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Results for “collider bias”

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PubMed2025

No More Free Lunch: Challenges to Mendelian Randomization Due to Sample Selection and Complex Methods.

Mendelian randomization (MR) is increasingly used in epidemiological studies to investigate causal relationships. MR depends on 3 fundamental instrumental variable assumptions: relevance, independence, and exclusion restriction. Studies often assume that MR mitigates bias from confounding due to the random allocation of genetic variants at conception. In this perspective, using causal directed acyclic graphs, we discuss several scenarios where biases in MR analyses may arise due to the nature of the data or methods being used. These include (1) collider bias due to the nonrandom selection of participants into study populations used for conducting genome-wide association studies (GWAS), (2) indirect genetic effects arising from population-based GWAS rather than within-family studies, and (3) collider bias due to gene-environment interaction effects on the exposure in nonlinear MR analyses. We provide practical considerations for examining and reducing these biases in MR analyses.

Humans↗

PubMed2026

Assessment of Methodological Bias in Studies Reporting Racial Differences in Retinopathy of Prematurity in the United States.

PURPOSE: To assess methodological biases in studies reporting racial and ethnic differences in retinopathy of prematurity (ROP). METHODS: Systematic review of peer-reviewed studies published between 2014 and 2024 that reported on ROP outcome measures by race, ethnicity, or social determinants of health (SDOH). Three reviewers independently assessed each observation for selection and collider bias using definitions derived from perinatal epidemiology literature. Findings were also compared using a structured comparative synthesis between studies with and without identified methodological bias. RESULTS: A structured PubMed search identified 78 articles; 13 met inclusion criteria, with one study contributing two distinct analytical approaches, yielding 14 total observations. Survivorship bias was identified in 6 of 14 observations (42.9%), primarily due to the exclusion of infants who died prior to ROP screening. Potential collider bias was most common, found in 9 of 14 observations (64.3%), and was introduced through adjustment or stratification by gestational age and/or birthweight. Three studies did not exhibit either assessed biases. Among studies with identified bias, 8 of 10 observations reported lower ROP risk among Black versus White infants, whereas 3 of 4 observations without identified bias reported higher ROP risk or incidence among Black infants. CONCLUSION: Methodological biases in ROP studies investigating race or ethnicity are prevalent. Adjustment for gestational age or birthweight may introduce spurious race-ROP associations and contribute to paradoxical findings. Further exploration of the impact of SDOH on disease outcomes may reduce the misattribution of race as a biological risk factor and improve the interpretation of ROP disparities.

Collider bias↗

PubMed2026

Associations of genetically predicted interleukin-6 and tumor necrosis factor signaling pathways with mortality among persons with colorectal cancer: a two-sample Mendelian randomization.

BACKGROUND: Despite significant progress in identifying risk factors for colorectal cancer (CRC), factors influencing survival in people with CRC remain less understood. Pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) have been implicated in cancer progression and may influence CRC outcomes. We investigated associations between genetically predicted levels of IL-6 and TNF-α signaling pathways and mortality in people with CRC. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using cis-acting single nucleotide polymorphisms (SNPs) associated with soluble IL-6 receptor alpha (sIL6-RA) and IL-6 signal transducer gp130 (IL6ST), representing IL-6 signaling, and with TNF-α, and its soluble receptors (sTNF-R1, sTNF-R2). SNPs were obtained separately from two large genome-wide association studies (GWAS): deCODE and UK Biobank (UKB). The outcome was CRC-specific mortality among 16,964 CRC cases (4010 deaths) in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Analyses were stratified by tumor site and stage. The inverse variance weighted (IVW) method, incorporating a correlation matrix for dependent SNPs, was used for primary analyses. Because literature links TNF-α to CRC incidence, we additionally performed a simulation study to evaluate the potential impact of collider bias resulting from restricting analyses to CRC cases. RESULTS: Genetically predicted sIL6-RA was weakly positively associated with CRC-specific mortality (deCODE-SNPs (n = 13) HR per 1 SD increase: 1.06; 95% CI: 1.00-1.12; UKB-SNPs (n = 11) HR: 1.09; 95% CI: 1.02-1.17). Genetically proxied IL6ST levels showed no association with CRC-specific mortality in the overall sample (deCODE-SNPs (n = 19) HR: 1.04; 95% CI: 0.90-1.21; UKB-SNPs (n = 9) HR: 1.11; 95% CI: 0.87-2.42), while higher IL6ST levels were associated with increased mortality among patients with stage 2/3 disease (deCODE-SNPs (n = 19) HR: 1.45; 95% CI: 1.10-1.91; UKB-SNPs (n = 9) HR: 1.87; 95% CI: 1.22-2.89). No associations were observed for TNF-α, sTNF-R1, or sTNF-R2. Findings for all exposures were consistent across both GWAS datasets. Simulation analyses for TNF-α indicated collider bias was present but limited in magnitude. CONCLUSIONS: Our findings suggest that IL-6 signaling may play a role in CRC progression although of limited magnitude, whereas TNF-related pathways appear less relevant for prognosis.

Humans↗

PubMed2026

Genetically Proxied Inhibition of Cholesterol-Lowering Drug Targets and Survival in HPV-Positive and Non-HPV-Driven Head and Neck Cancer: A Multicentre MR Study.

BACKGROUND: Cholesterol pathways may influence head and neck squamous cell carcinoma (HNSCC) progression, but evidence on prognosis is inconsistent. We used Mendelian randomization (MR) to test whether genetically proxied inhibition of major low-density lipoprotein cholesterol (LDL-C)-lowering drug targets and circulating lipid traits affects overall survival (OS) in HPV-positive and non-HPV-driven HNSCCs. METHODS: We proxied lifelong LDL-C lowering using 55 cis-acting single-nucleotide polymorphisms in HMGCR, NPC1L1, PCSK9, and LDL-receptor (LDLR) from the updated 2021 Global Lipids Genetics Consortium and instrumented circulating lipid traits. Two-sample MR estimated effects on OS in 4,869 multicentre HNSCC cases (1,291 HPV-positive; 3,578 non-HPV-driven) using minimally adjusted Cox models. Sensitivity analyses additionally adjusted for tumor stage and treatment, assessed collider bias using an external HNSCC incidence genome-wide association study, and examined between-center heterogeneity and colocalization. RESULTS: Using the updated Global Lipids Genetic Consortium 2021 instruments, genetically proxied HMGCR inhibition showed a directionally protective but nonsignificant association with OS in HPV-positive oropharyngeal HNSCC in the primary analysis [inverse variance weighted (IVW) HR = 0.19; 95% confidence interval (CI), 0.03-1.18; P = 0.08], with directionally concordant weighted median results. No corresponding protective association was observed for HMGCR in non-HPV-driven disease (IVW HR = 1.68; 95% CI, 0.78-3.63; P = 0.19). No clear evidence of association was observed for NPC1L1, PCSK9, LDLR, or circulating lipid traits in either HPV stratum. Colocalization did not support a shared causal variant. CONCLUSIONS: These analyses provide suggestive evidence that genetically proxied HMGCR inhibition may influence survival in HPV-positive oropharyngeal HNSCC. IMPACT: HMGCR-related pathways may be relevant to prognosis in HPV-positive oropharyngeal HNSCC, whereas clear survival effects of other cholesterol-lowering targets were not supported.

Humans↗