Genetic association studies and the effect of misclassification and selection bias in putative confounders

Genetic epidemiology studies often adjust for numerous potential confounders, yet the influences of confounder misclassification and selection bias are rarely considered. We used simulated data to evaluate the effect of confounder misclassification and selection bias in a case-control study of incident myocardial infarction. We show that putative confounders traditionally included in genetic association studies do not alter effect estimates, even when excessive levels of misclassification are incorporated. Conversely, selection bias resulting from covariates affected by the single-nucleotide polymorphism of interest can bias effect estimates upward or downward. These results support careful consideration of how well a study population represents the target population because selection bias may result even when associations are modest

Sparse meta-analysis with high-dimensional data

Meta-analysis plays an important role in summarizing and synthesizing scientific evidence derived from multiple studies. With high-dimensional data, the incorporation of variable selection into meta-analysis improves model interpretation and prediction. Existing variable selection methods require direct access to raw data, which may not be available in practical situations. We propose a new approach, sparse meta-analysis (SMA), in which variable selection for meta-analysis is based solely on summary statistics and the effect sizes of each covariate are allowed to vary among studies. We show that the SMA enjoys the oracle property if the estimated covariance matrix of the parameter estimators from each study is available. We also show that our approach achieves selection consistency and estimation consistency even when summary statistics include only the variance estimators or no variance/covariance information at all. Simulation studies and applications to high-throughput genomics studies demonstrate the usefulness of our approach

Quantitative trait locus-specific genotype × alcoholism interaction on linkage for evoked electroencephalogram oscillations

We explored the evidence for a quantitative trait locus (QTL)-specific genotype × alcoholism interaction for an evoked electroencephalogram theta band oscillation (ERP) phenotype on a region of chromosome 7 in participants of the US Collaborative Study on the Genetics of Alcoholism. Among 901 participants with both genotype and phenotype data available, we performed variance component linkage analysis (SOLAR version 2.1.2) in the full sample and stratified by DSM-III-R and Feighner-definite alcoholism categories. The heritability of the ERP phenotype after adjusting for age and sex effects in the combined sample and in the alcoholism classification sub-groups ranged from 40% to 66%. Linkage on chromosome 7 was identified at 158 cM (LOD = 3.8) in the full sample and at 108 in the non-alcoholic subgroup (LOD = 3.1). Further, we detected QTL-specific genotype × alcoholism interaction at these loci. This work demonstrates the importance of considering the complexity of common complex traits in our search for genes that predispose to alcoholism

Genetic association studies and the effect of misclassification and selection bias in putative confounders

Abstract Genetic epidemiology studies often adjust for numerous potential confounders, yet the influences of confounder misclassification and selection bias are rarely considered. We used simulated data to evaluate the effect of confounder misclassification and selection bias in a case-control study of incident myocardial infarction. We show that putative confounders traditionally included in genetic association studies do not alter effect estimates, even when excessive levels of misclassification are incorporated. Conversely, selection bias resulting from covariates affected by the single-nucleotide polymorphism of interest can bias effect estimates upward or downward. These results support careful consideration of how well a study population represents the target population because selection bias may result even when associations are modest

A General Framework for Association Tests With Multivariate Traits in Large-Scale Genomics Studies

Genetic association studies often collect data on multiple traits that are correlated. Discovery of genetic variants influencing multiple traits can lead to better understanding of the etiology of complex human diseases. Conventional univariate association tests may miss variants that have weak or moderate effects on individual traits. We propose several multivariate test statistics to complement univariate tests. Our framework covers both studies of unrelated individuals and family studies and allows any type/mixture of traits. We relate the marginal distributions of multivariate traits to genetic variants and covariates through generalized linear models without modeling the dependence among the traits or family members. We construct score-type statistics, which are computationally fast and numerically stable even in the presence of covariates and which can be combined efficiently across studies with different designs and arbitrary patterns of missing data. We compare the power of the test statistics both theoretically and empirically. We provide a strategy to determine genome-wide significance that properly accounts for the linkage disequilibrium (LD) of genetic variants. The application of the new methods to the meta-analysis of five major cardiovascular cohort studies identifies a new locus (HSCB) that is pleiotropic for the four traits analyzed

Research and Publishing during COVID-19

This discussion will explore the impact of the COVID-19 pandemic on scholarly research and publishing. Travel restrictions, retracted funding, delayed or halted projects, and an increase in caretaker and other personal responsibilities at home compound to create unprecedented challenges for producing and publishing research. Early indicators show women, those with significant unpaid care responsibilities, and members of minoritized groups have been disproportionately impacted. For graduate students and early career faculty who depend on research and publication for promotion and tenure, the stakes are especially high. Join our panelists for a conversation about the how the COVID-19 pandemic is impacting the research landscape. Watch the video to see the discussion. Click on the download button for a list of readings and resources.https://digitalcommons.usu.edu/inter_inclusion/1001/thumbnail.jp

Dietary quality and cardiometabolic indicators in the USA: A comparison of the Planetary Health Diet Index, Healthy Eating Index-2015, and Dietary Approaches to Stop Hypertension

Background. The Planetary Health Diet Index (PHDI) measures adherence to the sustainable dietary guidance proposed by the EAT-Lancet Commission on Food, Planet, Health. To justify incorporating sustainable dietary guidance such as the PHDI in the US, the index needs to be compared to health-focused dietary recommendations already in use. The objectives of this study were to compare the how the Planetary Health Diet Index (PHDI), the Healthy Eating Index34 2015 (HEI-2015) and Dietary Approaches to Stop Hypertension (DASH) relate to cardiometabolic risk factors.Methods and Findings. Participants from the National Health and Nutrition Examination Survey (2015-2018) were assigned a score for each dietary index. We examined disparities in dietary quality for each index. We used linear and logistic regression to assess the association of standardized dietary index values with waist circumference, blood pressure, HDL-C, fasting plasma glucose (FPG) and triglycerides (TG). We also dichotomized the cardiometabolic indicators using the cutoffs for the Metabolic Syndrome and used logistic regression to assess the relationship of the standardized dietary index values with binary cardiometabolic risk factors. We observed diet quality disparities for populations that were Black, Hispanic, low-income, a low-education. Higher diet quality was associated with improved continuous and binary cardiometabolic risk factors, although higher PHDI was not associated with high FPG and was the only index associated with lower TG. These patterns remained consistent in sensitivity analyses.Conclusions. Sustainability-focused dietary recommendations such as the PHDI have similar cross-sectional associations with cardiometabolic risk as HEI-2015 or DASH. Health-focused dietary guidelines such as the forthcoming 2025-2030 Dietary Guidelines for Americans can consider the environmental impact of diet and still promote cardiometabolic health

Adherence to the Planetary Health Diet Index and Correlation with Nutrients of Public Health Concern: An analysis of NHANES 2003-2018:Planetary Health Diet Index: Trends in the US

Background: The Planetary Health Diet Index (PHDI) is a novel measure adapted to quantify alignment with the dietary evidence presented by the EAT-Lancet Commission on Food, Planet Health.Objectives: To examine how population-level health and sustainability of diet as measured by the PHDI changed from 2003-2018, and to assess how PHDI correlated with inadequacy for nutrients of public health concern (iron, calcium, potassium, and fiber) in the US.Methods: We estimated survey-weighted trends in PHDI scores and median intake of PHDI components in a nationally-representative sample of 33,859 adults aged 20+ years from eight cycles (2003–2018) of the National Health and Nutrition Examination Survey with two days of dietary recall data. We used the NCI method to examine how PHDI correlated with inadequate intake of iron, calcium, potassium, and fiber.Results: Out of a theoretical range of 0 to 140, median PHDI value increased by 4.2 points over the study period, from 62.7 (95% CI: 62.0, 63.4) points in 2003-2004 to 66.9 (66.2, 67.7) points in 2017-2018 (ptrend<0.001), although most of this change occurred before 2011-2012 and plateaued thereafter. For adequacy components that are encouraged for consumption, non starchy vegetable intake significantly decreased over time, while whole grains, nuts and seeds, and unsaturated oils increased. For moderation components with recommended limits for consumption, poultry and egg intake increased, but red and processed meat, added sugars, saturated fats, and starchy vegetables decreased over time. Higher PHDI values were associated with lower probability of iron, fiber, and potassium inadequacy.Conclusions: Although there have been positive changes over the past 20 years, there is substantial room for improving the health and sustainability of the US diet. Shifting diets towards EAT-Lancet recommendations would improve nutrient adequacy for iron, fiber and potassium. Policy action is needed to support healthier, more sustainable diets in the US and globally

Comparison of study designs used to detect and characterize pharmacogenomic interactions in nonexperimental studies: a simulation study

Adverse drug reactions are common, serious, difficult to predict, and may be influenced by genetics, prompting the increasing popularity of pharmacogenomic studies. Many pharmacogenomic studies are conducted in non-experimental settings, yet little is known about the influence of confounding by contraindication. We therefore compared the two designs (the overall population (OPD) and the treated-only (TOD) design) by simulating a pharmacogenomic study of the electrocardiographic QT interval (QT)

Evaluating markers of epithelial-mesenchymal transition to identify cancer patients at risk for metastatic disease

Most cancer deaths are due to metastases. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells could be helpful to assess patient risk of metastatic disease, even among those otherwise diagnosed with local disease. Previous studies of EMT markers and patient outcomes used inconsistent methods and did not compare the clinical impact of different expression cut points for the same marker. Using digital image analysis, we measured the EMT markers Snail and E-cadherin in primary tumor specimens from 190 subjects in tissue microarrays from a population-based prospective cohort of colorectal cancer patients and estimated their associations with time-to-death. After measuring continuous marker expression data, we performed a systematic search for the cut point for each marker with the best model fit between dichotomous marker expression and time-to-death. We also assessed the potential clinical impact of different cut points for the same marker. After dichotomizing expression status at the statistically-optimal cut point, we found that Snail expression was not associated with time-to-death. When measured as a weighted average of tumor cores, low E-cadherin expression was associated with a greater risk of dying within 5 years of surgery than high expression (risk difference = 33 %, 95 % confidence interval 3–62 %). Identifying a clinically-optimal cut point for an EMT marker requires trade-offs between strength and precision of the association with patient outcomes, as well as consideration of the number of patients whose treatments might change based on using the marker at a given cut point