On 2017 May 13, David Keller commented:

Low LDL cholesterol was associated with significantly higher risk of Parkinson disease than was high LDL

The authors report that the adjusted hazard ratio for Parkinson disease ("PD") in subjects with LDL < 1.8 mmol/L versus those with LDL >4.0 mmol/L was 1.70 [1.03 - 2.79]. Note that the 95% confidence interval (in brackets) does not cross 1.0, so this association of low LDL with increased risk of PD is statistically significant.

The above data were then subjected to "genetic, causal analysis", which yielded a risk ratio for a lifelong 1 mmol/L lower LDL cholesterol level of 1.02 [0.26 - 4.00] for Parkinson's disease. Note that the 95% confidence crosses 1.0, and the mean risk ratio of 1.02 is barely elevated.

The tiny and non-significant increase in PD risk caused by a lifelong 1 mmol/L lower serum LDL level, as calculated by the genetic causal analysis, appears to contradict the significant increase in risk of PD for subjects with LDL < 1.8 mmol/L, as compared with subjects with LDL > 4.0 mmol/L seen in the observational analysis.

This apparent contradiction may be an artifact of the diminished statistical power of the genetic causal analysis (which compared change in PD risk for a change in LDL of only 1 mmol/L) versus the observational study, which found significantly higher PD risk associated with LDL < 1.8 mmol/L than with LDL > 4.0 mmol/L. In the observational analysis, the LDL in the high-PD-risk subjects was at least 2.2 mmol/L lower than in the low-risk subjects (ie: 4.0 - 1.8 = 2.2 mmol/L). Thus, the genetic causal analysis calculated the effect of an LDL lower by only 1.0 mmol/L, while the observational analysis looked at the effect of an LDL lower by at least 2.2 mmol/L.

I suggest that the authors compare apples with apples, by re-calculating the genetic, causal analysis to determine the effect of lifelong lowering of LDL by at least 2.2 mmol/L, the minimum separation of LDL levels between subjects in the comparator groups in the observational analysis. Comparing the effect of a larger decrease in LDL may enhance the size and significance of the results calculated by the genetic analysis, and bring it into agreement with the significantly increased risk of lower LDL found in the observational analysis.

On 2017 May 13, David Keller commented:

Low LDL cholesterol was associated with significantly higher risk of Parkinson disease than was high LDL

The authors report that the adjusted hazard ratio for Parkinson disease ("PD") in subjects with LDL < 1.8 mmol/L versus those with LDL >4.0 mmol/L was 1.70 [1.03 - 2.79]. Note that the 95% confidence interval (in brackets) does not cross 1.0, so this association of low LDL with increased risk of PD is statistically significant.

The above data were then subjected to "genetic, causal analysis", which yielded a risk ratio for a lifelong 1 mmol/L lower LDL cholesterol level of 1.02 [0.26 - 4.00] for Parkinson's disease. Note that the 95% confidence crosses 1.0, and the mean risk ratio of 1.02 is barely elevated.

The tiny and non-significant increase in PD risk caused by a lifelong 1 mmol/L lower serum LDL level, as calculated by the genetic causal analysis, appears to contradict the significant increase in risk of PD for subjects with LDL < 1.8 mmol/L, as compared with subjects with LDL > 4.0 mmol/L seen in the observational analysis.

This apparent contradiction may be an artifact of the diminished statistical power of the genetic causal analysis (which compared change in PD risk for a change in LDL of only 1 mmol/L) versus the observational study, which found significantly higher PD risk associated with LDL < 1.8 mmol/L than with LDL > 4.0 mmol/L. In the observational analysis, the LDL in the high-PD-risk subjects was at least 2.2 mmol/L lower than in the low-risk subjects (ie: 4.0 - 1.8 = 2.2 mmol/L). Thus, the genetic causal analysis calculated the effect of an LDL lower by only 1.0 mmol/L, while the observational analysis looked at the effect of an LDL lower by at least 2.2 mmol/L.

I suggest that the authors compare apples with apples, by re-calculating the genetic, causal analysis to determine the effect of lifelong lowering of LDL by at least 2.2 mmol/L, the minimum separation of LDL levels between subjects in the comparator groups in the observational analysis. Comparing the effect of a larger decrease in LDL may enhance the size and significance of the results calculated by the genetic analysis, and bring it into agreement with the significantly increased risk of lower LDL found in the observational analysis.