The terms multivariate and multivariable are often used interchangeably in the public health literature. However, these terms actually represent 2 very distinct types of analyses. We define the 2 types of analysis and assess the prevalence of use of the statistical term multivariate in a 1-year span of articles published in the American Journal of Public Health. Our goal is to make a clear distinction and to identify the nuances that make these types of analyses so distinct from one another.

Known genetic susceptibility loci for type 2 diabetes (T2D) explain only a small proportion of heritable T2D risk. We hypothesize that DNA methylation patterns may contribute to variation in diabetes-related risk factors, and this epigenetic variation across the genome can contribute to the missing heritability in T2D and related metabolic traits. We conducted an epigenome-wide association study for fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) among 837 nondiabetic participants in the Genetics of Lipid Lowering Drugs and Diet Network study, divided into discovery (N = 544) and replication (N = 293) stages. Cytosine guanine dinucleotide (CpG) methylation at ∼470,000 CpG sites was assayed in CD4+ T cells using the Illumina Infinium HumanMethylation 450 Beadchip. We fit a mixed model with the methylation status of each CpG as the dependent variable, adjusting for age, sex, study site, and T-cell purity as fixed-effects and family structure as a random-effect. A Bonferroni corrected P value of 1.1 × 10−7 was considered significant in the discovery stage. Significant associations were tested in the replication stage using identical models. Methylation of a CpG site in ABCG1 on chromosome 21 was significantly associated with insulin (P = 1.83 × 10−7) and HOMA-IR (P = 1.60 × 10−9). Another site in the same gene was significant for HOMA-IR and of borderline significance for insulin (P = 1.29 × 10−7 and P = 3.36 × 10−6, respectively). Associations with the top two signals replicated for insulin and HOMA-IR (P = 5.75 × 10−3 and P = 3.35 × 10−2, respectively). Our findings suggest that methylation of a CpG site within ABCG1 is associated with fasting insulin and merits further evaluation as a novel disease risk marker.

Recently, epigenetic age acceleration—or older epigenetic age in comparison to chronological age—has been robustly associated with mortality and various morbidities. However, accelerated epigenetic aging has not been widely investigated in relation to inflammatory or metabolic markers, including postprandial lipids. We estimated measures of epigenetic age acceleration in 830 Caucasian participants from the Genetics Of Lipid Lowering Drugs and diet Network (GOLDN) considering two epigenetic age calculations based on differing sets of 5′-Cytosine-phosphate-guanine-3′ genomic site, derived from the Horvath and Hannum DNA methylation age calculators, respectively. GOLDN participants underwent a standardized high-fat meal challenge after fasting for at least 8 h followed by timed blood draws, the last being 6 h postmeal. We used adjusted linear mixed models to examine the association of the epigenetic age acceleration estimate with fasting and postprandial (0- and 6-h time points) low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels as well as five fasting inflammatory markers plus adiponectin. Both DNA methylation age estimates were highly correlated with chronological age (r > 0.90). We found that the Horvath and Hannum measures of epigenetic age acceleration were moderately correlated (r = 0.50). The regression models revealed that the Horvath age acceleration measure exhibited marginal associations with increased postprandial HDL (p = 0.05), increased postprandial total cholesterol (p = 0.06), and decreased soluble interleukin 2 receptor subunit alpha (IL2sRα, p = 0.02). The Hannum measure of epigenetic age acceleration was inversely associated with fasting HDL (p = 0.02) and positively associated with postprandial TG (p = 0.02), interleukin-6 (IL6, p = 0.007), C-reactive protein (C-reactive protein, p = 0.0001), and tumor necrosis factor alpha (TNFα, p = 0.0001). Overall, the observed effect sizes were small and the association of the Hannum residual with inflammatory markers was attenuated by adjustment for estimated T cell type percentages. Our study demonstrates that epigenetic age acceleration in blood relates to inflammatory biomarkers and certain lipid classes in Caucasian individuals of the GOLDN study. Future studies should consider epigenetic age acceleration in other tissues and extend the analysis to other ethnic groups.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

An estimated 250 million people worldwide suffer from knee osteoarthritis (KOA), with older adults having greater risk. Like other age-related diseases, residents of high-deprivation neighborhoods experience worse KOA pain outcomes compared to their more affluent neighbors. The purpose of this study was to examine the relationship between neighborhood deprivation and pain severity in KOA and the influence of epigenetic age acceleration (EpAA) on that relationship. The sample of 128 participants was mostly female (60.9%), approximately half non-Hispanic Black (49.2%), and had a mean age of 58 years. Spearman bivariate correlations revealed that pain severity positively correlated with EpAA (ρ = 0.47, p ≤ 0.001) and neighborhood deprivation (ρ = 0.25, p = 0.004). We found a positive significant relationship between neighborhood deprivation and EpAA (ρ = 0.47, p ≤ 0.001). Results indicate a mediating relationship between neighborhood deprivation (predictor), EpAA (mediator), and pain severity (outcome variable). There was a significant indirect effect of neighborhood deprivation on pain severity through EpAA, as the mediator accounted for a moderate portion of the total effect, PM = 0.44. Epigenetic age acceleration may act as a mechanism through which neighborhood deprivation leads to worse KOA pain outcomes and may play a role in the well-documented relationship between the neighborhood of residence and age-related diseases.