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Emulating a target trial in case-control designs: an application to statins and colorectal cancer.
Dickerman, BA, García-Albéniz, X, Logan, RW, Denaxas, S, Hernán, MA
International journal of epidemiology. 2020;(5):1637-1646
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Abstract
BACKGROUND Previous case-control studies have reported a strong association between statin use and lower cancer risk. It is unclear whether this association reflects a benefit of statins or is the result of design decisions that cannot be mapped to a (hypothetical) target trial (that would answer the question of interest). METHODS We outlined the protocol of a target trial to estimate the effect of statins on colorectal cancer incidence among adults with low-density lipoprotein (LDL) cholesterol below 5 mmol/L. We then emulated the target trial using linked electronic health records of 752 469 eligible UK adults (CALIBER 1999-2016) under both a cohort design and a case-control sampling of the cohort. We used pooled logistic regression to estimate intention-to-treat and per-protocol effects of statins on colorectal cancer, with adjustment for baseline and time-varying risk factors via inverse-probability weighting. Finally, we compared our case-control effect estimates with those obtained using previous case-control procedures. RESULTS Over the 6-year follow-up, 3596 individuals developed colorectal cancer. Estimated intention-to-treat and per-protocol hazard ratios were 1.00 (95% confidence interval [CI]: 0.87, 1.16) and 0.90 (95% CI: 0.71, 1.12), respectively. As expected, adequate case-control sampling yielded the same estimates. By contrast, previous case-control analytical approaches yielded estimates that appeared strongly protective (odds ratio 0.57, 95% CI: 0.36, 0.91, for ≥5 vs. <5 years of statin use). CONCLUSIONS Our study demonstrates how to explicitly emulate a target trial using case-control data to reduce discrepancies between observational and randomized trial evidence. This approach may inform future case-control analyses for comparative effectiveness research.
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Guideline-Based Physical Activity and Survival Among US Men With Nonmetastatic Prostate Cancer.
Dickerman, BA, Giovannucci, E, Pernar, CH, Mucci, LA, Hernán, MA
American journal of epidemiology. 2019;(3):579-586
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Abstract
The survival impact of adhering to current physical activity guidelines after prostate cancer diagnosis is unknown. We therefore emulated a target trial of guideline-based physical activity interventions and 10-year survival among US men with nonmetastatic prostate cancer. We used observational data on 2,299 men in the Health Professionals Follow-up Study who were diagnosed with nonmetastatic prostate cancer from 1998 to 2010 and were free of conditions that might have precluded participation at baseline (first postdiagnostic questionnaire). We estimated their survival under several guideline-based physical activity interventions starting at baseline and ending at the development of conditions limiting physical ability. We adjusted for baseline and time-varying risk factors for death using the parametric g-formula. Compared with the observed 15.4% mortality risk, the estimated 10-year risks of mortality were 13.0% (95% confidence interval (CI): 10.9, 15.4) and 11.1% (95% CI: 8.7, 14.1) for ≥1.25 hours/week and ≥2.5 hours/week of vigorous activity, respectively, and 13.9% (95% CI: 12.0, 16.0) and 12.6% (95% CI: 10.6, 14.7) for ≥2.5 hours/week and ≥5 hours/week of moderate activity, respectively. We estimated that these men would have experienced clinically meaningful reductions in mortality had they followed current physical activity recommendations until the development of conditions limiting physical ability. These findings may help guide clinical recommendations for prostate cancer patients and the design of future randomized trials.
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Zinc, Magnesium, Selenium and Depression: A Review of the Evidence, Potential Mechanisms and Implications.
Wang, J, Um, P, Dickerman, BA, Liu, J
Nutrients. 2018;10(5)
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Adequate micronutrient consumption and mental health are of major public health importance. Recent findings suggest micronutrient deficiencies may play a role in the development and progression of depression, yet the findings remain unclear. The aim of this review is to present the recent evidence on the association between several micronutrients and depression and discuss the potential mechanisms and clinical implications. Based on the current literature, evidence shows an association between both zinc and magnesium deficiency and the risk of depression, with stronger evidence supporting zinc. Studies on selenium are limited or inconclusive. According to these findings, the authors support the importance of adequate micronutrient consumption for promoting mental health. They suggest future research should investigate the safety and efficacy of micronutrient supplementation as an adjunct treatment for depression to better inform current prevention and treatment strategies.
Abstract
Micronutrient deficiency and depression are major global health problems. Here, we first review recent empirical evidence of the association between several micronutrients—zinc, magnesium, selenium—and depression. We then present potential mechanisms of action and discuss the clinical implications for each micronutrient. Collectively, empirical evidence most strongly supports a positive association between zinc deficiency and the risk of depression and an inverse association between zinc supplementation and depressive symptoms. Less evidence is available regarding the relationship between magnesium and selenium deficiency and depression, and studies have been inconclusive. Potential mechanisms of action involve the HPA axis, glutamate homeostasis and inflammatory pathways. Findings support the importance of adequate consumption of micronutrients in the promotion of mental health, and the most common dietary sources for zinc and other micronutrients are provided. Future research is needed to prospectively investigate the association between micronutrient levels and depression as well as the safety and efficacy of micronutrient supplementation as an adjunct treatment for depression.