes AIDS established a cause-and-effect relationship about a pathogen and was very powerful; GOF experiments have established cause-and-effect relationships concerning pathogens; therefore, GOF experiments are very powerful.

      Debate about GOF experiments has always been about whether the value of the knowledge they might yield is sufficient to justify their risks. Many claims for particular benefits have been abandoned, and some have been undermined by arguments put forth to downplay safety concerns. Referring to knowledge as “epistemic gain” adds nothing to the debate.


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    1. On 2016 Aug 17, Mohammed AlJasser commented:

      I have noticed that the language in which this article was written was labelled as Hebrew. However, the text is written in Arabic.

      Thank you.


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    1. On 2017 Jan 11, Vinay Pasupuleti commented:

      The abstract was erroneously deleted by journal editors and was published as an erratum at a later date. The full text clearly mentions that 6 articles were included (one article had results from a retrospective cohort study as well as a prospective cohort study)....therefore, a total of 7 observational studies. Total N in Table 1 is 102,767 as mentioned in the abstract (351+58+625+27+1848+246+170+160+96806+322+1077+1077 = 102,767).


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    2. On 2016 Jul 04, Swapnil Hiremath commented:

      Looks like the abstract was erroneously deleted, see the erratum.

      On the other hand, the point about number of studies is valid (6 in full text, 7 in abstract) - also the total N in full text (from table 1) adds up to > 200,000, compared to 102, 767 above in abstract. Does need to be clarified and addressed by the authors, in my opinion.


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    3. On 2016 Jun 30, Gabriel Rada commented:

      This abstract contains several mistakes, most of them minor formatting issues. However, it states there are 7 included studies, when the actual number reported in the full text is 6. On the other hand, there is no abstract in the journal website, so it seems it was created for indexing purposes. I don't see any indication of this abstract being 'in process' in Pubmed/MEDLINE. My main issue is who is responsible of the information displayed here? The publisher or Pubmed?


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    1. On 2014 Sep 19, Ian Dworkin commented:

      In addition to all of the data and scripts for analysis being available at Dryad, we have also made it available on github as a repository. https://github.com/DworkinLab/PitchersJEB2014_cricket_wings


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    1. On 2014 Sep 16, Mohamed Soliman commented:

      I think this can be a subject of a prospective study to clarify this issue.


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    1. On 2014 Oct 11, Igor Zwir commented:

      Pre-selected SNPs The list of 2,891 pre-selected SNPs from the MGS study (1) utilized in (2) (see supplemental material) is available at http://m4m.ugr.es/resources/2891-SNP-PreSelection.txt. This list contains 99% of the SNPs reported in the supplemental material of (1).

      (1) Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe'er I, Dudbridge F, Holmans PA, Whittemore AS, Mowry BJ, Olincy A, Amin F, Cloninger CR, Silverman JM, Buccola NG, Byerley WF, Black DW, Crowe RR, Oksenberg JR, Mirel DB, Kendler KS, Freedman R, Gejman PV. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. 2009;460I:753-7.

      (2) Arnedo J, Svrakic DM, del Val C, Romero‑Zaliz R, Hernández-Cuervo H, Molecular Genetics of Schizophrenia Consortium, et al. Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies. American J of Psychiatry 2014 (in press);172:1–15. Epub 9/15/2014.


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    2. On 2014 Oct 07, Igor Zwir commented:

      Interdisciplinary work not so fast … Geneticist with a statistic background vs. engineers/computer scientists with a genetic background

      Unfortunately, interdisciplinary works have been concurrently stimulated and frozen at the same time. Much of this contradiction is due to the lack of universal reviewers that know about everything. Science is specialized, in terms of education and consequently in terms of results. For example, most studies of complex disorders usually focus on single sources of data (genetics, neuroimages), eliminating the possibility of having complementary perspectives of the patients. In addition, there is a sort of disrupted communication between the biomedical researchers and math or computer science investigators. Biologist and physicians use to search for articles in pubmed (http://www.ncbi.nlm.nih.gov/pubmed), however, most of the engineers look for the Institute of Electrical and Electronics Engineers (IEEE) communications (https://www.ieee.org) and many of them ignore Pubmed. In contrast, many molecular biologists ignore what IEEE exists and what it represents. There are few IEEE publications that are available in pubmed and most of them are old. However, many of those that are not in Pubmed are much more rigorous than any method proposed in the best biomedical journals. This comment encourages both Pubmed and IEEE sites to solve their differences, which in turn, will help to have more and more informed reviewers for novel techniques in the post genomic era.


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    3. On 2014 Oct 07, Igor Zwir commented:

      Rationale of the method applied in Arnedo et. al.

      Clustering methods have been applied for long time in pattern recognition problems and in a variety of fields and actually are embedded in most of our devices, from a simple refrigerator to a Boing engine. In biomedical sciences there is a trend of considering that few classes of clustering exist (e.g., hierarchical cluster of K-Means). However, datamining, knowledge discovering, and machine leaning are fields of computer sciences with very rich and different either theoretical or empirical methods. Much of the power of these methods is based on the fusion of them, taking advantages of each one.

      The methodology and framework proposed in this Arnedo et. al encodes a generalized factorization method (GFM) that was designed to identify structural patterns or clusters (substructures) that characterize complex objects (1-8) embedded in databases (6, 7, 9, 10). Unfortunately, solving these kinds of complex problems cannot be performed by a single clustering method but utilizing and combining the advantages of many of them, as were implemented in the GFM and summarized below.

      First, we utilized the notion of Model-based clusters (5, 11, 12), where the centroid/prototype of a cluster is not a point but a model (e.g., line segment, ellipsoids, (5, 13, 14) or see C-varieties algorithm (12)) -or a family of models (8) - defined as a relation between cohesive subset of points that meet certain constraints (e.g., Relational clustering (12), undirected graph (12)). When the subjacent equations of the models are unknown, they can be estimated from the data by identifying relations between subsets of observations that show similar patterns under a specific subset of relevant descriptive features (attributes) (4, 5, 15). Here we proposed that in a pure data driven analysis these unknown models (grey boxes) can be learned as local relationships between subsets of features and observations, which are termed biclusters. The biclusters are often represented as sub-matrices (4, 5, 15). Other models proposed in this work (black boxes) consist of those that are encoded by a particular method devoted to recognize certain classes of patterns.

      Second, to identify a family of models (8) or biclusters we planned the use of the NMF (16) factorization algorithms (tensor analysis), which can uncover cohesive data represented as sub-matrices (factors). When sorted and thresholded, each sub-matrix represents a bicluster. Notably, biclustering produces several local models of the data (17), each one capturing intrinsic relationships between subsets of observations sharing subsets –instead of all- features. Diverse biclusters –instead of uniform data explanations- provide a better understanding of the described object that is diluted when together, all features are used in a single global model of data typically performed by clustering methods (17).

      Third, we proposed in this work that biclusters can be fuzzy (overlapping, see Fuzzy clustering (18)), where voxels and/or subjects can belong to more than one bicluster), as well as possibilistic (non-exhaustive partitions, see Possibilistic clustering (12)), where certain voxels and/or subjects may not be assigned to any bicluster, and thus, outliers can be detected.

      Fourth, we demonstrated that biclusters could be identified without choosing a priori a particular number of clusters (11, 13, 14, 19). Setting this parameter as a small number may eventually generate few but large data partitions here defined as general biclusters that may underfit the data. In contrast, using a big number of clusters will generate many clusters with partitions of small size (i.e., more granular partitions) here defined as specific biclusters that may overfit the data (1, 5, 11, 13, 14, 19-21). Although there are many different validity indices (12, 18) that suggest the best number of clusters for a given dataset, they often produce contradictory results (11, 13, 14, 19). This problem is exacerbated when Centroid-based (e.g., k-means, NMF) or Distribution-based clustering (e.g., EM) is utilized because two successive numbers of clusters may generate completely different cluster arrangements (see (12, 18) for a review). Instead of fighting over the lost battle of uncovering a single optimal number of clusters, biclusters were calculated from partitions generated by all number of clusters between 2 and √n (12), where n is the number of observations (subjects). We postponed the selection of the best clusters until all partitions were examined to select a set of clusters that together provide an optimal description of the sample. These clusters could be chosen from different partitions that were generated by different number of clusters (see Consensus clustering (1, 5, 11, 13, 14, 19-21)).

      Fifth, formulation of the bicluster identification problem from different partitions may produce redundant, excessively specific and/or excessively general biclusters (4, 5, 15, 22, 23). To select optimal biclusters, we proposed a GFM that performs the following Consensus clustering strategy: (i) eliminates all redundant biclusters by comparing the similarity between their subjacent sub-matrices using Hypergeometric statistics (see Methods and Material in Supplement 1), and selecting only one representative bicluster from each set of equivalent sub-matrices. Biclusters harboring <10% of the total number of subjects were not considered to avoid a trend to obtain singleton biclusters. (ii) From the non-redundant biclusters, GMF selects all biclusters that are optimal in terms of specificity, generality and diversity. To do so, it selects all non-dominated biclusters where one bicluster is not worse (i.e. dominated) than another in both objectives: specificity and generality (4, 5, 15, 22, 23). Moreover, to ensure diversity, GMF applies the non-dominance metric only among biclusters within a neighborhood (22, 23) (i.e., biclusters with a relatively high overlapping of subjects and voxels with). This Multiobjective and Multimodal optimization process is analogous to Minimum Description-Length methods (24) and was carried out as described in (1-8). (iii) The remaining optimal biclusters are hierarchically organized by inclusion of their subjects into connected or disjoint hierarchies (i.e., subgraphs or subnetworks).

      Sixth, and after the first step of identifying interesting patterns describing objects embedded in the data, we went one step further by also finding characteristic descriptions for each group, where each group represents a concept or class using Conceptual clustering. In this work we incorporated factors such as the generality and simplicity of the derived bicluster descriptions by (1) relational clustering validation against data driven independent descriptions obtained in other domains of knowledge, and (2), incorporate the previous structured knowledge into predictive multiclassifiers mixing machine learning and multiobjetive optimization techniques.


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    4. On 2014 Oct 07, Igor Zwir commented:

      References

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      18. Bezdek JC, Pal SK, IEEE Neural Networks Council (1992): Fuzzy models for pattern recognition : methods that search for structures in data. New York: IEEE Press.
      19. Latorre Carmona P, Sánchez JS, Fred ALN, SpringerLink (Online service) (2013): Mathematical Methodologies in Pattern Recognition and Machine Learning Contributions from the International Conference on Pattern Recognition Applications and Methods, 2012. Springer Proceedings in Mathematics & Statistics,. New York, NY: Springer New York : Imprint: Springer,, pp VIII, 194 p. 158 illus., 140 illus. in color.
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    5. On 2014 Oct 07, Igor Zwir commented:

      None


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    6. On 2014 Oct 07, Igor Zwir commented:

      None


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    7. On 2014 Oct 07, Igor Zwir commented:

      None


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    8. On date unavailable, commented:

      None


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    9. On 2014 Oct 06, C. Robert Cloninger commented:

      References

      1. Arnedo J, Svrakic DM, Del Val C, Romero-Zaliz R, Hernandez-Cuervo H, Fanous AH, et al. Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies. The American journal of psychiatry. 2014.
      2. Arnedo J, del Val C, de Erausquin GA, Romero-Zaliz R, Svrakic D, Cloninger CR, et al. PGMRA: A web server for (Phenotype X Genotype) many-to-many relation analysis in GWAS. Nucleic Acids Res. 2013(Web Server issue). PMCID: 2447763.
      3. Risch N. Linkage strategies for genetically complex traits. I. Multilocus models. American journal of human genetics. 1990;46(2):222-8. PMCID: 1684987.
      4. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421-7. PMCID: 4112379.
      5. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. American journal of human genetics. 2007;81(3):559-75. PMCID: 1950838.
      6. Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe'er I, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature. 2009;460(7256):753-7. PMCID: 2775422.
      7. Graves JA. Review: Sex chromosome evolution and the expression of sex-specific genes in the placenta. Placenta. 2010;31 Suppl:S27-32.
      8. Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, et al. Linkage disequilibrium in the human genome. Nature. 2001;411(6834):199-204.
      9. Slatkin M. Linkage disequilibrium--understanding the evolutionary past and mapping the medical future. Nat Rev Genet. 2008;9(6):477-85.
      10. Wiehe T, Slatkin M. Epistatic selection in a multi-locus Levene model and implications for linkage disequilibrium. Theor Popul Biol. 1998;53(1):75-84.
      11. Pritchard JK, Donnelly P. Case-control studies of association in structured or admixed populations. Theor Popul Biol. 2001;60(3):227-37.
      12. Koch E, Ristroph M, Kirkpatrick M. Long range linkage disequilibrium across the human genome. PLoS One. 2013;8(12):e80754. PMCID: 3861250.
      13. Wright S. The shifting balance theory and macroevolution. Annual review of genetics. 1982;16:1-19.
      14. Wu MC, Kraft P, Epstein MP, Taylor DM, Chanock SJ, Hunter DJ, et al. Powerful SNP-set analysis for case-control genome-wide association studies. Am J Hum Genet.86(6):929-42. PMCID: 3032061.
      15. Zwir I, Shin D, Kato A, Nishino K, Latifi T, Solomon F, et al. Dissecting the PhoP regulatory network of Escherichia coli and Salmonella enterica. Proc Natl Acad Sci U S A. 2005;102(8):2862-7.
      16. Zwir I, Huang H, Groisman EA. Analysis of Differentially-Regulated Genes within a Regulatory Network by GPS Genome Navigation. Bioinformatics. 2005;21(22):4073-83.
      17. Romero-Zaliz R, Del Val C, Cobb JP, Zwir I. Onto-CC: a web server for identifying Gene Ontology conceptual clusters. Nucleic Acids Res. 2008;36(Web Server issue):W352-7.
      18. Romero-Zaliz R, C. Rubio R, Cordón O, Cobb P, Herrera F, Zwir I. A multi-objective evolutionary conceptual clustering methodology for gene annotation within structural databases: a case of study on the gene ontology database. IEEE Transactions on Evolutionary Computation . 2008;12:6:679-701.
      19. Harari O, Park SY, Huang H, Groisman EA, Zwir I. Defining the plasticity of transcription factor binding sites by Deconstructing DNA consensus sequences: the PhoP-binding sites among gamma/enterobacteria. PLoS Comput Biol. 2010;6(7):e1000862. PMCID: 2908699.
      20. Lee DD, Seung HS. Learning the parts of objects by non-negative matrix factorization. Nature. 1999;401(6755):788-91.
      21. Mejia-Roa E, Carmona-Saez P, Nogales R, Vicente C, Vazquez M, Yang XY, et al. bioNMF: a web-based tool for nonnegative matrix factorization in biology. Nucleic Acids Res. 2008;36(Web Server issue):W523-8. PMCID: 2447803.
      22. Pascual-Montano A, Carmona-Saez P, Chagoyen M, Tirado F, Carazo JM, Pascual-Marqui RD. bioNMF: a versatile tool for non-negative matrix factorization in biology. BMC Bioinformatics. 2006;7:366. PMCID: 1550731.
      23. Tamayo P, Scanfeld D, Ebert BL, Gillette MA, Roberts CW, Mesirov JP. Metagene projection for cross-platform, cross-species characterization of global transcriptional states. Proc Natl Acad Sci U S A. 2007;104(14):5959-64. PMCID: 1838404.
      24. Cichocki A. Nonnegative matrix and tensor factorizations: applications to exploratory multi-way data analysis and blinded separation. Chichester, U.K.: John Wiley; 2009.
      25. Tavazoie S, Hughes JD, Campbell MJ, Cho RJ, Church GM. Systematic determination of genetic network architecture. Nat Genet. 1999;22(3):281-5.


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    10. On 2014 Oct 06, C. Robert Cloninger commented:

      Conclusion

      We appreciate the opportunity to clarify the fundamental differences between the assumptions and goals of traditional GWAS and our novel approach that addresses the complexity of common disorders with sophisticated and well-validated machine-learning and data-mining methods. We hope that the profound differences in the approaches with which Breen and colleagues are familiar and those developed by us should stimulate greater understanding of the challenges faced by the fields of psychiatric and medical genetics. We recognize that this new approach will cause a period of reexamination of standard methodology in this field, but every major advance in genetics, and in all of science for that matter, has always required flexibility and creative thinking. There are always things that we can improve upon in any method, and we recognize that many incremental improvements are essential for the advance of science.

      We have put forth a new data-driven method that allows the uncovering of complex genotypic-phenotypic relations when they are present without imposing this as an a priori assumption. We uncovered relationships are in fact highly complex, which allowed us to identify individuals at high risk and to associate specific SNP clusters with specific clinical syndromes despite the presence of extensive pleiotropy and heterogeneity. This approach, like all those that have preceded it, is undoubtedly imperfect and will also require refinement and may ultimately give way to yet another approach that will explain more. Such methodological evolution is nothing more than the typical course of advancement in science. We hope that these exciting developments will lead to new ways to push the boundaries of accepted science, and help us to question a priori assumptions that restrict our understanding of all the information embedded in data.

      If this discussion has shown us nothing else, it is that this process of questioning and reflection has already begun. Ultimately, beyond all of the technical issues, our main goal is to help those in need. With schizophrenia, we know the need is great from the tremendous outpouring of requests for guidance and help that we have received, and we know that there are many people with other diseases who may benefit from our new approach. We can all be comforted knowing that our debate can bring us closer to doing what we are really here to do – that is, helping those suffering from debilitating diseases and finding ways to promote their health and well-being. Whatever path leads us there is worth considering. So let us not permit our philosophical or scientific differences to prevent us from allowing for a sufficient diversity in our tactics, because we never know what path will lead us towards our common goals of improving health and reducing the burden of disease.


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    11. On 2014 Oct 06, C. Robert Cloninger commented:

      The Facts about Replication and Significance Testing of SNP Selection

      B-S expressed concern about our replication process. Of course in traditional GWAS, replication has always been a serious problem, which is the basis for the rationale of PGC to carry out meta-analysis of large collections of samples despite their heterogeneity and limited phenotypic description. It was most challenging for us to identify samples with adequate clinical description to apply our novel approach, but the reward was in identifying strong effects that replicated consistently across three samples, including the Portuguese Islands study that used the same diagnostic instrument in a specific ethnic sample. The samples were independently recruited and independently analyzed, as we stated clearly in the published report. SNP sets, phenotypic sets and associations were separately calculated for the three samples to avoid weighted or biased aggregations. Then, we used a well-known co-clustering test based on the hypergeometric distribution to establish the replicability of results from one sample in the other. This test has been used widely in molecular biology (15, 16, 25), and as a general strategy for validating clusters. For example, it has also been implemented into software packages such as TIBCO/Spotfire. The concerns expressed by B-S about replication have no reasonable justification. Thus we feel that the concerns expressed by B-S about replication are overstated and empirically unfounded. Again, the strength of this new approach is it allows us to avoid some of the major problems that plague traditional GWAS approaches.

      B-S also expressed their concern about the use of a permutation test, claiming that "because SNP sets differ in allele frequency between cases and controls, this procedure does not generate a valid null distribution". The permutation test was used not to establish the significance of the SNP sets, which was evaluated by the SKAT method (14), but rather to test the validity (and approximate probability) of the association between SNP sets and symptom sets. Controls were not used in this test at all, as they have no symptoms of psychosis. Moreover, these symptoms were not even evaluated in the reported inventories. The misunderstanding of B-S is probably due to a lack of familiarity with this new statistical procedure, which highlights the previously discussed difficulties people have when first trying to understand a novel approach.


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    12. On 2014 Oct 06, C. Robert Cloninger commented:

      The Facts about Linkage Disequilibrium

      B-S also expressed concern that it is likely that our SNP sets may be merely artifacts of blocks of markers in linkage disequilibrium (LD). LD is strictly defined as the non-random association of alleles of neighboring polymorphisms derived from single ancestral chromosomes, but some broad measures of LD extend the concept to include covariation of polymorphisms that are not linked, including even associations among genetic variants on separate chromosomes (8). Many variables influence covariation of polymorphisms, including demographic variables (admixture, population size, migration, ancestral population bottlenecks), selection (including epistasis), and variation In recombination rates in different parts of the genome (9, 10). Consequently LD is a serious problem for the traditional group-wise statistical approach of traditional GWAS, so care is taken to analyze groups with distinct ancestries separately in order to help disentangle different causes of association. However, in our novel person-centered approach, the identification of subpopulations is an intrinsic aspect of identifying the genotypic-phenotypic architecture. We identify sets of variables that naturally cluster within individual subjects as measured by covariance of polymorphisms or phenotypic traits within particular subgroups of individuals in a population. We identify SNP sets and phenotypic sets independently of one another and then test how these independently identified sets fit together like a lock and a key. In a strictly data-driven manner the hidden structure of the overall population is decomposed into subpopulations of subjects to allow valid tests of genotypic-phenotypic association despite admixture in the total population from which SNP sets and phenotypic sets are extracted (11). We allow the possibility that some constituent SNPs of a particular set may be associated (in LD) as adventitious hitchhikers that are closely linked or may be epistatic sets that are functionally adaptive and maintained by selection pressure even though they are unlinked (12). However, being linked (co-localized) or in LD is neither a necessary nor a sufficient condition for being a constituent in a SNP set: set membership depends on co-variation of polymorphisms in particular subpopulations of individuals whether the genetic variants are in LD in the total population or not. LD is actually one way that epistatic sets of genetic variants can be maintained in functionally adaptive blocks if the epistatic selection is strong, but most interactive sets of genetic variants are not in LD. Accordingly, we uncover constituents of SNP sets regardless of their LD status as candidates for functionally adaptive epistatic sets. Then we measure their potential functional interaction by testing for their differential association with phenotypic variability. We also consider the known function of the genes and regulatory sites as part of our analysis of the complex pathway from genotypic networks to distinct clinical syndromes. Thus we jointly utilize genotypic, biological, and phenotypic information as part of an integrated systems analysis that allows for observed or hidden stratification in the total population.

      In addition to this fundamental difference in conceptual and procedural approach to LD, the concerns of B-S about our findings are simply unfounded empirically. In total, approximately 2/3 of the SNPs in high-risk sets map to regions that are so far apart in genomic distance (greater than 100,000 base pairs) that they are highly unlikely to be in LD. We found that 9 of 42 high-risk SNP sets have some SNPs located on different chromosomes. These facts indicate that the identified SNP sets are not the result of particular genomic constraints such as LD or being within the region of the same gene. In any case, the presence of LD would not explain or invalidate the association of groups of SNPs within a particular SNP set with a particular phenotypic set. For example, one of our SNP sets maps exclusively to SNPs upstream of the NTRK3 gene, as was also found to be strongly associated with schizophrenia by standard GWAS techniques published by the authors of the commentary. In addition SNPs from another SNP set map inside the same gene. Each of these SNP sets involving different components of the NTRK3 gene are associated with different symptoms. Although LD is viewed as a statistical problem for traditional GWAS, in our person-centered approach it is viewed as the result of adaptive mechanisms that can conserve the functional connectivity of epistatic sets of genetic variants, thereby contributing to the differential development of individuals in subpopulations. The functional adaptation facilitated by gene-gene interactions is fundamentally important for healthy development of individuals and for the evolution of populations, as described in Sewall Wright’s classical work on complex adaptive systems and evolution (13). Our concurrent consideration of the functions of gene products and associations between different genotypic networks with specific phenotypic syndromes precludes any suggestion that the highly replicable effects we observed are artifacts.

      B-S have also suggested matrix factorization algorithms similar to the methods employed by us have been used to identify regions with long-range LD. This is certainly true and is not a problem in itself. Long-range LD is an indicator of functional connectivity that is not adequately explained by physical proximity, so it is included in what we want to detect in order to account for gene-gene interactions thoroughly (14). Matrix factorization methods like ours have been used for most of the current software applications in data-mining, including a wide variety of biomedical problems (15-19), facial recognition (20), gene expression (21-23), and other complex problems (24). There is no reason to avoid the use of this powerful method for pattern recognition within fuzzy data sets for uncovering hidden order within the complex association of genotypic and phenotypic variables that characterize complex medical disorders.


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    13. On 2014 Oct 06, C. Robert Cloninger commented:

      The Challenge of Understanding and Accepting a Change in Perspective

      Is our approach to concurrent genotypic-phenotypic of possible complex relationships a fruitful new approach without the limiting assumptions of standard GWAS, or are our observations really artifactual in ways that have been overlooked by us and by multiple sets of peer reviewers with relevant expertise about these novel methods? The American Journal of Psychiatry gave us generous space for the published article, including clinical vignettes with associated genotypic information to help people see what we have done even if the technical details of the statistical procedures may seem obscure when you first start looking at complex genotype-phenotype relationships through the illuminating lens of sophisticated machine-learning and data mining procedures. We expected that there would be widespread interest and scrutiny of this new data-driven approach with less restrictive assumptions, so we prepared an extensive online supplement specifying procedures, all components of the sets of SNPs and clinical variables as well as a detailed analysis of the associated gene products, their functions, and disease associations.

      The full list of SNPs used in our analysis is being made available for others to continue to test. We believe in transparency and collegiality as key ingredients in the advance of science because it is essential for the spirit of empiricism that our data driven method emphasizes. The precise procedures for reproducing the list of SNPs was detailed already in our supplemental information and should be reproducible by experienced investigators. We will continue to consider reasonable requests for assistance from qualified investigators.

      B-S expressed their concern that the “methodology is opaque (even to experts), meaning that their results cannot be independently validated”. First of all, the complexity of a method does not invalidate the approach: complex methods may be necessary to deconstruct and understand complex processes. We cannot continue to look for hidden relationships with methods that do not shine light where it is needed. That said, the manuscript was exhaustively evaluated under strict peer review process, which included a separate report from an independent statistician. Because of their many insightful comments, there is no doubt that the referees understood the method and provided recommendations that we conscientiously addressed in the re-submission process. Moreover, the PGMRA method utilized in this work was also evaluated by expert reviewers in bioinformatics and genetics for the journal Nucleic Acid Research (2). The method is well-described but does require relevant expertise beyond what is required for traditional GWAS. Fortunately, we have made a web-server application of the method publicly available as a service to the field. PGMRA is applicable to a wide variety of analyses besides GWAS, including brain imaging and related methods for uncovering order in complex hidden relationships, which may help to further characterize the pathway from genotype to phenotype more objectively than can be done by categorical diagnoses or symptom inventories in samples so large that costs become prohibitive for thorough assessment. We know that many are increasingly criticizing overspecialization in the fields of science, but the neglect of strictly data-driven techniques from machine-learning and data-mining that do not require restrictive a priori assumptions may well be precisely what has prevented us from understanding the complex genotypic-phenotypic architecture of common disorders like the schizophrenias.

      We understand that our new approach is challenging long-held assumptions and that there may be a desire by some to put the genie back in the bottle, but we feel that looking at the complexity of the schizophrenias is a necessary evolution for the field; it is an evolution whose time has come and is currently transforming other fields of science and genetics. There is overwhelming evidence across multiple disciplines that living systems and psychosocial behavior are simply too complex and interactive to ignore the real underlying complexity. Nonetheless, we were a bit surprised to see this discussion in a public forum that is not peer reviewed. We would rather have thoughtful constructive consideration of the scientific merits of alternative approaches, including their fundamental philosophical differences in perspective and goals, as well as scientific differences in assumptions and procedures. One of the major obstacles to evaluating GWAS is that it can be difficult or impossible for scientists in many fields to evaluate complex technical procedures with which they are unfamiliar. The challenge of changing one’s perspective can be great and feel counterintuitive, as physicists experienced more than a century ago when quantum mechanics called into question our more natural inclination to a Newtonian perspective. That is why we feel it would have been more constructive to have neutral review by people with relevant expertise in many aspects of methods that span bioinformatics, statistics, genomics, and phenomics, all of which are needed to adequately judge the strengths and weaknesses of a novel approach like ours. Even people with extensive experience in traditional approaches to GWAS may not be sufficiently knowledgeable about these well-tested, but relatively new, machine-learning and data-mining techniques that have allowed us to develop a new, and, we hope, more generative approach to GWAS.

      Nevertheless, as scientists we are dedicated to identifying and learning how to move our fields of inquiry forward in order to better understand the underlying mechanisms of disease and to identify effective personalized treatments for complex disorders. We have found it is crucial to pay balanced attention to both phenotypic variability and genotypic variability if we are ever to describe the complex development of common and complex medical disorders like the schizophrenias. We do not feel that this public forum is the best place to have this discussion with Breen and colleagues, but here too we may have a philosophical difference. That said, because they have chosen this forum to voice their criticism, we feel it is important that we take the time to address the facts and give people a broader context so that they can understand the arguments and our responses to their concerns. Ultimately, we feel that this is more of a misunderstanding and a miscommunication due to a lack of a common scientific and philosophical approach, and that with time we hope to find more common ground. Ultimately, the data will settle any dispute.


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    14. On 2014 Oct 06, C. Robert Cloninger commented:

      Reply to Breen et al (their Part 2 of 2) On behalf of: C. Robert Cloninger, M.D., Ph.D. (Departments of Psychiatry and Genetics, Washington University School of Medicine, St. Louis, MO, USA); Igor Zwir, Ph.D. (Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Department of Computer Science and Artificial Intelligence, University of Granada, Spain); Gabriel A. de Erausquin, M.D., Ph.D. (Roskamp Laboratory of Brain Development, Modulation and Repair, Department of Psychiatry and Behavioral Neurosciences, University of South Florida, Tampa, FL, USA); Dragan M. Svrakic, M.D., Ph.D. (Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA); Coral del Val, Ph.D. (Department of Computer Science and Artificial Intelligence, University of Granada, Spain); Javier Arnedo, M.S. (Department of Computer Science and Artificial Intelligence, University of Granada, Spain); Rocío Romero-Zaliz, Ph.D. (Department of Computer Science and Artificial Intelligence, University of Granada, Spain); Helena Hernández-Cuervo, M.D., B.Sc. (Roskamp Laboratory of Brain Development, Modulation and Repair, Department of Psychiatry and Behavioral Neurosciences, University of South Florida, Tampa, FL, USA);

      The reply to the comments of Breen et al (their Part 2 of 2) by Cloninger on behalf of all of us responsible for analysis in the Arnedo et al article has the following five components which are posted separately as follows: (4) The Challenge of Understanding and Accepting a Change in Perspective (5) The Facts about Linkage Disequilibrium (6) The Facts about Replication and Significance Testing of SNP Selection (7) Conclusion (8) References for all sections of our postings


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    15. On 2014 Sep 28, Gerome Breen commented:

      Part 2 of 2 (see below) On behalf of: Gerome Breen, PhD (Institute of Psychiatry, King’s College London, London, UK) * Brendan Bulik-Sullivan (Broad Institute, Cambridge, MA, USA) * Mark Daly, PhD (Broad Institute, Cambridge, MA, USA) * Sarah Medland, PhD (QIMR Berghofer, Brisbane, Australia) * Benjamin Neale, PhD (Broad Institute, Cambridge, MA, USA) * Michael O’Donovan, MD PhD (Cardiff University, Cardiff, UK) * Stephan Ripke, PhD (Broad Institute, Cambridge, MA, USA) * Patrick Sullivan, MD (Karolinska Institutet, Stockholm, Sweden) * Peter Visscher, PhD (University of Queensland, Brisbane, Australia) * Naomi Wray, PhD (University of Queensland, Brisbane, Australia) *

      • Authors ordered alphabetically, all made equivalent contributions

      C. Linkage disequilibrium (LD).

      Pairs of SNPs that are physically close in the genome are often correlated due to LD. Furthermore, in samples containing individuals with different ancestry, SNPs on different chromosomes whose allele frequencies differ between populations will appear to be correlated. These are both well-known phenomenon from population genetics.

      The typical size of blocks defined by high LD is on the order of 20,000 bases, but LD is far from uniform across the genome. Using a large European sample genotyped with Affymetrix 6.0 arrays, we had previously computed the locations of particularly large blocks of LD (defined using SNPs with r2 > 0.5). The first step in the statistical methodology described by Arnedo et al. is to identify so-called “SNP sets” – sets of SNPs that travel together – which the authors believe contain some information about clinical subtypes of schizophrenia: “we first identified sets of interacting … SNPs that cluster within subgroups of individuals … regardless of clinical status” (no LD limitations were imposed). Of the 237 SNPs in Table S3 from Arnedo et al., 153 (65%) mapped to exceptionally large LD blocks larger than 100,000 bases (median 275kb, interquartile range 165-653kb, maximum 1.2 mb).

      Arnedo et al. claim repeatedly that sets of SNPs that travel together are informative about clinical subtypes of schizophrenia. A more parsimonious interpretation of the SNP clusters identified by Arnedo et al. is that these SNPs represent a combination of (1) SNPs in large LD blocks and (2) SNPs whose allele frequencies differ substantially between European and African sample subsets. Indeed, matrix factorization algorithms similar to the methods employed by Arnedo et al. have been used to identify regions with long-range LD (see Price et al., AJHG, 2008, link below).

      D. SNP selection.

      Arnedo et al. conducted genetic clustering analyses on 2,891 SNPs selected on the basis of in-sample P-values from analysis of association with case-control status and selected from a total of ~700,000 SNPs. It is therefore expected that linear or non-linear combinations of these SNPs will be associated with case-control status in the same sample (their risk statistic); this is true even if the selected SNPs are not truly associated. A permutation test is used to assess the significance of the observed phenotype/genotype clustering. In this permutation test, subjects are randomly allocated to “SNP sets” but, since the SNPs were selected because they differ in allele frequency between cases and controls, this procedure does not generate a valid null distribution. As a result, the reported P-values are incorrect.

      The strategy used by Arnedo etl al. is an example of estimation and selection of effects in a dataset and then testing (or re-estimating) them in the same data, a common pitfall of prediction analyses (Wray et al. 2013, Nature Reviews Genetics, link below). To construct a valid permutation test, the authors should have randomized case-control status in the association analysis step, selected a new set of ~3,000 SNPs and generated a distribution of their coincident test index under a truly null distribution.

      E. Replication.

      Replication of results is a well-acknowledged strategy for generating confidence in reported findings. Arnedo et al. state that they replicated their findings in two samples but, upon closer examination, it is unclear precisely what replicated, exactly how this was done, and whether the degree of “replication” deviated from that expected by chance. It was also unclear whether the replication control samples were or were not independent from the discovery sample. Such non-independence is another common pitfall in prediction or validation analysis.

      Conclusions.

      Given the remarkable claims made by Arnedo et al., it is essential that alternative explanations be excluded. Unfortunately, the authors do not provide the necessary evidence. As presented, their methodology is opaque (even to experts), meaning that their results cannot be independently validated. Arnedo et al. do not consider alternative explanations for the phenomena that they observe, such as confounding from ancestry and LD, even though these are well-known issues for the statistical methods that they employ and have been studied extensively in the statistical and population genetics literature. In addition, their multistep analysis approach is subject to multiple issues as noted above.

      We believe that it is highly likely that the results of Arnedo et al. are not relevant for schizophrenia. We urge great caution in the interpretation of the results of study.

      Links: • Arnedo et al. in PubMed, http://www.ncbi.nlm.nih.gov/pubmed/25219520 • Press release from Washington University (St Louis), https://news.wustl.edu/news/Pages/27358.aspx • Media coverage via Google News, https://news.google.com/news?ncl=dwmwseq1Mco0xVMLXz5qVDa7uJqbM&q=cloninger&lr=English&hl=en&sa=X&ei=hgIjVO-0GoGOyASxtIGAAw&ved=0CD0QqgIwCQ • Nonnegative matrix factorization and ancestry inference: http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001117 • Pitfalls of predicting complex traits from SNPs: http://www.ncbi.nlm.nih.gov/pubmed/23774735 • Using principal components analysis to identify regions with long-range LD: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2443852


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    16. On 2014 Sep 28, Gerome Breen commented:

      None


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    17. On 2014 Oct 06, C. Robert Cloninger commented:

      The Facts about Gender and the X-Chromosome

      B-S express concern about gender effects in our results. Traditional GWAS focuses on average effects in heterogeneous groups, but our novel approach focuses on uncovering genotypic-phenotypic relationships in individuals regardless of their gender. B-S were concerned about the possible bias of results from 15 SNPs on the X-chromosome among 245 SNPs in high-risk SNP sets. However, a simple test based on the number of chromosomes shows that 15 SNPs cannot substantially confound the results. It is true that three of our 42 high-risk SNP sets have some SNPs on the X Chromosome, but when this is considered in context along with the remaining 39 SNP sets, the influence of gender was insignificant by a Kolmogorov test. All SNP sets have consistent associations with distinct phenotypic sets regardless of gender. The effects of gender and location of genetic variants on the X-chromosome have a negligible influence on our findings. In fact, the small number of SNPs on the X-chromosome in SNP sets at high risk for schizophrenia shows that our person-centered method does not select SNPs that are in LD indiscriminately; the X-chromosome has many highly conserved sets of epistatic genes in LD that influence gender and brain function (7), but these are not overrepresented in our SNP sets at high risk for schizophrenia. We thank B-S for calling attention to another finding that demonstrates that our method for identifying SNP sets is highly selective for particular phenotypes.


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    18. On 2014 Oct 06, C. Robert Cloninger commented:

      The Facts about Ancestry and Population Stratification

      B-S expressed concern that our findings may be an artifact. As scientists we are committed to trying to disconfirm findings we have made, no matter how strong the existing evidence may be. Findings about association need to be resolved experimentally at the molecular level not only for our findings but also for the findings of other published GWAS, which we plan to do in the near future. We have previously considered the variables that concern B-S carefully, but did not report these observations in detail for two reasons. First, their impact was empirically negligible for our approach, as we will describe, and we prioritized space to the variables that were most significant. Second, although the phenomena that concern B-S are often a serious problem for traditional group-wise approaches to GWAS, they are not problematic for our novel approach because it directly tests the association between genotypic variability and phenotypic variability within individuals after deconstruction of the observed or hidden structure of the population. We will describe the facts about each of these phenomena and explain why these criticisms fall short of explaining our findings.

      B-S expressed concern that we did not take the necessary steps to correct for population stratification bias in the way they would have done using their traditional group-wise statistical approach. They suggest that the clusters we identified simply reflect “SNPs whose allele frequencies differ substantially between European and African sample subsets”, and go so far as to claim that the SNP sets we uncovered may not be relevant to schizophrenia at all. However, for that claim to be valid, ethnicity must have a strong influence on the risk and symptoms of schizophrenia, but that requirement is unlikely to be satisfied based on previous observations and was not found in our data. We did consider both sex and ancestry as co-variates in the pre-selection of SNPs with at least loose association with schizophrenia. This pre-selection was performed to reduce the large search space using the logistic association function included in the PLINK software suite (5). Our analysis was performed in this way to be compatible with the supplementary tables reported in (6) for African Americans (AA), European-Americans (EA), and individuals of mixed African and European ancestry (AA-EA). The most important fact about ethnic stratification is that there were multiple examples of SNP sets containing varying mixes of subjects from different subpopulations for each disease sub-type in each of our three independent samples of subjects. For example, in the Molecular Genetics of Schizophrenia (MGS) sample, the SNP set 22-11 was represented by 48% AA and 52% EA, SNP set 21-8 by 55% AA and 45% EA, SNP set 31-22 by 53% AA and 47% EA, SNP set 54-51 by 79% AA and 21% EA, and SNP set 71-55 by 52% AA and 48% EA.

      In fact, all the SNP sets that appeared to be ethnically stratified (i.e., contained mostly AA or EA subjects in MGS sample, such as 56-30 or 42-37) replicated their association with specific phenotypic indicators of different classes of schizophrenia in subjects of another ethnicity in CATIE or in the Portuguese sample. Although concerns about ethnic stratification may be valid elsewhere, ethnic stratification had little impact on our results and cannot explain the robust association of specific SNP sets with specific phenotypic sets regardless of ethnicity or sample. These observations show the great utility of detailed consideration of phenotypic variability in individual people in our approach, compared to the sensitivity to confounding by population stratification in traditional GWAS when heterogeneous phenotypes are lumped together indiscriminately as cases. The concerns of B-S about ethnic stratification point out a limitation of traditional group-wise GWAS that is averted by our novel approach. We thank them for drawing attention to another strength of our approach, one that we did not have enough space to report previously.

      We will discuss population stratification in more detail together with our reply about linkage disequilibrium (see posting 5), and discuss significance testing following our comments on replication in later sections of our reply to Part 2 of their comments (see posting 6).
      


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    19. On 2014 Oct 06, C. Robert Cloninger commented:

      Two Distinct Perspectives and Methodological Approaches to GWAS

      We expected our paper uncovering the hidden risk architecture of the schizophrenias to be controversial because it takes a fundamentally new approach to solve problems that have plagued the field of medical genetics for more than a decade without resolution (1). We went through rigorous peer review regarding the method with experts in bioinformatics and genetics (2) and then again regarding the application of our new approach to the schizophrenias (1). The critical comments of Breen and other colleagues of Sullivan (B-S) highlight the fact that we have a fundamentally new approach with a distinct perspective and properties from the traditional method they have used for several years. It is important to understand how our novel approach differs from the traditional one in order to appreciate the opportunities it provides for the advancement of science.

      First, in our novel approach, common disorders are recognized to have a complex etiology in which multiple genetic and environmental variables interact in complex ways to influence the risk of disease in an individual person. B_S are experienced in approaches to genome-wide association studies (GWAS) that allow detection of only the average (additive) effects of individual genes in groups of people. We regard the traditional group-wise approach to GWAS as overly restrictive because it is well established that genes typically function in concert with one another, resulting in substantial epistasis in schizophrenia and many other common disorders (3). Fitness, health, and behavior are properties of persons, not genes. Nevertheless, the traditional approach can be useful when its a priori assumptions are satisfied. The traditional and novel approaches to GWAS should be viewed as being complementary perspectives and procedures.

      Second, our novel approach allows for the possibility of complex relationships between multilocus genotypes and multifaceted phenotypes. In other words, different sets of genetic polymorphisms can be associated with the same phenotype (“equi-finality” or genetic heterogeneity), and the same set of genetic polymorphisms can be associated with multiple distinct phenotypes (“multifinality” or pleiotropy). They focus only on heterogeneous groups of cases, neglecting phenotypic variability among cases. It is important to note that our novel approach does not make any a priori assumption that complexity is present, but we do allow it to emerge from the data when present, as occurred clearly in our analysis of multiple independent samples of people with the schizophrenias.

      Third, we carry out person-centered analyses that specify genotypic-phenotypic relationships within each individual by using clustering methods in which subjects are one matrix dimension and the other matrix dimension is either genotypic or phenotypic information. In other words, our analyses are informative about each individual, thereby providing a basis for identifying specific causes of illness in each person as a basis for tailoring treatment in a personalized way. In contrast, the traditional GWAS considers only average effects in groups of people, making it unjustified to say anything with confidence about a specific individual. Such traditional methods have failed to produce any reliable genetic test for the diagnosis of any psychiatric disorder in an individual person. In addition, phenomena such as population stratification and linkage disequilibrium may confound interpretation of the group-wise statistics of traditional GWAS, whereas these phenomena are easily evaluated in our person-centered approach.

      Fourth, our approach is entirely data-driven using machine learning and data mining procedures that are unbiased and unsupervised (i.e., no a priori assumptions are made). Such data-driven methods have been used successfully in many fields of science but not for GWAS prior to our work. In contrast, the a priori assumptions made in the traditional GWAS approach, as used by B-S, have produced only weak associations between the average effects of individual genes and the diagnosis of schizophrenia. In fact, Sullivan and others proposed the formation of the Psychiatric Genetics Consortium (PGC) to address the problem of weak and inconsistent associations. Unfortunately, even large samples still produce only weak associations (4). In addition, even large collections of subjects have encountered what is called the “missing heritability problem” in medical genetics: most of the variability in risk for the schizophrenias has remained unexplained. For example, the resemblance of monozygotic cotwins of people with schizophrenia is much greater than can be explained by the average effects of individual genes, indicating that multiple genes act in concert to influence risk (3). Whereas the heritability of schizophrenia is estimated to be 81% from twin studies, only about 25% of the variability has been explained by traditional GWAS.

      In contrast, by applying our novel approach to GWAS we observed that sets of single nucleotide polymorphisms (SNPs) allow identification of individuals at very high risk (70% or more) and replicated the findings consistently in three independent samples. Our results can explain much more about disease risk than traditional group-wise approaches, so we are not surprised that such strong findings may come as a shock to those who have become accustomed to the weak associations identified by traditional GWAS. Again, we expected that this would be very controversial, but we’re optimistic that this fundamentally new approach will open up many new opportunities for people interested in medical genetics. Our results were so unexpected that peer-reviewers demanded replication in independent samples before acceptance. Even we were delighted with the strong replication: 81% of 42 SNP sets associated with 70 to 100% risk of schizophrenia replicated almost exactly across three independent samples, and different SNP sets were associated with distinct phenotypic syndromes in which the gene products suggest possible pathways by which the functions and expression of the genes in the brain may explain the different clinical features of individual patients.

      In summary, traditional approaches to GWAS focus on the average effects of individual genes in groups of people, whereas our novel approach focuses on the interactive effects of groups of genes in an individual person. Consequently the differences between these two approaches have profound consequences for the way they view and handle phenomena like linkage disequilibrium, population stratification, and X-linkage. Unfortunately, Breen and colleagues have not adequately appreciated the profound differences between the traditional methods of GWAS with which they are familiar and the novel approach we have developed. As a result, the criticisms they made reflect their concerns about problems that regularly occur when a traditional group-wise approach is implemented, but these concerns may have minimal pertinence to our person-centered approach and findings.


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    20. On 2014 Oct 06, C. Robert Cloninger commented:

      None


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    21. On 2014 Oct 06, C. Robert Cloninger commented:

      Reply to Breen et al (their Part 1 of 2)

      On behalf of: C. Robert Cloninger, M.D., Ph.D. (Departments of Psychiatry and Genetics, Washington University School of Medicine, St. Louis, MO, USA); Igor Zwir, Ph.D. (Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Department of Computer Science and Artificial Intelligence, University of Granada, Spain); Gabriel A. de Erausquin, M.D., Ph.D. (Roskamp Laboratory of Brain Development, Modulation and Repair, Department of Psychiatry and Behavioral Neurosciences, University of South Florida, Tampa, FL, USA); Dragan M. Svrakic, M.D., Ph.D. (Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA); Coral del Val, Ph.D. (Department of Computer Science and Artificial Intelligence, University of Granada, Spain); Javier Arnedo, M.S. (Department of Computer Science and Artificial Intelligence, University of Granada, Spain); Rocío Romero-Zaliz, Ph.D. (Department of Computer Science and Artificial Intelligence, University of Granada, Spain); Helena Hernández-Cuervo, M.D., B.Sc. (Roskamp Laboratory of Brain Development, Modulation and Repair, Department of Psychiatry and Behavioral Neurosciences, University of South Florida, Tampa, FL, USA);

      The reply to the comments of Breen et al (their Part 1 of 2) from all of us responsible for analysis in the Arnedo et al article has the following three components which are posted separately as comments as follows: (1) Two Distinct Perspectives and Methodological Approaches to GWAS (2) The Facts about Ancestry and Population Stratification (3) The Facts about Gender and the X-chromosome

      The references for all the parts of our reply are included in the final postings about Part 2 of their comments (see posting 8 of our reply).


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    22. On 2014 Sep 28, Gerome Breen commented:

      Part 1 of 2. On behalf of Gerome Breen, PhD (Institute of Psychiatry, King’s College London, London, UK) * Brendan Bulik-Sullivan (Broad Institute, Cambridge, MA, USA) * Mark Daly, PhD (Broad Institute, Cambridge, MA, USA) * Sarah Medland, PhD (QIMR Berghofer, Brisbane, Australia) * Benjamin Neale, PhD (Broad Institute, Cambridge, MA, USA) * Michael O’Donovan, MD PhD (Cardiff University, Cardiff, UK) * Stephan Ripke, PhD (Broad Institute, Cambridge, MA, USA) * Patrick Sullivan, MD (Karolinska Institutet, Stockholm, Sweden) * Peter Visscher, PhD (University of Queensland, Brisbane, Australia) * Naomi Wray, PhD (University of Queensland, Brisbane, Australia) *

      • Authors ordered alphabetically, all made equivalent contributions

      In this study published on September 15, Arnedo et al. asserted that schizophrenia is a heterogeneous group of disorders underpinned by different genetic networks mapping to differing sets of clinical symptoms. As a result of their analyses, Arnedo et al. have made remarkable and perhaps unprecedented claims regarding their capacity to subtype schizophrenia. This paper has received considerable media attention. One claim features in many media reports, that schizophrenia can be delineated into “8 types”. If these claims are replicable and consistent, then the work reported in this paper would constitute an important advance into our knowledge of the etiology of schizophrenia.

      Unfortunately, these extraordinary claims are not justified by the data and analyses presented. Their claims are based upon complex (and we believe flawed) analyses that are said to reveal links between clusters of clinical data points and patterns of data generated by looking at millions of genetic data points. Instead of the complexities favored by Arnedo et al., there are far simpler alternative explanations for the patterns they observed. We believe that the authors have not excluded important alternative explanations – if we are correct, then the major conclusions of this paper are invalidated.

      Analyses such as these rely on independence in many ways: among variables used in prediction, absence of artifactual relationships between genotypes and clinical variables, and between the methods of assessing significance and replication. Below we identify five specific areas of concern that are not adequately addressed in the manuscript, each of which calls into question the conclusions of this study.

      A. Ancestry/population stratification.

      Two of the three samples the authors studied (MGS and CATIE) have substantial proportions of subjects of European and African ancestry. The third sample is from southern Europe. Ancestry is an extremely well known confounder in genetic studies with a great capacity to yield false associations. Correct inference from genomic data in samples like these requires exceptional care. In the analyses they present, there is almost no mention of how this known bias was addressed or evaluation of its impact on their results. In the samples they used, their references to sets of SNPs that track together is essentially the definition of uncorrected population structure/stratification. Indeed, a central component of their statistical methodology – nonnegative matrix factorization – has been previously employed as a method for ancestry inference in the population genetics literature (Englehardt and Stephens, PLoS Genetics, 2010, link below).

      We were unsuccessful in attempts to obtain the full list of SNPs that Arnedo et al. analyzed. Instead, we evaluated the SNPs listed in Table S3 (448 SNP entries, 245 unique SNPs as SNPs could be present more than once, and 237 SNPs with valid allele frequencies in HapMap3). We computed the absolute value of the difference in allele frequencies between the CEU (northwest European) and YRI (Yorubas from Nigeria) groups for all HapMap3 SNPs passing basic quality control (688K SNPs genotyped using Affymetrix 6.0 arrays to match the MGS sample). We then contrasted the SNPs used by Arnedo et al. with all other affy6 SNPs. The Table S3 SNPs had markedly larger differences between a European and an African group. The mean for the absolute difference in allele frequency was 0.27 for the Table S3 SNPs used by Arnedo et al. versus 0.19 for all other SNPs. These highly significant differences underscore our concerns about population stratification bias.

      B. X chromosome (chrX).

      We noted that 15 of 237 of the SNPs in Table S3 were on chrX (again, Table S3 contains a fraction of the SNPs used in the modeling). Inclusion of chrX SNPs will partly reflect the sex of participants. Arnedo et al. say in their supplement that they include sex as a covariate in their regressions, but they do not describe how they account for sex in their matrix factorization. For example, since males have only one copy of chrX, genotypes for males will be either 0 or 1 whereas chrX genotypes for females will be either 0, 1 or 2. This difference will be salient to clustering algorithms such as those employed by the authors, so it seems likely that some component of the clusters of individuals identified by Arnedo et al. simply reflect genotype differences between sexes rather than clinical features of schizophrenia. It is well-known in statistical genetics that the sex chromosomes require special handling, but this issue is not addressed by Arnedo et al.


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    1. On 2014 Oct 12, GianCarlo Panzica commented:

      Behavioral effects of the treatment are detailed in this paper: Lagunas N, 2010


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    1. On 2015 Apr 24, Melissa Raven commented:

      Inappropriate generalisation of mortality in mental disorders

      This paper is one of an increasing number that inappropriately and dramatically generalise mortality estimates from samples of patients in secondary and very often tertiary treatment for serious chronic mental disorders (in many cases psychotic disorders) to the much broader population of people with potentially diagnosable mental disorders, which are usually much less severe and are associated with much lower mortality.

      In this case, Mehta et al. have claimed that people with common mental disorders die 15-20 years earlier than people without such disorders. However, there is evidence of such a mortality gap only for people with chronic serious mental disorders (particularly psychosis) treated in secondary/tertiary settings. They have thereby grossly inflated the premature mortality associated with (and in effect attributable to) common mental disorders.

      This statement is the problem:

      'Interventions based on robust evidence with this approach have the potential to address a public health challenge that results in a 15–20 year premature mortality gap, in which 75% of people with common mental disorders receive no treatment,24,25 and which is increasingly sidelined as wellbeing policy ahead of the evidence.' (p. 3)

      Mehta et al.'s reference 24, Ormel et al. (2008, p. 370), supports the claim that 75% of people with common mental disorders receive no treatment (in high-income countries). So far so good.

      The source of the 15-20 year premature mortality gap statistic is neither of the two references cited. It is most likely Wahlbeck et al. (2011), which reported 'men with mental disorders still live 20 years less, and women 15 years less, than the general population' (p. 453). However, the sample was of people admitted to hospital for mental disorders. Wahlbeck et al. acknowledged that the patients were not representative of all people with mental disorders: 'Less serious non-hospitalised cases of mental disorders, possibly with a better life expectancy outcome, are not included' (p. 457).

      The Wahlbeck et al. study was cited by Thornicroft and Docherty (2014) in support of their claim of a 15-20 year mortality gap, in their chapter in the UK Chief Medical Officer's Annual Report (Davies 2014) (the focus of Mehta et al.'s paper):

      'men with mental disorders on average live 20 years less, and women 15 years less, than the general population' (p. 198)

      Davies prominently and uncritically repeated Thornicroft & Docherty's claim (without citing any references) in her chapter 1, in her rationale for focusing on population mental health:

      'There is an unacceptably large 'premature mortality gap': people with mental illness die on average 15–20 years earlier than those without, often from avoidable causes.' (p. 12)

      A box below that claim unequivocally states that 'Mental illness … includes common mental disorder (including anxiety and depression), which affects nearly 1 in 4 of the population, and severe mental illness, such as psychosis, which is less common, affecting 0.5–1% of the population', leaving no doubt that the mortality claim applies to common mental disorders.

      Mehta et al.'s reference 25 (Chang et al. 2010) did not report a mortality gap. However, another paper by several of the same authors (Chang et al. 2011) reported a somewhat smaller premature mortality gap (8 to14.6 years for men, and 9.8 to 17.5 years for women). [Clearly Mehta et al. have accidentally cited the wrong paper by Chang et al., making it harder to check the validity of their claim.] Again the sample was unrepresentative and biased towards more severe and more chronic cases. Chang et al. appropriately emphasised:

      'Potential limitations include the secondary healthcare setting; this should present no problem for high penetrance disorders, such as schizophrenia and bipolar disorder, where most cases will have received secondary care input. However, findings for substance use disorders and depressive disorders should be viewed with circumspection since those appearing on a secondary care register are likely to be an unrepresentative (and probably more severe) subset of community cases. Ultimately, the findings for life expectancy should be taken as referring to people with these mental disorders who had made contact with secondary mental health services within the given time period and are not necessarily applicable to all cases in a given community.' (p. 5)

      Mehta et al. (and Thornicroft & Docherty, and Davies) have ignored these authors' cautions. Their claim that people with common mental disorders die 15-20 years earlier than people without such disorders seriously misrepresents the evidence. It is ironic that Mehta et al.'s misleading sentence begins and ends with a focus on evidence, and occurs in a paper subtitled 'evidence-based priorities'. Similarly, it is ironic that this misleading claim is repeatedly emphasised in a report subtitled 'Investing in the Evidence'.

      See also my PubMed Commons comment about Walker et al.'s (2015) systematic review and meta-analysis of mortality in mental disorders http://www.ncbi.nlm.nih.gov/pubmed/25671328, which similarly inappropriately generalises mortality from treatment samples of severe cases to the broader population of people with potentially diagnosable disorders, and my more detailed comment about it in JAMA Psychiatry (Raven 2015).

      References

      Chang CK, Hayes RD, Broadbent M, et al. (2010). All-cause mortality among people with serious mental illness (SMI), substance use disorders, and depressive disorders in southeast London: a cohort study. BMC Psychiatry, 10, 77. http://www.biomedcentral.com/1471-244X/10/77

      Chang CK, Hayes RD, Perera G, et al. (2011). Life expectancy at birth for people with serious mental illness and other major disorders from a secondary mental health care case register in London. PLoS One, 6(5), e19590. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0019590

      Davies SC. (2014). Annual Report of the Chief Medical Officer 2013: Public Mental Health Priorities: Investing in the Evidence. London: Department of Health. https://www.gov.uk/government/publications/chief-medical-officer-cmo-annual-report-public-mental-health

      Mehta N, Croudace T, & Davies SC. (2014). Public mental health: evidenced-based priorities. Lancet, 385(9976), 1472-1475. http://www.sciencedirect.com/science/article/pii/S0140673614614008

      Ormel J, Petukhova M, Chatterji S, et al. (2008). Disability and treatment of specific mental and physical disorders across the world. British Journal of Psychiatry, 192(5), 368-375. http://bjp.rcpsych.org/content/192/5/368.long

      Raven M. (2015). Inappropriate use of epidemiological data in analysis of mortality in mental disorders , JAMA Psychiatry. [comment re Walker et al. 2015) http://archpsyc.jamanetwork.com/article.aspx?articleid=2110027#tab10

      Thornicroft G, & Docherty M. (2014). Chapter 12 Mind the gaps – treatment, funding, access and service provision. In S. C. Davies, Annual Report of the Chief Medical Officer 2013: Public Mental Health Priorities: Investing in the Evidence. London: Department of Health. 2014. https://www.gov.uk/government/publications/chief-medical-officer-cmo-annual-report-public-mental-health

      Wahlbeck K, Westman J, Nordentoft M, Gissler M, Laursen TM. (2011). Outcomes of Nordic mental health systems: life expectancy of patients with mental disorders. British Journal of Psychiatry, 199(6), 453-458. http://bjp.rcpsych.org/content/199/6/453

      Walker, ER, McGee R, & Druss BJ. (2015). Mortality in Mental Disorders and Global Disease Burden Implications: A Systematic Review and Meta-analysis. JAMA Psychiatry, 72(4), 334-341. http://archpsyc.jamanetwork.com/article.aspx?articleid=2110027


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    1. On 2017 Sep 30, Misha Koksharov commented:

      When using firefly luciferases as an output signal in synthetic biology circuits in bacteria, it is really beneficial to use thermostable versions because they are dramatically brighter at 37°C (and other elevated temperatures) - as exemplified on the following slide:

      http://forumbgz.ru/user/upload/file593017.jpg

      Though, when growing bacteria at common room temperatures (or lower) this is not that important (as can be seen above). The reason for these effects is relatively low thermostability of WT firefly luciferases (P. pyralis, L. mingrelica, etc) combined with poor efficiency of bacterial chaperones in keeping luciferase properly folded at elevated temperatures.


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    1. On 2017 Jun 16, Jacob H. Hanna commented:

      The first of three papers from Smith group describing human transgene free "Reset cells", have failed to describe ability to generate teratomas from "transgene free" cells. Mouse naive pluripotent cells have the intrinsic "self organizing capacity" to enter a formative/primed state after in vivo SC injection and make teratomas within 4-8 weeks. I find this stunning and scientifically disturbing and wonder whether the human "reset" cells being induced do not qualify to be annotated as pluripotent cells at all. I hope the authors can clearly point out and directly address this critical caveat.


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    1. On 2014 Sep 15, Samir Ounzain commented:

      Very nice editorial discussing the interesting observations recently published from the Yvan Devaux laboratory (Vausort M, Wagner DR, Devaux Y. Long Noncoding RNAs in Patients With Acute Myocardial Infarction. Circ Res. 2014 Sep 12;115(7):668-77. doi:10.1161/CIRCRESAHA.115.303836. Epub 2014 Jul 17. PubMed PMID: 25035150).

      The potential for lncRNAs to serve as biomarkers in cardiovascular disease is very exciting and warrants further investigation. In this editorial Skroblin and Mayr raise a couple of very interesting points that need further investigation and discussion.

      They state ''All selected lncRNAs have been identified in noncardiac tissues. This lack of cardiac specificity questions their usefulness as predictors of cardiac dysfunction. At best, measuring lncRNA expression in full blood might reflect inflammation at the site of MI''.

      We agree strongly with this statement and would like to emphasise that cardiac specific/restricted lncRNAs likely represent the most important candidates both as biomarkers but also as highly specific therapeutic targets for future manipulation. Indeed, we recently demonstrated that through utilising very deep RNA-sequencing coupled with ab initio transcript reconstructions it is possible to identify 1000s of novel heart specific lncRNAs. Importantly we feel sequencing to a high depth, in a very specific context (we sequenced to a depth of 400x106 PE-reads per sample in isolated border zones post myocardial infarction, as compated to 50x106 PE-reads used in most comparable studies)is critical for the idenfication of highly cell/tissue and context specific lncRNAs, that ultimately we believe will represent the most attractive biomarkers and therapeutic targets.

      It is worth noting that when utilising this approach, we found that novel previously unknown lncRNAs were both a) much more cardiac specific than mRNAs and annotated lncRNAs (indeed many exhibit cell type specificity within the heart, b) were better correlated with cardiac physiological traits vs cannonical biomarker mRNAs and annotated lncRNAs, supporting the notion novel heart enriched lncRNAs could represent very attractive biomarkers, c) were highly associated with unique heart specific chromatin signatures linked to active -cis control enhancers, again has implications in therapeutic settings as enhancer reprogramming post stress underpins the fetal activation of gene program that is implicated in pathological remodelling and finally d) using a novel approach to infer lncRNA functions based on developmental chromatin state transitions, we found that novel lncRNAs were highly enriched in functional clusters linked to very specific cardiac functional processes including contractility etc.

      Many of the novel lncRNAs we identified in this study were conserved in human, and we hope future studies will leverage our data for the identificaiton of novel heart specific biomarkers that may be circulating in the blood. Most studies to date have only assesed the annotated long non-coding transcriptome in this setting, and we believe our paper demonstrates that novel cardiac enriched lncRNAs are likely much more interesting candidates for analysis.

      Ounzain S, Micheletti R, Beckmann T, Schroen B, Alexanian M, Pezzuto I, Crippa S, Nemir M, Sarre A, Johnson R, Dauvillier J, Burdet F, Ibberson M, Guigó R, Xenarios I, Heymans S, Pedrazzini T. Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. Eur Heart J. 2014 Apr 30. [Epub ahead of print] PubMed PMID: 24786300.


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    1. On 2016 Nov 22, MICHAEL BALLARD commented:

      This is the republication of an article that was previously retracted from the Journal of Neuroscience. According to the authors' retraction notice, they: “...discovered errors in the quantification of the expression and/or phosphorylation of a subset of signaling pathways, particularly related to Figures 4 and 5D. Despite these errors, the major conclusions of the paper remain substantiated." The inaccurate figures and results have been excluded from this republication. The original, retracted version can be found on PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23658180 and at the Journal of Neuroscience site: http://www.jneurosci.org/content/33/19/8423.long


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    1. On 2014 Sep 15, Amanda Capes-Davis commented:

      The authors use the KB cell line to study autophagy in oral squamous cell carcinoma (OSCC). Please be aware that KB is cross-contaminated with the HeLa cell line and is cervical adenocarcinoma, not OSCC.

      Cell lines should be tested for cross-contamination, using a consensus method such as short tandem repeat (STR) profiling. For a list of known cross-contaminated cell lines, see http://iclac.org/databases/cross-contaminations/.

      Many journals now require authentication testing before publication. KB is extensively used in specialist oral journals such as J Oral Pathol Med. A requirement for authentication testing in these journals would make oral research more reliable and reproducible.


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    1. On 2014 Nov 24, Guillaume Filion commented:

      This article is one of the "CISCOM meta-analyses", which are very similar papers written by different authors. For more information about the CISCOM meta-analyses, check the blog post "A flurry of copycast on PubMed" at the following link http://blog.thegrandlocus.com/2014/10/a-flurry-of-copycats-on-pubmed


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    1. On 2014 Dec 30, MARK WEST commented:

      Comment on “Striatal firing rate reflects head movement velocity” by Namsoo Kim, Joseph W. Barter, Tatyana Sukharnikova and Henry H. Yin

      We read the experiments conducted by Kim et al. with enthusiasm. We feel that it is important to comment on previous studies that demonstrated a direct relationship between striatal activity and movement velocity, which Kim et al. support. Originally demonstrated in the nonhuman primate (DeLong, 1973), several studies in rodents have shown relationships between firing rates of dorsolateral striatal neurons and movement velocity. Kim et al. find that both putative dorsal striatal projection neurons and putative fast-spiking interneurons fire during head movements and exhibit a firing rate relationship with the velocity of head movement. Given our previous demonstration of firing rate correlations with head movement velocity in the subpopulation of dorsolateral striatal projection neurons selectively related to head movement (Pederson et al., 1997; Tang et al., 2007), it is interesting that firing of putative striatal interneurons also exhibits a relationship to movement velocity (although not subjected to sensorimotor examination of the entire body by Kim et al). We want to add information regarding dorsolateral striatal projection neurons, over half of which fire selectively in relation to activity of single body parts (Carelli and West, 1991; Cho and West, 1997), as revealed by sensorimotor examination of the entire body. These neurons exhibit movement properties which may have been outside the scope of the authors’ study. First, movement-related firing patterns are not limited to neurons phasically related to head movements, as they are found throughout the dorsolateral striatum containing single body part neurons. For instance, we have also demonstrated similar properties in neurons phasically related to vibrissae movement (Carelli and West, 1991), forelimb movement (Carelli et al, 1997) or tongue movement (Mittler et al., 1994; Tang et al., 2008). Second, each single body part neuron exhibits a preferred direction of movement. Third, though velocity of movement is a major predictor of firing rate change for many single body part neurons, not all these neurons are sensitive to velocity and some may be sensitive to one or a combination of several movement-related characteristics (e.g., movement length, movement position, etc). References: Carelli RM, West MO (1991) Representation of body by single neurons in the dorsolateral striatum of the awake, unrestrained rat. J Comp Neurol 309:231 249. Carelli RM, Wolske M, West MO (1997) Loss of lever press-related firing of rat striatal forelimb neurons after repeated sessions in a lever pressing task. J Neurosci 17: 1804-1814. Cho J, West MO (1997) Distributions of single neurons related to body parts in the lateral striatum of the rat. Brain Res 756:241-6. DeLong, MR (1973) Putamen: Activity of Single Units during Slow and Rapid Arm Movements, Science 179:1240-1242. Mittler T, Cho J, Peoples LL, West MO (1994) Representation of the body in the lateral striatum of the freely moving rat: Single neurons related to licking, Exp Brain Res 98:163-167. Pederson CL, Wolske M, Peoples LL, West MO (1997) Firing rate dependent effect of cocaine on single neurons of the rat lateral striatum. Brain Res 760:261-5. Tang C, Pawlak AP, Prokopenko V, West MO (2007) Changes in activity of the striatum during formation of a motor habit. Eur J Neurosci 25:1212-1227. Tang CC, Root DH, Duke DC, Zhu Y, Teixeria K, Ma S, Barker DJ, West MO (2009) Decreased firing of striatal neurons related to licking during acquisition and overtraining of a licking task. J Neurosci 29(44):13952-13961.


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    1. On 2015 Dec 11, Mark Johnston commented:

      An interactive protocol from this article is freely available at protocols.io.


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    1. On 2014 Oct 15, Amanda Capes-Davis commented:

      Kudos to the authors for their integrity in retracting this article. Cell lines ACCM and ACC2 are known to be misidentified; instead of arising from salivary gland, ACCM and ACC2 are actually HeLa, from cervical adenocarcinoma.

      For a list of known misidentified cell lines, see http://iclac.org/databases/cross-contaminations/.


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    1. On 2014 Sep 30, Ryan Radecki commented:

      Post-publication commentary:

      "Alas, Poor (Literally) Detroit"

      High-quality care can mean many things. In the ideal sense, it conveys cooperation and coordination between the many facets of healthcare delivery – great physician care, the best possible translation of medical evidence to an individual patient, outstanding nursing, electronic systems that double-check and triple-check for safety, and an army of staff to support patients in all settings to ensure best possible health.

      Or, high-quality care can just be a number. A surrogate number, obliquely related to the ideals of quality care....

      http://www.emlitofnote.com/2014/09/alas-poor-literally-detroit.html


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    1. On 2014 Dec 21, Massimiliano Tognolini commented:

      Dear Colleagues, I do not want to discuss the connection between Alzheimer’s disease and EphA4 when demonstrated with biological tools (siRNA, mutant mice, peptides, antibodies…) in vitro or in vivo. However, major concerns raises when rhynchophylline was used. Its pharmacological characterization was very weak and flaws were present. More details are reported as comment of original paper: http://www.ncbi.nlm.nih.gov/pubmed/?term=epha4+ameliorates


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    1. On 2014 Sep 30, Ryan Radecki commented:

      Post-publication commentary:

      "Are a Third of Research Conclusions Wrong?"

      As I covered last year, half of what you’ve been taught in medicine is wrong – we just don’t know which half.

      And, it turns out, sometimes even the same authors taking a second look at the same data as before, can come up with new – and wildly different – conclusions.

      This is a review of 37 randomized-controlled trials published after 1966 paired with 37 “re-analyses” of the same data. These trials span the entire medical domain, from mycophenolate therapy after cardiac transplantation to homeopathy for fibrosis. Of these 37 re-analyses, 32 of them involved authors from the original research group. These re-analyses differed by changing statistical techniques, outcome definitions, or other study interpretation methods....

      http://www.emlitofnote.com/2014/09/are-third-of-research-conclusions-wrong.html


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    1. On 2017 Aug 11, Kerin Tyrrell commented:

      The genus Alistipes is characterized as an obligate anaerobe and asaccharolytic; however, this study describes the new species as microaerophilic and "asaccharolytic" although "Activities present are α-glucosidase, β-glucosidase, N-acetyl-β-glucos-aminidase, mannose and rafinnose (sp) fermentation". Can the authors please comment?


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    1. On 2017 Aug 07, Seán Turner commented:

      Both Enorma timonensis Ramasamy et al. 2016 [PMID 25197477] and Collinsella massiliensis Padmanabhan et al. 2016 [PMID 25197489] are described as Gram-positive, non-motile, non-sporulating rods isolated from the feces of a 53 year-old woman in an intensive care unit. Their genomes are >99.9% similar, identical within the limits of sequencing/assembly error. They should be considered heterotypic synonyms.

      Strain CSUR P902 is cited as the type strain of both "Corynebacterium ihumii" Padmanabhan et al. 2014 [PMID 25197488] and Collinsella massiliensis Padmanabhan et al. 2016 [PMID 25197489].


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    1. On 2017 Aug 07, Seán Turner commented:

      Strain CSUR P902 is cited as the type strain of both "Corynebacterium ihumii" Padmanabhan et al. 2014 [PMID 25197488] and Collinsella massiliensis Padmanabhan et al. 2016 [PMID 25197489].


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    1. On 2017 Aug 07, Seán Turner commented:

      Both Enorma timonensis Ramasamy et al. 2016 [PMID 25197477] and Collinsella massiliensis Padmanabhan et al. 2016 [PMID 25197489] are described as Gram-positive, non-motile, non-sporulating rods isolated from the feces of a 53 year-old woman in an intensive care unit. Their genomes are >99.9% similar, identical within the limits of sequencing/assembly error. They should be considered heterotypic synonyms.


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    1. On 2015 Sep 28, Donald Forsdyke commented:

      General Principle of Juxtaposition- and Concentration-Dependent Activation of Complement

      Seeking to understand "immune system … ability to discriminate self from nonself," the authors here describe an elegant “clustering-based mechanism” for complement activation by MBL that is “akin to the mechanism governing signaling through many cellular receptors,” and distinguishes the lectin and classical pathways of complement activation (1). Their demonstration of the general principle of “juxtaposition- and concentration-dependent activation,” is in keeping with studies with the MBL, concanavalin-A, that were reported in 1977 (2).

      However, the latter studies were not mentioned (1), and a new review states that “the ‘lectin pathway’ was discovered in the early 1980s” (3). Thus, it is possible that those engaged in this fascinating field are unaware of the earlier work that began to be reported in 1970 (4). Subsequent studies in the 1970s (5-8) culminated in demonstration of “the importance of the sequence of binding events” (9). It is to be hoped that the full relationship of our earlier work to modern studies will be determined in future work.

      (1) Degn SE, et al. (2014) Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes. Proc. Natl. Acad. Sci. USA 111:13445-13450.

      (2) Forsdyke DR (1977) Role of receptor aggregation in complement-dependent inhibition of lymphocytes by high concentrations of concanavalin-A. Nature 267:358-360. Forsdyke DR, 1977

      (3) Thielens NM, Gaborlaud C, Thiel S (2015) Complement: classical and lectin pathways. In: eLS John Wiley & Sons, Chichester.

      (4) Milthorp P, Forsdyke DR (1970) Inhibition of lymphocyte activation at high ratios of concanavalin A to serum depends on complement. Nature 227:1351-1352. Milthorp P, 1970

      (5) Milthorp P, Forsdyke DR (1973) Serum factors affecting the incorporation of (3H)uridine by lymphocytes stimulated by concanavalin A. Studies of the role of complement. _Biochem. J. 132:803-812.Milthorp P, 1973

      (6) Milthorp P, Forsdyke DR (1973) A comparison of the activation of thymus and lymph-node cells by concanavalin A and phytohaemagglutinin. Effects of complement. J. Immun. Meth. 2:269-277.Milthorp P, 1973

      (7) Forsdyke DR (1978) Role of complement in the toxicity of dietary legumes. Med. Hypoth. 4:97-100 Forsdyke DR, 1978

      (8) Forsdyke DR, Milthorp P (1979) Early onset inhibition of lymphocytes in heterologous serum by high concentrations of concanavalin-A. Further studies of the role of complement with suramin and heated serum. Int. J. Immunopharmacol. 1:133-139.Forsdyke DR, 1979

      (9) Forsdyke DR (1980) Lectin pulses as determinants of lymphocyte activation and inactivation during the first six hours of culture: sequential action of concanavalin-A and complement cause cell lysis. Can. J. Biochem. 58:1387-1396. Forsdyke DR, 1980


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    1. On 2014 Nov 22, IRWIN FEINBERG commented:

      Giedd et al suggest that the changes they measured longitudinally in MRI-estimated cortical volume (and in cortical thickness in previous reports) might index synaptic proliferation and elimination. This seems implausible. As the authors of this study likely recognize, changes in dendritic spines are well-below the limits of current MRI resolution. In addition, the trajectories and magnitudes of the MRI changes deviate from those of the best available data for synaptic density (Huttenlocher 1979). Synaptic density is falling steeply while MRI cortical measures are changing only slightly across adolescence. Although Huttenlocher’s synaptic density data do not contain measurements during adolescence, they do show a 40 to 50% drop off from late childhood to early adulthood, much larger than the 10-15% decline in gray matter volume reported by Giedd et al. There are other brain measures (cortical metabolic rate and NREM delta amplitude) with cross-sectionally measured trajectories that visually and statistically more closely parallel the synaptic density data and might therefore better index this developmentally critical brain variable (Feinberg, Thode et al. 1990). The NREM delta trajectories have recently been confirmed in a longitudinal study which also identified ages 12-16.5 yrs as a period of accelerated brain maturation (Campbell and Feinberg 2009). In contrast to the sleep EEG, MRI measures do not reveal any period of accelerated change, nor would one expect this in post-natal measures of brain structure.

      While I do not believe the MRI studies index synaptic elimination, I strongly agree with Giedd et al that it is critical to establish the cellular basis of the developmental MRI changes. (Our laboratory has also emphasized this point (Campbell and Feinberg 2009)). However, it is unlikely that animal studies of the sort proposed by Giedd et al could provide conclusive answers because of species differences. For example, cortical synaptic development in monkeys is isochronic rather than heterochronic as in humans ((Rakic, Bourgeois et al. 1986)). What is urgently needed is a large scale multisite replication of Huttenlocher’s heroic, post-mortem study of human brains. New investigations could include biochemical as well as ultramicroscopic measures of dendritic components and morphology. Such data could also fill in the age gaps in Huttenlocher’s dataset, providing more detailed maturational trajectories for synaptic connectivity. In addition, when ante-mortem MRI studies are available, they could be related to the post-mortem findings, so that the anatomic basis of developmental MRI changes could be determined. Replications lack research glamor. In this instance, however, a replication (and major extension) is urgently needed to understand existing findings and to provide a firm foundation for interpreting MRI and other studies of post-natal brain development.

      Campbell, I. G. and I. Feinberg (2009). "Longitudinal trajectories of non-rapid eye movement delta and theta EEG as indicators of adolescent brain maturation." Proceedings of the National Academy of Sciences of the United States of America 106(13): 5177-5180, PMID 19307577.

      Feinberg, I., et al. (1990). "Gamma distribution model describes maturational curves for delta wave amplitude, cortical metabolic rate and synaptic density." Journal of Theoretical Biology 142(2): 149-161, PMID 2161971.

      Huttenlocher, P. R. (1979). "Synaptic density in human frontal cortex - developmental changes and effects of aging." Brain Research 163(2): 195-205, PMID 427544.

      Rakic, P., et al. (1986). "Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex." Science 232(4747): 232-235, 3952506.


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    1. On 2014 Sep 13, Hilda Bastian commented:

      The authors make an important point: just because a systematic review has not assessed publication bias (PB), it does not mean that there is none.

      However, in this study, there were only 36 reviews that did not assess publication bias, and nearly half of those were in the minority subset of reviews that didn't have a comprehensive search strategy. For many, a comprehensive search strategy is a defining characteristic of a systematic review (e.g. in DARE, the Database of Reviews of Effects). Those reviews may not be able to provide an adequate overview of published studies, either.

      The authors point out that a limitation of their study is that there were many (planned) subgroup analysis - and it's on a small number of reviews. Especially as the number of adequately systematic reviews was small, the exclusion of the Cochrane Database of Systematic Reviews - a journal that publishes systematic reviews and was eligible for their study - is disappointing. The reason given for the exclusion was because the results of the (Moher D, 2007) study showed that publication bias "is regularly performed in articles published in this database." However the authors of that study concluded the assessment of publication bias was disappointing overall. For Cochrane reviews in that study, publication bias was assessed (or intended to be assessed) in only 32% of those reviews (and it was considered in another 39%).

      (Disclosure: I work on projects related to systematic reviews at the NCBI (National Center for Biotechnology Information, U.S. National Library of Medicine.)


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    1. On 2014 Sep 29, Allan Frey commented:

      I am a scientist and was an editor of a major biological journal for several years. A portion of my basic research involved the use of very low intensity microwave radiation as a tool to study the function of biological organisms. This latter resulted in numerous published journal articles, book chapters and a book.

      The authors of the Koyama et al journal article (1) present a rather peculiar exercise that they did. It appears that they wanted to gather some data and present it in a cell phone context as though it has relevance to cell phones. They lead off their abstract and also lead off their introduction talking about cell phones. Their extensive interpretations of their data are not relevant to cell phones and thus the article is misleading from a Public Health perspective.

      It appears that they used a microwave oven frequency signal generator to produce an unmodulated signal. Such a signal is suitable for a study on heating tissue, not for a study which starts off discussing cell phones. Since cell phones use modulated signals, a cell phone relevant study requires a modulated signal and also requires a relevant carrier frequency. There is an enormous amount of published biological data that shows that the biological effects are different when one uses an unmodulated oven type signal instead of a modulated signal with a relevant carrier frequency. This is well known; it was even brought out in my book that was published 20 years ago (2).

      There appear to be other major faults in their exercise that make it irrelevant to cell phone research and possibly other research. But since their energy frequency and modulation were inappropriate and this, in itself, discredits their discussing it in the context of cell phones, there is no need to discuss other faults in their exercise.

      1. Koyama S, Narita E, Suzuki Y, Taki M, Shinohara N, Miyakoshi J. Effect of a 2.45-GHz radiofrequency electromagnetic field on neutrophil chemotaxis and phagocytosis in differentiated human HL-60 cells.J Radiat Res. 2014 Sep 5. pii: rru075. PMID 25194051. [Epub ahead of print]

      2. Frey AH. Ed. On the nature of electromagnetic field interactions with biological systems. R. G. Landes Co., Austin, 1994


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    1. On 2016 Feb 21, Daniel Corcos commented:

      It would be interesting to know the prevalence of mammography in recent vs earlier birth cohort. Epidemiological evidence suggest a strong effect of mammography in triggering breast cancer in these populations. http://www.ncbi.nlm.nih.gov/pubmed/25082516/#comments


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    1. On 2016 Mar 18, ZHONGMING ZHAO commented:

      My lab recently moved to the University of Texas Health Science Center at Houston. The software is now available at https://bioinfo.uth.edu/DESnowball/.


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    1. On 2014 Nov 24, Guillaume Filion commented:

      This article is one of the "CISCOM meta-analyses", which are very similar papers written by different authors. For more information about the CISCOM meta-analyses, check the blog post "A flurry of copycast on PubMed" at the following link http://blog.thegrandlocus.com/2014/10/a-flurry-of-copycats-on-pubmed


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    1. On 2015 Sep 16, F Morceau commented:

      Despite HL-60 cells are classified in APL they do not express PML-RARa:

      Cell. 1993 Aug 13;74(3):423-31. The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Grignani F et al.,


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    1. On 2017 Oct 10, A. Mesut Erzurumluoglu commented:

      We seem to have found the same results (i.e. same nonsense variant in CCDC151 and same disease phenotype) round about the same time (check "Manuscript Received" dates of both papers, May/June 2014) but it seems our cilia ultrastructure photos do not match exactly. Maybe something to look into for future research...

      Our paper's (Alsaadi and Erzurumluoglu et al, 2014) URL: http://onlinelibrary.wiley.com/doi/10.1002/humu.22698/abstract


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    1. On 2015 Jun 30, thomas samaras commented:

      This an excellent report on the relation between nutrition, genes and socioeconomic factors on height. Unfortunately,a worldwide taller height has harmful ramifications and the assumption that reaching our genetic potential is beneficial has not been explored by most researchers. For example, we have the genetic potential to weigh 300 lb (136 kg) but we know this would create a lot of health and environmental problems. Therefore, we shouldn't assume that reaching our genetic potential for height is desirable.

      The 2007 WCRF report stated that as a result of industrialization and urbanization, chronic diseases have increased along with growth in height and weight. The lack of Western chronic disease before industrialization also applied to the elderly. WHO also attributed our chronic diseases to the Western diet. Many studies have found pre-Western people following traditional diets have very few Western diseases even at older ages. Many of these populations were found to be short and free of coronary heart disease and stroke.

      While demographers and epidemiologists have associated increased height with better health and longevity, many biologists, gerontologists and other researchers have found smaller body size is best for a healthy and long life. Many biological mechanisms support their conclusions.

      Research on the ramifications of increasing human height covers over 40 years. The evidence is solid that slower growth, later sexual maturation and shorter height promote health and longevity. As Levine recently reported, animal protein is not best for good health. See below.

      Note that Levine’s study finds higher protein is tied to a 4 times increase in type 2 diabetes for all ages over 50 years. Also animal protein after 65 years of age is good for us only if it doesn’t increase IGF-1 levels. The paradox is that animal protein increases IGF-1 per their own study, but other researchers have found plant protein reduces it somewhat.

      A few papers for further reading are listed next.

      Further reading

      1 Levine, Longo, Fontana, et al. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. March, 2014, Cell Metabolism,19, 407-417.

      2 Samaras TT. Evidence from eight different types of studies showing that smaller body size is related to greater longevity. Journal of Scientific Research & Reports. 2014: 3 (16): 2150-2160, 2014; article no. JSRR.2014.16.003.

      3 Samaras TT (ed): Human Body Size and the Laws of Scaling: Physiological, Performance, Growth, Longevity and Ecological Ramifications. New York: Nova Science Pub; 2007.

      4 He Q, Morris BJ, Grove JS, Petrovitch H, Ross W, Masaki KH, et al. Shorter men live longer: Association of height with longevity and FOXO3 genotype in American men of Japanese ancestry. Plos ONE 9(5): e94385. doi:10.1371/journal.pone.0094385.

      5 Salaris L, Poulain M, Samaras TT. Height and survival at older ages among men born in an inland village in Sardinia (Italy), 1866-2006. Biodemography and Social Biology, 58:1, 1-13.

      6 Bartke A. Healthy Aging: Is Smaller better? A mini-review. Gerontology 2012; 58:337-43.

      7 Thomas Samaras, Commentary: Human growth, height, size: Reasons of be small. WPHNA World Public Health Nutrition Association, vol. 2, No. 3, March 2011.

       8 Samaras,Thomas T. Why Smaller Humans Are in Our Future, Policy Innovations, 10/20/2014


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    1. On 2016 Oct 11, Gillian Parker commented:

      It would be good to look at this paper alongside Julia Twigg's classification, similarly developed from qualitative research in the late 1980s (see https://www.cambridge.org/core/journals/journal-of-social-policy/article/models-of-carers-how-do-social-care-agencies-conceptualise-their-relationship-with-informal-carers/257776AD70ADD40F45683DF45086813A).

      There are echoes here of her model of how service providers view carers: as resources; as co-workers; and or as co-clients (with the person they are caring for).

      There are even stronger echoes of Lewis and Meredith's work (Daughters Who Care, 1988; London:Routledge ISBN 0-415-00682-1) where, again based on qualitative work, they classified three types of response to caring: balancing care; integrating care; and immersion in care.

      It would be good to think about how all three models/typologies stack up with each other, across different types of carers in different circumstances, and across time!


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    1. On 2014 Nov 20, Bernard Carroll commented:

      This report breaks some new ground in design – the between-site train-and test exercise and the cross-validation of case assignment to unipolar or bipolar groups. As the authors stated, the data are not sufficiently strong for clinical use. My comments are intended to improve the quality of reporting of this and similar studies.

      1. There is selective highlighting of some results and a failure to present all the important findings clearly. In particular, the performance of the classification algorithms in distinguishing patients from normal control subjects was relegated to the Supplementary Material. It can be calculated from eTable 7 that between 27.5% and 38% of controls would be misclassified in the 1-way comparison with unipolar depressed cases. The corresponding Kappa coefficients of concordance would be fair at 0.48 for the SVM method and poor at 0.28 for the GPC method. Results for the bipolar contrast with control subjects were similarly weak. If the method cannot do better than this with normal subjects then clinical use is a very long way away. These sobering data properly belong in the main body of the paper.

      2. The cross-site training - testing results for the algorithms were described as “highly significant” (page 1226). Actually, for the train (Munster) and test (Pittsburgh) exercise the Kappa values that can be calculated from Table 3 were weak at 0.28 for SVM and 0.24 for GPC methods. They were only slightly better for the Pittsburgh – Munster exercise (Kappas each 0.38).

      3. P-values were given in Table 3 and in eTables 5,6,7 – but there is no statement of what statistical analyses generated these P-values. Were they Goodness of Fit Chi-squared tests? Standard tradecraft requires that such analyses be clearly described.

      4. No correction of P-values was made for multiple comparisons. That is another aspect of standard tradecraft.

      5. No data were shown for test-retest reliability of the algorithm-derived group assignments.

      6. All the analyses were predicated on the untenable assumption that the clinical diagnoses were 100% accurate. As the DSM-5 field trials taught us, that is far from the case in the real world of clinical assessment – the Kappa value for major depressive disorder diagnoses averaged over 4 sites was poor at 0.28 (Regier et al 2013). The authors failed to consider whether this confound degraded the strength of their findings (see a discussion of this issue in Carroll BJ 1989). At the very least, a statement of diagnostic reliability for the cases in this study is needed.

      References

      Carroll BJ. Diagnostic validity and laboratory studies. Rules of the game.<br> In: The Validity of Psychiatric Diagnosis, eds., L.N. Robins and J.E. Barrett, Raven Press, New York, 1989, pp. 229-245.

      Regier DA et al. DSM-5 Field Trials in the United States and Canada, Part II: Test-Retest Reliability of Selected Categorical Diagnoses. Amer J Psychiatry 2013; 170: 59-70.


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    1. On 2014 Sep 11, Samir Ounzain commented:

      Very nice piece of work from the Visel and Pennacchio laboratories. Enhancer-templated ncRNA transcription is emerging as a common feature associated with active tissue specific enhancers. We have recently using the excellent ChIP-Seq data sets generatated by this laboratory made similiar observations specifically within the heart in various in vivo and in vitro models of cardiac differentiation and pathological remodelling. Interestingly many of these enhancers are not only templating eRNAs, as described in this study, but also PolyA+, unidirectional and multi-exonic lncRNAs. Furthermore loss of function demonstrates these enhancer templated lncRNAs are critical for the regulation of enhancer target coding genes.

      I would be fascinated to see how many of the TSTRs identified in this study are producing spliced lncRNAs and furthermore if loss-of-function leads to repressed enhancer activity on target genes.

      Great work and I look forward to future studies from this group exploring these possibilities.

      For those more interested in heart specific enhancer templated lncRNAs, please refer to our recent publications.

      Ounzain, S., Micheletti, R., Beckmann, T., Schroen, B., Alexanian, M., Pezzuto, I., Crippa, S., Nemir, M., Sarre, A., Johnson, R., et al. (2014a). Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. European heart journal.

      Ounzain, S., Pezzuto, I., Micheletti, R., Burdet, F., Sheta, R., Nemir, M., Gonzales, C., Sarre, A., Alexanian, M., Blow, M.J., et al. (2014b). Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease. Journal of molecular and cellular cardiology 76C, 55-70.


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    1. On 2015 May 12, University of Lausanne Genomics, Ecology and Evolution Journal Club commented:

      This paper presents very interesting example of adaptive radiation analysis. This is a summary of the discussion at our journal club. Authors aimed to understand the molecular mechanisms and genetic changes underlying phenotypic diversity in African cichlid fish. For this purpose, they sequenced the genomes of five lineages of African cichlids, including an ancestral lineage with low diversity, and analyzed six closely related species underwent recent radiation from Lake Victoria. According observed results, authors postulate that multiple evolutionary mechanisms, such as increased gene duplication, accelerated evolution of coding and regulatory elements, regulation of gene expression by novel microRNAs and transposons insertion, retention of ancient polymorphism, together with relaxed purifying selection can trigger rapid diversification in African cichlids. However, Figure 2 and some figures presented in supplementary information are unclear. It is not clear that application of three different analyses for investigation of gene duplicates was necessary due to evident constraints of methods and expected low level of overlap between results. In any case, this paper provides a great resource to extend our understanding of adaptive radiation.


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    1. On 2014 Sep 08, Raha Pazoki commented:

      Inflammation in Arrhythmia

      The role of inflammation in risk of arrhythmia is still unclear and the study by Lazzerini and colleagues Lazzerini PE, 2015 demonstrate important findings. Systemic inflammation as reflected by a rise in serum inflammatory biomarkers has been linked to arrhythmia and sudden cardiac death in the setting of other diseases such as myocardial infarction Elmas E, 2008 where the majority of fatal arrhythmia occurs. The question that is arisen by this study is that whether treatment of other types of systemic or local inflammation as is during myocardial infarction prevents arrhythmia and sudden cardiac death?


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    1. On 2014 Sep 16, Serge Ahmed commented:

      In this new Shattuck Lecture, Eric Kandel and Denise Kandel (K2) announce that they will let science speaks for itself about the role of “nicotine as a gateway drug” to other drug addictions and will not distort “what science does and does not tell us” about this controversial matter, as many others would generally do.

      However, this paper is more about cross-sensitization between nicotine and other drugs in mice than about “nicotine as a gateway drug” to other drug addictions in human populations. Basically, K2 present evidence showing that forced pre-exposure to nicotine can enhance the proportion of individual mice that become sensitive to the stimulant and rewarding effects of a low dose of cocaine. In fact, after nicotine pre-exposure, a large majority of mice become sensitized to cocaine (i.e., up to 78-98% of mice). This proportion contrasts with the small minority of cigarette smokers who go on to develop cocaine addiction in human populations (i.e., 20%). This large discrepancy complicates the extrapolation between mice and humans but is ignored by K2. Would it imply that nicotine-exposed mice are more vulnerable to cocaine addiction than cigarette smokers? Or, more likely, would it indicate that nicotine-induced sensitization to cocaine per se should not be confused with cocaine addiction?

      Research on cross-sensitization between different drugs, including nicotine and cocaine, in rats and mice were very popular among addiction researchers in the 80s and 90s. However, because drug sensitization is clearly not drug addiction, these studies have since been replaced by other, more valid animal models of drug addiction. This research is entirely ignored by K2. Thus, it remains to be demonstrated whether and to what extent initial nicotine self-administration in mice or rats can increase the proportion of individuals that develop more relevant behavioral features of cocaine addiction. Thus, we are back to the initial “scientific question of the role of nicotine as a gateway drug” to other drug addictions.

      It is perhaps the privilege of a Nobel laureate (Eric Kandel is one of the recipients of the 2000 Nobel Prize in Physiology or Medicine) to write on any subject matter by ignoring the relevant work of most other prize-free scientists. Ironically, however, a laureate is awarded this prize precisely because many other scientists have recognized the importance and relevance of his/her own previous work.

      Reading this Shattuck lecture, one is reminded of the novel “Pierre Menard, author of The Quixote” by Jorge Luis Borges. This novel illustrates how knowing the author of a text can dramatically impact our reading and interpretation of it. So I propose the following test for the interested reader. Please try to read this article as if it had not been co-authored by Eric Kandel. I bet that you will be surprised by how little this article contributes to the scientific question that it seeks to address.


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    1. On 2014 Sep 07, Jonathan Eisen commented:

      I wrote a blog post about this article for the microbiology of the Built Environment network blog. See Nice summary of the Earth Microbiome Project by Gilbert et al..

      Also I then asked the 1st author pif the paper to discuss the history behind the paper which he did in this blog post: Behind the scenes at the Earth Microbiome Project.


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    1. On 2014 Nov 24, Guillaume Filion commented:

      This article is one of the "CISCOM meta-analyses", which are very similar papers written by different authors. For more information about the CISCOM meta-analyses, check the blog post "A flurry of copycast on PubMed" at the following link http://blog.thegrandlocus.com/2014/10/a-flurry-of-copycats-on-pubmed


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    1. On 2015 Feb 27, Geriatric Medicine Journal Club commented:

      This interesting randomized trial of melatonin to prevent incident delirium following hip fracture was discussed at the October 2014 Geriatric Medicine Journal Club (follow #GeriMedJC on Twitter). The full transcript of the discussion can be found here: http://gerimedjc.blogspot.com/2014/11/gerimedjc-october-31-2014.html?spref=tw Highlights of the discussion include the disappointment in the negative result but that this may not be the end of the melatonin and delirium story.


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    1. On 2014 Sep 20, Ryan Radecki commented:

      Post-Publication Peer Review:

      "Patient Satisfaction: It’s Door-to-Room Times (Duh)"

      As customer satisfaction becomes rapidly enshrined as our reimbursement overlord, we are all eager to improve our satisfaction scores. And, by scores, I mean: Press Ganey.

      So, as with all studies attempting to describe patient satisfaction, we unfortunately depend on the validity of the proprietary Press Ganey measurement instrument....

      http://www.emlitofnote.com/2014/09/patient-satisfaction-its-door-to-room.html


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    1. On 2015 Nov 16, Raphael Stricker commented:

      Response to the Study of Fallon et al.

      Jyotsna S. Shah PhD, Nick S. Harris PhD

      IGeneX Reference Laboratory, Palo Alto, CA

      November 15, 2015

      The analysis of Lyme disease serologic testing by Fallon et al. [1] reported that “Specialty Lab B” had an overall Borrelia burgdorferi test specificity of 42.5%. We therefore asked Dr. Fallon to send us the key for the study samples that were tested by “Specialty Lab B”, and we reviewed the data for all positive and negative samples.

      In the study by Fallon et al., it is notable that two-tier testing endorsed by the Centers for Disease Control and Prevention (CDC) had a sensitivity of only 48.6% for patients with persistent symptoms following Lyme disease treatment, similar to the low sensitivity described in the medical literature [2]. In contrast, if both the IgM and IgG Western blot (WB) results are considered positive, 33 of 37 patients (89%) with persistent Lyme disease symptoms were positive by “Specialty Lab B” interpretation.

      “Specialty Lab B” includes bands 31 kDa (Osp A) and 34 kDa (Osp B) in its interpretation of WB results [3]. Antibodies to these proteins are present later in the disease [4] as well as in patients vaccinated with the now-defunct Osp A vaccine. In addition, “Specialty Lab B” uses two strains of B. burgdorferi (B31 and 297) to make WB strips. In strain 297, the 39 kDa antigen is well expressed [5], whereas in strain B31 expression of the 39 kDa antigen can vary between 4-50% [4, 6]. These factors may explain the higher WB sensitivity of “Specialty Lab B”.

      According to the revised interpretive criteria of “Specialty Lab B”, a WB is considered positive if two of the following six bands are reactive with patient serum: 23-25 kDa (Osp C), 31 kDa (Osp A), 34 kDa (Osp B), 39 kDa (BmpA), 41 kDa (Flagellin) and 83-93 kDa. However at position 31 kDa on the WB, a non-specific protein co-migrates with Osp A [3]. Therefore both the IgM and IgG WBs are reported as indeterminate if only bands 31 kDa and 41 kDa are present. Likewise, it is known that some viral antibodies cross-react with the 83-93 kDa B. burgorferi antigen. Therefore the IgM WB is reported as negative if only bands 41 kDa and 83-93 kDa are present, and an indeterminate IgM WB is reported if only bands 31 kDa and 83-93 kDa are present. Thus “Specialty Lab B” offers the option to retest using a recombinant Osp A antigen WB to clarify whether a positive band at 31kDa indeed represents reactivity to B. burgdorferi or not.

      “Specialty Lab B” reported a significantly higher number of “healthy” controls (23/40) as positive compared to other labs. In contrast, only one “healthy” control was positive by two-tier test criteria. Of the 23 positive “healthy” controls, three had insufficient samples for retesting and therefore were excluded from further analysis. Three control samples with bands 41 kDa and 83-93 kDa on IgM WB were considered negative. The remaining 17 samples were tested with recombinant antigen WBs. Thirteen, including two positive by CDC two-tier criteria, had B. burgdorferi-specific antibodies. Two sera with a band at 31 kDa on WB were considered negative as they did not test positive on the Osp A recombinant antigen WB. Therefore 13/37 healthy controls had B. burgdorferi specific antibodies, and only two had a false-positive WB. Thus the performance of the WB by “Specialty Lab B”, when using revised interpretation criteria and recombinant antigen WB, demonstrates a specificity of 91.7%.

      According to the study by Fallon et al. [1], the sensitivity of Lyme disease antibody testing was 48.6% in the best laboratories using CDC two-tier criteria. In an effort to improve that sensitivity, “Specialty Lab B” uses additional band criteria to raise its combined IgM and IgG WB sensitivity to 89% [3]. Considering the significant underdiagnosis of Lyme disease based on poor two-tier test sensitivity, it is important to improve this sensitivity so that clinical cases of Lyme disease will not be missed.

      Lyme serology continues to be problematic and we continue to look for ways to improve sensitivity and specificity. In particular, the specificity of the tests is problematic because people living or traveling to endemic areas can have antibodies without disease [7], and antibodies of other diseases can cross-react with B. burgdorferi antigens. Therefore analysis of clinical history and symptoms is essential for the accurate diagnosis of Lyme disease. We agree with the conclusions drawn by Fallon et al. [1] that interlaboratory variability is considerable and remains a problem in Lyme disease testing.

      References

      1.Fallon BA, Pavlicova M, Coffino SW, Brenner C. A comparison of Lyme disease serologic test results from four laboratories in patients with persistent symptoms after antibiotic treatment. Clin Infect Dis. 2014; 59:1705-10.

      2.Stricker RB, Johnson L. Lyme disease diagnosis and treatment: Lessons from the AIDS epidemic. Minerva Med 2010;101:419-25.

      3.Shah JS, Du Cruz I, Narciso W, Lo W, Harris NS. Improved sensitivity of Lyme disease Western blots prepared with a mixture of Borrelia burgdorferi strains 297 and B31. Chronic Dis Int. 2014;1:7.

      4.Ma B, Christen B, Leung D, Vigo-Pelfrey C. Serodiagnosis of Lyme borreliosis by Western immunoblot: reactivity of various significant antibodies against Borrelia burgdorferi. J Clin Microbiol.1992; 30: 370–376.

      5.Engstrom, SM, Shoop E, Johnson RC. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol. 1995; 33: 419–427.

      6.Aguero-Rosenfeld ME, Nowakowski J, Bittker S, Cooper D, Nadelman RB, et al. Evolution of the serologic response to Borrelia burgdorferi in treated patients with culture-confirmed erythema migrans. J Clin Microbiol. 1996; 34: 1–9.

      7.Steere AC, Sikand VK, Schoen RT, Nowakowski J. Asymptomatic infection with Borrelia burgdorferi. Clin Infect Dis. 2003; 37: 528–532.

      Disclosure: RBS is a member of the International Lyme and Associated Diseases Society (ILADS) and a director of LymeDisease.org. He has no financial or other conflicts to declare. JSS and NSH are members of ILADS, and they have financial interests in IGeneX Reference Laboratory.


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    1. On 2015 Apr 24, Robert Knight commented:

      The morpholino used is designed to the start ATG and has been described previously by Cornell and Eisen (2002) and by Andermann, Ungos and Raible (2002). Titration of this morpholino was shown to lead to a loss of RB neurons and progressively trigeminal neurons, lateral line nerve and dorsal root ganglia. Crucially, this also caused a reduction or loss of neuroD expression and did not affect development of primary motor neurons, revealing a specific affect on sensory neurons. We validated our use of this morpholino by quantifying the effects on RB neuron development relative to morpholino dose and showed that despite a near total loss of RB neurons in an embryos, there was no affect on the number of neurons in the mesencephalic trigeminal nucleus (MTN) or in the nucleus of the tract of the posterior commissure (nTPC). We further showed that we could not detect ngn1 expression in either MTN or nTPC neurons, supporting the results of the morpholino knockdowns. We did not examine trigeminal ganglia neurons, therefore cannot comment on whether these were also affected by loss of ngn1 function as previously described.


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    2. On 2015 Apr 19, Sandra Rieger commented:

      Knocking down ngn1 with a morpholino does not always lead to 100% knockdown of both trigeminal and RB neurons. It largely depends on the morpholino concentration and the type of morpholino used. Therefore, the statement that ngn1 is not required for trigeminal neuron development is not convincing, especially since crucial controls for the functionality of the morpholino injections are missing.


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    1. On 2015 May 04, Dorothy V M Bishop commented:

      This is a very useful study. Thanks. Will be sharing it with colleagues.

      Here in the UK we have been concerned with similar issues. We did some surveys using focus groups for those with trisomy X and XYY, and similar topics cropped up.

      We have not written this up formally, but we used the information as background when developing materials for parents and for children to help those deciding whether and how to disclose a diagnosis. These are freely available for download here:

      http://figshare.com/articles/Booklets_for_parents_and_children_XYY_and_Trisomy_X/1203560


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    1. On 2014 Sep 20, Ryan Radecki commented:

      Post-publication commentary:

      "Appropriate Resource Utilization Can Be Taught!"

      At least, that is the implication of this paper – and even though it’s probably not the most reliable demonstration of such an effect, its observations are likely valid.

      This is a very convoluted study design aiming to comment upon whether residents trained in “conservative” practice environments differed from residents trained in “aggressive” practice environments. However, “conservative” and “aggressive” were defined by utilizing a Medicare database to calculate the “End-of-Life Visit Index”. Residents trained in a region where elderly patients received greater frequency of inpatient and outpatient care at the end-of-life were judged to have trained in an “aggressive” environment....

      http://www.emlitofnote.com/2014/09/appropriate-resource-utilization-can-be.html


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    1. On 2014 Sep 08, Jean-Jacques Letesson commented:

      THE COMPLETE TITLE IS

      Replication of Brucella abortus and Brucella melitensis in fibroblasts does not require Atg5-dependent macroautophagy


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    1. On 2014 Sep 03, David Keller commented:

      Why physicians should intensify, not abandon, PSA screening

      The recommendation to stop screening for prostate cancer is incorrect and will lead to a large increase in preventable cancer deaths. This monumental error was caused by the fallacy that the results of randomized, controlled trials are superior evidence to epidemiological observation, no matter how badly the trials were designed, no matter how contaminated the trial data, and without regard to the effects of intention-to-treat analysis on diminishing the measured benefits of screening. The 16 physicians and allied healthcare professionals on the USPSTF (United States Preventative Services Task Force) all hold positions of high esteem in primary-care specialties, and are expected to volunteer an average of about 4 hours of service per week. Incredibly, no urologists were enlisted to provide their crucial perspectives on PSA screening. The "D"-level recommendation against PSA screening was based on 2 poorly-designed and badly-executed clinical trials, which both generated highly corrupted data.

      First of all, one must keep in mind the important epidemiological observation that, since the introduction of widespread PSA screening in the early 1990’s, there has been a 40% decrease in prostate cancer deaths. While even such powerful observational data cannot prove cause-and-effect, it also cannot be overturned by questionable results from flawed randomized trials. The two trials used by USPSTF do not withstand even casual scrutiny.

      Both of the large randomized PSA screening trials were done in a manner which ignores the essential biological behavior of cancer cells, which is to grow and propagate faster than healthy cells. Both trials set a fixed threshold PSA level for biopsy (such as 4.0 ng/mL). Consider two men: the first man has a PSA of 3.9 in year 1 and a PSA of 4.1 in year 2. The second man has a PSA of 0.5 in year 1 and a PSA of 3.5 in year 2. Which man should have his prostate biopsied? Any rational physician would biopsy the second man, whose PSA rose by 700%, rather than the first man, whose PSA rose only about 5%. Yet, a study with a fixed biopsy threshold trigger of 4.0 would biopsy only the first man, who clearly is much less likely to have prostate cancer. By not including the rate of increase of PSA in the biopsy decision, both trials ignored information in the PSA which has the strongest correlation with the presence of prostate cancer.

      In the U.S.-based PLCO trial, 52% of the men in the control group had off-protocol PSA screening by their private physicians, while only 86% of men in the screening group adhered to the full screening protocol. The men in the PLCO control group had an average of 2.7 PSA screening tests done off-protocol over the 6-year course of study (1). The purpose of PLCO was to compare outcomes in PSA-screened men versus non-screened men, which simply did not occur. The results of PLCO were distorted beyond recognition by mandatory intention-to-treat analysis, which assigned outcomes to each subject's original randomization group, regardless of what they did during the study. The majority of "control" subjects who actually received PSA screening by their private doctors were counted as unscreened, thus diminishing the apparent benefit of PSA screening.

      The Europe-based ERSPC study, which had lower rates of protocol violations, produced data showing a significant decrease in prostate cancer mortality due to PSA screening. An ERSPC sub-study done in the city of Goteborg had a particularly low rate of off-protocol PSA testing, and showed correspondingly higher benefits in mortality reduction. The number needed to screen (NNS) to prevent one prostate cancer death at 14 years of follow-up was 293 in Göteborg, despite the fact that 24% of the men invited to be screened never showed up but were included in the intention-to-treat analysis, thus diminishing the measured benefit of screening (2).

      Another flaw in the ERSPC study was the long interval between sequential PSA tests, which averaged about 4 years (3). Such a long interval of time between samples can allow the most aggressive, fast-growing cancers to evade detection while still confined to the prostate and curable. Men over 50 should have their PSA checked at least once a year for this reason, more often if fluctuations occur, which can be averaged to produce a better estimate of the baseline PSA, deviations from the baseline, and the rate of increase of PSA. The noisier a signal, the more data samples are required to characterize it accurately.

      Prostate cancer kills more men every year than any other cancer except lung cancer. It is a serious threat to all men over age 50 with a life expectancy of greater than 10 years. We know that it is curable when confined to the prostate. More PSA testing, not less, is called for. Improved diagnostic techniques, such as high-resolution prostate MRI imaging, and numerical filtering of PSA values, are being developed. One final randomized trial, which includes all of these improvements, must be conducted to obtain a fair assessment of PSA screening. The problem will be to find enough men willing to forgo screening to fill the control group.

      In general, a man whose PSA is 0.1 has little to fear from prostate cancer, and a man whose PSA is 100 has much to fear from prostate cancer. The problem is to clearly and accurately determine how to proceed within those 3 orders of magnitude of data. The art of medicine is to act in the best interests of the patient when the scientific facts are not perfectly understood. Clinical common sense and scientific intuition demand that we measure and carefully consider the PSA levels of men over the age of 50, pending the results of further trials. Watchful waiting is always an option, which at least provides prognostic awareness.

      The results of poorly-designed and poorly-executed controlled clinical trials give the mere illusion of high-quality data. Their results should not be relied upon as a basis for treatment decisions when they contradict powerful epidemiological data and our understanding of the biological basis of the disease.

      References

      1: Gulati R, Tsodikov A, Wever EM, Mariotto AB, Heijnsdijk EA, Katcher J, de Koning HJ, Etzioni R. The impact of PLCO control arm contamination on perceived PSA screening efficacy. Cancer Causes Control. 2012 Jun;23(6):827-35. doi: 10.1007/s10552-012-9951-8. Epub 2012 Apr 10. PubMed PMID: 22488488; PubMed Central PMCID: PMC3556907.

      2: Hugosson J, Carlsson S, Aus G, Bergdahl S, Khatami A, Lodding P, Pihl CG, Stranne J, Holmberg E, Lilja H. Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010 Aug;11(8):725-32. doi: 10.1016/S1470-2045(10)70146-7. Epub 2010 Jul 2. PubMed PMID: 20598634; PubMed Central PMCID: PMC4089887.

      3: Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, Kwiatkowski M, Lujan M, Lilja H, Zappa M, Denis LJ, Recker F, Berenguer A, Määttänen L, Bangma CH, Aus G, Villers A, Rebillard X, van der Kwast T, Blijenberg BG, Moss SM, de Koning HJ, Auvinen A; ERSPC Investigators. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009 Mar 26;360(13):1320-8. doi: 10.1056/NEJMoa0810084. Epub 2009 Mar 18. PubMed PMID: 19297566.


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    1. On 2016 Feb 18, Kristina Hanspers commented:

      The pathway in the graphical abstract for this paper (at CellPress) is available in the "Open Access Publication" collection at WikiPathways: http://www.wikipathways.org/index.php/Pathway:WP2942. This pathway can be downloaded for use in network analysis tools such as Cytoscape and PathVisio.


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    1. On 2014 Oct 16, Gaetano Santulli commented:

      This study strongly endorses the hypothesis that counteracting neurohormonal hyperactivation represents a cornerstone for the treatment of heart failure. Remarkably, the Authors did not provide any data on the smoking status of the patients nor on catecholamine levels, which I believe would contribute compelling pathophysiological insights about the modulation of autonomic nervous system by neprilysin/angiotensin receptor inhibition. Indeed, cigarette smoking has been shown to increase catecholamine release, generating important effects on cardiovascular regulation essentially via sympathetic nervous system activation (1). Supporting this view, when examining the diabetic population (one third of the enrolled patients) no significant difference was found in the specific outcome ‘death from cardiovascular causes’. This finding could be at least in part ascribable to the autonomic neuropathy and neurovascular dysfunction described in diabetes mellitus (2). In this sense, an analysis that takes into account the duration of diabetes and therapy [i.e. insulin vs oral hypoglycemics (3)] in this population would also be interesting to the Reader.

      References 1. Grassi G, Seravalle G, Calhoun DA, et al. Mechanisms responsible for sympathetic activation by cigarette smoking in humans. Circulation 1994;90:248-53. 2. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes care 2003;26:1553-79. 3. Sardu C, Marfella R, Santulli G. Impact of diabetes mellitus on the clinical response to cardiac resynchronization therapy in elderly people. J Cardiovasc Transl Res. 2014 Apr;7(3):362-8.

      Gaetano Santulli, MD, PhD Columbia University Medical Center, New York, NY, USA


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    1. On 2014 Sep 06, Ryan Radecki commented:

      Post-publication commentary:

      "Early P2Y12 Antagonists Just Don't Seem Useful"

      When undergoing an early invasive strategy for myocardial infarction, the guidelines and trials typically support dual platelet inhibition. Most commonly, this regimen consists of aspirin and clopidogrel. However, the P2Y12 receptor antagonists ticagrelor and prasugrel have been promoted as options due to incremental increased platelet inhibition over clopidogrel. The theoretical benefits of early dual platelet inhibition include spontaneous lysis and prevention of re-thrombosis, as well as decreased early in-stent thrombosis. Unfortunately, the ACCOAST trial demonstrated early prasugrel was associated only with increased bleeding and no associated cardiovascular endpoint benefits.

      Now we have ATLANTIC, with a similar treatment strategy, utilizing ticagrelor.

      Which is also negative.

      http://www.emlitofnote.com/2014/09/early-p2y12-antagonists-just-dont-seem.html


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    1. On 2015 Jan 05, Peter Gøtzsche commented:

      Gastrointestinal cancers in the The SOLID-TIMI 52 trial

      The SOLID-TIMI 52 trial assessed whether darapladib had any effect on major coronary events compared with placebo (1). A small table of adverse events showed that people on active drug had diarrhea twice as often as those on placebo whereas there was no difference in “any adjudicated gastrointestinal cancer.” Readers may wonder why gastrointestinal cancers were listed in such a small table, as diarrhea doesn’t usually lead to cancer. The word cancer was only mentioned in the table, with no comment in the text as to why. I think the reason for listing it in the table is that studies in rats and mice have shown that they developed jejunal adenocarcinomas – a very rare cancer - after exposure to darapladib (2). This should have been mentioned in the paper. I also believe that the investigators and the sponsor, GlaxoSmithKline, have an ethical duty to follow-up the 13,026 participants in the trial in the coming years to find out whether they develop jejunal cancers. A patient who stopped his participation in the trial because of diarrhea felt he had been used as a human guinea pig, as these animal studies had not been carried out when he was asked to enroll in the trial (3).

      Conflicts of interest: none.

      1. O'Donoghue ML, Braunwald E, White HD, et al. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA;312:1006-15.

      2. GlaxoSmithKline. Toxicology section from the Investigator's Brochure on darapladip (24 pages). RM2003/00513/06. Undated.

      3. Gøtzsche PC. “Human guinea pig” asks for animal studies. BMJ 2014;349:g6714.


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