On 2017 Jun 01, JOANN MANSON commented:

We are writing in response to the comment by EE Hatch, LA Wise, and KJ Rothman that was posted on PubMed Commons on May 9. The authors questioned our interpretation [1] of the key finding of the recent randomized trial by Lappe et al. [2], asserting that we relied solely on the p-value of 0.06 and noting that “Scientific conclusions…should not be based only on whether a p-value passes a specific threshold.” However, the p-value in isolation was not the basis for our interpretation of this trial’s results or our conclusion regarding the effectiveness of vitamin D supplementation as a chemopreventive strategy. As we stated in our editorial, “...the absence of a clear benefit for this endpoint [in the Lappe et al. trial] is in line with the totality of current evidence on vitamin D and/or calcium for prevention of incident cancer..... [F]indings from observational epidemiologic studies and randomized clinical trials to date have been inconsistent. Previous trials of supplemental vitamin D, albeit at lower doses ranging from 400 to 1100 IU/d and administered with or without calcium, have found largely neutral results for cancer incidence; a 2014 meta-analysis of 4 such trials [3-6] with a total of 4333 incident cancers among 45,151 participants yielded a summary relative risk (RR) of 1.00 (95% CI, 0.94-1.06) [7]. Similarly, previous trials of calcium administered with or without vitamin D have in aggregate demonstrated no effect on cancer incidence, with a 2013 meta-analysis reporting a summary RR of 0.95 (0.76-1.18) [8].” (Parenthetically, we note that, in aggregate, vitamin D trials do find a small reduction in cancer mortality [summary RR=0.88 (0.78-0.98)] [7], but, as stated in our editorial, “[t]he modest size, relatively short duration, and relatively small numbers of cancers in the [recent Lappe et al.] trial … preclude[d] robust assessment” of the cancer mortality endpoint.) If the commenters believe that a p-value of 0.06 in the context of the generally null literature (at least for the endpoint of cancer incidence) should be interpreted as a positive finding, then where do they draw the line? A p-value of 0.07, 0.10, 0.20, or elsewhere? Large-scale randomized trials of high-dose supplemental vitamin D are in progress and are expected to provide definitive answers soon regarding its utility for cancer prevention.

--JoAnn E. Manson, MD, DrPH1,2, Shari S. Bassuk, ScD1, Julie E. Buring, ScD1,2

1Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston<br> 2Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston

References

1. Manson JE, Bassuk SS, Buring JE. Vitamin D, calcium, and cancer: approaching daylight? JAMA 2017;317:1217-8.
2. Lappe J, Watson P, Travers-Gustafson D, et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. JAMA 2017;317:1234-43.
3. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003;326:469.
4. Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-96.
5. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85:1586-91.
6. Avenell A, MacLennan GS, Jenkinson DJ, et al. Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D3 and/or calcium (RECORD trial). J Clin Endocrinol Metab 2012;97:614-22.
7. Keum N, Giovannucci E. Vitamin D supplements and cancer incidence and mortality: a meta-analysis. Br J Cancer 2014;111:976-80.
8. Bristow SM, Bolland MJ, MacLennan GS, et al. Calcium supplements and cancer risk: a meta-analysis of randomised controlled trials. Br J Nutr 2013;110:1384-93.

On 2017 May 09, Kenneth J Rothman commented:

Lappe et al. (1) reported that women receiving vitamin D and calcium supplementation had 30% lower cancer risk than women receiving placebo after four years (hazard ratio (HR)=0.70, 95% confidence interval (CI): 0.47 to 1.02). Remarkably, they interpreted this result as indicating no effect. So did the authors of the accompanying editorial (2), who described the 30% lower risk for cancer as “the absence of a clear benefit,” because the P-value was 0.06. Given the expected bias toward a null result in a trial that comes from non-adherence coupled with an intent-to-treat analysis (3), the interpretation of the authors and editorialists is perplexing. The warning issued last year by the American Statistical Association (ASA) (4) about this type of misinterpretation of data should be embraced by researchers and journal editors. In particular, the ASA stated: “Scientific conclusions …should not be based only on whether a p-value passes a specific threshold.” Editors in particular ought to guide their readership and the public at large to avoid such mistakes and foster more responsible interpretation of medical research.

EE Hatch, LA Wise

Boston University School of Public Health

KJ Rothman

Research Triangle Institute & Boston University School of Public Health

References

(1) Lappe J,Watson P, Travers-Gustafson D, et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women. JAMA. 2017; 317:1234-1243. doi:10.1001/jama.2017.2115

(2) Manson JE, Bassuk SS, Buring JE. Vitamin D, Calcium, and Cancer. Approaching Daylight? JAMA 2017; 317:1217-1218.

(3) Rothman KJ. Six persistent research misconceptions. J Gen Intern Med 2014; 29:1060-1064. doi: 10.1007/s11606-013-2755-z

(4) ASA statement on statistical significance and P-values. Am Stat. 2016. doi:10.1080/ 00031305.2016.1154108.

On 2017 May 09, Kenneth J Rothman commented:

Lappe et al. (1) reported that women receiving vitamin D and calcium supplementation had 30% lower cancer risk than women receiving placebo after four years (hazard ratio (HR)=0.70, 95% confidence interval (CI): 0.47 to 1.02). Remarkably, they interpreted this result as indicating no effect. So did the authors of the accompanying editorial (2), who described the 30% lower risk for cancer as “the absence of a clear benefit,” because the P-value was 0.06. Given the expected bias toward a null result in a trial that comes from non-adherence coupled with an intent-to-treat analysis (3), the interpretation of the authors and editorialists is perplexing. The warning issued last year by the American Statistical Association (ASA) (4) about this type of misinterpretation of data should be embraced by researchers and journal editors. In particular, the ASA stated: “Scientific conclusions …should not be based only on whether a p-value passes a specific threshold.” Editors in particular ought to guide their readership and the public at large to avoid such mistakes and foster more responsible interpretation of medical research.

EE Hatch, LA Wise

Boston University School of Public Health

KJ Rothman

Research Triangle Institute & Boston University School of Public Health

References

(1) Lappe J,Watson P, Travers-Gustafson D, et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women. JAMA. 2017; 317:1234-1243. doi:10.1001/jama.2017.2115

(2) Manson JE, Bassuk SS, Buring JE. Vitamin D, Calcium, and Cancer. Approaching Daylight? JAMA 2017; 317:1217-1218.

(3) Rothman KJ. Six persistent research misconceptions. J Gen Intern Med 2014; 29:1060-1064. doi: 10.1007/s11606-013-2755-z

(4) ASA statement on statistical significance and P-values. Am Stat. 2016. doi:10.1080/ 00031305.2016.1154108.

On 2017 Jun 01, JOANN MANSON commented:

We are writing in response to the comment by EE Hatch, LA Wise, and KJ Rothman that was posted on PubMed Commons on May 9. The authors questioned our interpretation [1] of the key finding of the recent randomized trial by Lappe et al. [2], asserting that we relied solely on the p-value of 0.06 and noting that “Scientific conclusions…should not be based only on whether a p-value passes a specific threshold.” However, the p-value in isolation was not the basis for our interpretation of this trial’s results or our conclusion regarding the effectiveness of vitamin D supplementation as a chemopreventive strategy. As we stated in our editorial, “...the absence of a clear benefit for this endpoint [in the Lappe et al. trial] is in line with the totality of current evidence on vitamin D and/or calcium for prevention of incident cancer..... [F]indings from observational epidemiologic studies and randomized clinical trials to date have been inconsistent. Previous trials of supplemental vitamin D, albeit at lower doses ranging from 400 to 1100 IU/d and administered with or without calcium, have found largely neutral results for cancer incidence; a 2014 meta-analysis of 4 such trials [3-6] with a total of 4333 incident cancers among 45,151 participants yielded a summary relative risk (RR) of 1.00 (95% CI, 0.94-1.06) [7]. Similarly, previous trials of calcium administered with or without vitamin D have in aggregate demonstrated no effect on cancer incidence, with a 2013 meta-analysis reporting a summary RR of 0.95 (0.76-1.18) [8].” (Parenthetically, we note that, in aggregate, vitamin D trials do find a small reduction in cancer mortality [summary RR=0.88 (0.78-0.98)] [7], but, as stated in our editorial, “[t]he modest size, relatively short duration, and relatively small numbers of cancers in the [recent Lappe et al.] trial … preclude[d] robust assessment” of the cancer mortality endpoint.) If the commenters believe that a p-value of 0.06 in the context of the generally null literature (at least for the endpoint of cancer incidence) should be interpreted as a positive finding, then where do they draw the line? A p-value of 0.07, 0.10, 0.20, or elsewhere? Large-scale randomized trials of high-dose supplemental vitamin D are in progress and are expected to provide definitive answers soon regarding its utility for cancer prevention.

--JoAnn E. Manson, MD, DrPH1,2, Shari S. Bassuk, ScD1, Julie E. Buring, ScD1,2

1Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston<br> 2Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston

References

1. Manson JE, Bassuk SS, Buring JE. Vitamin D, calcium, and cancer: approaching daylight? JAMA 2017;317:1217-8.
2. Lappe J, Watson P, Travers-Gustafson D, et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. JAMA 2017;317:1234-43.
3. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003;326:469.
4. Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-96.
5. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85:1586-91.
6. Avenell A, MacLennan GS, Jenkinson DJ, et al. Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D3 and/or calcium (RECORD trial). J Clin Endocrinol Metab 2012;97:614-22.
7. Keum N, Giovannucci E. Vitamin D supplements and cancer incidence and mortality: a meta-analysis. Br J Cancer 2014;111:976-80.
8. Bristow SM, Bolland MJ, MacLennan GS, et al. Calcium supplements and cancer risk: a meta-analysis of randomised controlled trials. Br J Nutr 2013;110:1384-93.