Academic medicine : journal of the Association of American Medical Colleges · 2020
Yoon Soo Park、Lars Konge、Anthony R Artino
Research paradigms guide scientific discoveries through their assumptions and principles. Understanding paradigm-specific assumptions helps illuminate the quality of findings that support scientific studies and identify gaps in generating sound evidence. This article focuses on the research paradigm of positivism, examining its definition, history, and assumptions (ontology, epistemology, axiology, methodology, and rigor). Positivism is aligned with the hypothetico-deductive model of science that builds on verifying a priori hypotheses and experimentation by operationalizing variables and measures; results from hypothesis testing are used to inform and advance science. Studies aligned with positivism generally focus on identifying explanatory associations or causal relationships through quantitative approaches, where empirically based findings from large sample sizes are favored-in this regard, generalizable inferences, replication of findings, and controlled experimentation have been principles guiding positivist science. Criteria for evaluating the quality of positivist research are discussed. An example from health professions education is provided to guide positivist thinking in study design and implementation.
medRxiv · 2023
M. Zhang、Arun Durvasula、Colby Chiang 等
The genetic architecture of human diseases and complex traits has been extensively studied, but little is known about the relationship of causal disease effect sizes between proximal SNPs, which have largely been assumed to be independent. We introduce a new method, LD SNP-pair effect correlation regression (LDSPEC), to estimate the correlation of causal disease effect sizes of derived alleles between proximal SNPs, depending on their allele frequencies, LD, and functional annotations; LDSPEC produced robust estimates in simulations across various genetic architectures. We applied LDSPEC to 70 diseases and complex traits from the UK Biobank (average N=306K), meta-analyzing results across diseases/traits. We detected significantly nonzero effect correlations for proximal SNP pairs (e.g., -0.37{+/-}0.09 for low-frequency positive-LD 0-100bp SNP pairs) that decayed with distance (e.g., -0.07{+/-}0.01 for low-frequency positive-LD 1-10kb), varied with allele frequency (e.g., -0.15{+/-}0.04 for common positive-LD 0-100bp), and varied with LD between SNPs (e.g., +0.12{+/-}0.05 for common negative-LD 0-100bp) (because we consider derived alleles, positive-LD and negative-LD SNP pairs may yield very different results). We further determined that SNP pairs with shared functions had stronger effect correlations that spanned longer genomic distances, e.g., -0.37{+/-}0.08 for low-frequency positive-LD same-gene promoter SNP pairs (average genomic distance of 47kb (due to alternative splicing)) and -0.32{+/-}0.04 for low-frequency positive-LD H3K27ac 0-1kb SNP pairs. Consequently, SNP-heritability estimates were substantially smaller than estimates of the sum of causal effect size variances across all SNPs (ratio of 0.87{+/-}0.02 across diseases/traits), particularly for certain functional annotations (e.g., 0.78{+/-}0.01 for common Super enhancer SNPs)--even though these quantities are widely assumed to be equal. We recapitulated our findings via forward simulations with an evolutionary model involving stabilizing selection, implicating the action of linkage masking, whereby haplotypes containing linked SNPs with opposite effects on disease have reduced effects on fitness and escape negative selection.
Blood · 2023
Luca Stefanucci、Janine Collins、Matthew C Sims 等
Rare genetic diseases affect millions, and identifying causal DNA variants is essential for patient care. Therefore, it is imperative to estimate the effect of each independent variant and improve their pathogenicity classification. Our study of 140 214 unrelated UK Biobank (UKB) participants found that each of them carries a median of 7 variants previously reported as pathogenic or likely pathogenic. We focused on 967 diagnostic-grade gene (DGG) variants for rare bleeding, thrombotic, and platelet disorders (BTPDs) observed in 12 367 UKB participants. By association analysis, for a subset of these variants, we estimated effect sizes for platelet count and volume, and odds ratios for bleeding and thrombosis. Variants causal of some autosomal recessive platelet disorders revealed phenotypic consequences in carriers. Loss-of-function variants in MPL, which cause chronic amegakaryocytic thrombocytopenia if biallelic, were unexpectedly associated with increased platelet counts in carriers. We also demonstrated that common variants identified by genome-wide association studies (GWAS) for platelet count or thrombosis risk may influence the penetrance of rare variants in BTPD DGGs on their associated hemostasis disorders. Network-propagation analysis applied to an interactome of 18 410 nodes and 571 917 edges showed that GWAS variants with large effect sizes are enriched in DGGs and their first-order interactors. Finally, we illustrate the modifying effect of polygenic scores for platelet count and thrombosis risk on disease severity in participants carrying rare variants in TUBB1 or PROC and PROS1, respectively. Our findings demonstrate the power of association analyses using large population datasets in improving pathogenicity classifications of rare variants.
Research Square · 2023
M. Zhang、Arun Durvasula、Colby Chiang 等
The genetic architecture of human diseases and complex traits has been extensively studied, but little is known about the relationship of causal disease effect sizes between proximal SNPs, which have largely been assumed to be independent. We introduce a new method, LD SNP-pair effect correlation regression (LDSPEC), to estimate the correlation of causal disease effect sizes of derived alleles between proximal SNPs, depending on their allele frequencies, LD, and functional annotations; LDSPEC produced robust estimates in simulations across various genetic architectures. We applied LDSPEC to 70 diseases and complex traits from the UK Biobank (average N=306K), meta-analyzing results across diseases/traits. We detected significantly nonzero effect correlations for proximal SNP pairs (e.g., −0.37±0.09 for low-frequency positive-LD 0–100bp SNP pairs) that decayed with distance (e.g., −0.07±0.01 for low-frequency positive-LD 1–10kb), varied with allele frequency (e.g., −0.15±0.04 for common positive-LD 0–100bp), and varied with LD between SNPs (e.g., +0.12±0.05 for common negative-LD 0–100bp) (because we consider derived alleles, positive-LD and negative-LD SNP pairs may yield very different results). We further determined that SNP pairs with shared functions had stronger effect correlations that spanned longer genomic distances, e.g., −0.37±0.08 for low-frequency positive-LD same-gene promoter SNP pairs (average genomic distance of 47kb (due to alternative splicing)) and −0.32±0.04 for low-frequency positive-LD H3K27ac 0–1kb SNP pairs. Consequently, SNP-heritability estimates were substantially smaller than estimates of the sum of causal effect size variances across all SNPs (ratio of 0.87±0.02 across diseases/traits), particularly for certain functional annotations (e.g., 0.78±0.01 for common Super enhancer SNPs)—even though these quantities are widely assumed to be equal. We recapitulated our findings via forward simulations with an evolutionary model involving stabilizing selection, implicating the action of linkage masking, whereby haplotypes containing linked SNPs with opposite effects on disease have reduced effects on fitness and escape negative selection.
Journal of affective disorders · 2016
Jon D Elhai、Robert D Dvorak、Jason C Levine 等
BACKGROUND: Research literature on problematic smartphone use, or smartphone addiction, has proliferated. However, relationships with existing categories of psychopathology are not well defined. We discuss the concept of problematic smartphone use, including possible causal pathways to such use. METHOD: We conducted a systematic review of the relationship between problematic use with psychopathology. Using scholarly bibliographic databases, we screened 117 total citations, resulting in 23 peer-reviewer papers examining statistical relations between standardized measures of problematic smartphone use/use severity and the severity of psychopathology. RESULTS: Most papers examined problematic use in relation to depression, anxiety, chronic stress and/or low self-esteem. Across this literature, without statistically adjusting for other relevant variables, depression severity was consistently related to problematic smartphone use, demonstrating at least medium effect sizes. Anxiety was also consistently related to problem use, but with small effect sizes. Stress was somewhat consistently related, with small to medium effects. Self-esteem was inconsistently related, with small to medium effects when found. Statistically adjusting for other relevant variables yielded similar but somewhat smaller effects. LIMITATIONS: We only included correlational studies in our systematic review, but address the few relevant experimental studies also. CONCLUSIONS: We discuss causal explanations for relationships between problem smartphone use and psychopathology.
Scientific reports · 2024
Zhongheng Zhang、Lin Chen、Haoyang Zhang 等
Cardio-metabolic traits have been reported to be associated with the development of sepsis. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability, or are confounded by environmental factors. We performed three analyses to explore the relationships between cardio-metabolic traits and sepsis. Mendelian randomization (MR) study to evaluate the causal effects of multiple cardio-metabolic traits on sepsis. Global genetic correlation analysis to explore the correlations between cardio-metabolic traits and sepsis. Local genetic correlation (GC) analysis to explore shared genetic heritability between cardio-metabolic traits and sepsis. Some loci were further examined for related genes responsible for the causal relationships. Genetic associations were obtained from the UK Biobank data or published large-scale genome-wide association studies with sample sizes between 200,000 to 750,000. In MR, we found causality between BMI and sepsis (OR: 1.53 [1.4-1.67]; p < 0.001). Body mass index (BMI), which is confirmed by sensitivity analyses and multivariable MR adjusting for confounding factors. Global GC analysis showed a significant correlation between BMI and sepsis (rg = 0.55, p < 0.001). More cardio-metabolic traits were identified to be correlated to the sepsis onset such as CRP (rg = 0.37, p = 0.035), type 2 diabetes (rg = 0.33, p < 0.001), HDL (rg = - 0.41, p < 0.001), and coronary artery disease (rg = 0.43, p < 0.001). Local GC revealed some shared genetic loci responsible for the causality. The top locus 1126 was located at chromosome 7 and comprised genes HIBADH, JAZF1, and CREB5. The present study provides evidence for an independent causal effect of BMI on sepsis. Further detailed analysis of the shared genetic heritability between cardio-metabolic traits and sepsis provides the opportunity to improve the preventive strategies for sepsis.
Psychological bulletin · 2013
Theodore F Robles、Richard B Slatcher、Joseph M Trombello 等
This meta-analysis reviewed 126 published empirical articles over the past 50 years describing associations between marital relationship quality and physical health in more than 72,000 individuals. Health outcomes included clinical endpoints (objective assessments of function, disease severity, and mortality; subjective health assessments) and surrogate endpoints (biological markers that substitute for clinical endpoints, such as blood pressure). Biological mediators included cardiovascular reactivity and hypothalamic-pituitary-adrenal axis activity. Greater marital quality was related to better health, with mean effect sizes from r = .07 to .21, including lower risk of mortality (r = .11) and lower cardiovascular reactivity during marital conflict (r = -.13), but not daily cortisol slopes or cortisol reactivity during conflict. The small effect sizes were similar in magnitude to previously found associations between health behaviors (e.g., diet) and health outcomes. Effect sizes for a small subset of clinical outcomes were susceptible to publication bias. In some studies, effect sizes remained significant after accounting for confounds such as age and socioeconomic status. Studies with a higher proportion of women in the sample demonstrated larger effect sizes, but we found little evidence for gender differences in studies that explicitly tested gender moderation, with the exception of surrogate endpoint studies. Our conclusions are limited by small numbers of studies for specific health outcomes, unexplained heterogeneity, and designs that limit causal inferences. These findings highlight the need to explicitly test affective, health behavior, and biological mechanisms in future research, and focus on moderating factors that may alter the relationship between marital quality and health.
Diabetes & vascular disease research · 2025
Yi-Keng Huang、Xiaoyin Xu、Xin-Yu Zhang 等
Aims To evaluate the potential causal role of sleep traits (STs) on diabetic retinopathy (DR). Methods The cross-sectional study included 23,851 patients with type 2 diabetes from the UK Biobank and used multivariate logistic models to investigate the observational association between STs and DR. Genetic correlation analysis and two-sample Mendelian randomization (MR) were conducted using ST data from the UK Biobank and DR data from the FinnGen consortium to investigate the genetic and causal associations between STs and DR. Results Patients who experienced daytime sleepiness often/all of the time had a higher risk for DR (OR: 1.40; 95% CI, 1.09–1.79; p = .008) compared with those who sometimes/never/rarely experienced daytime sleepiness. Genetic correlations between several STs and DR were detected by cross-trait linkage disequilibrium score regression. MR suggested a causal effect of self-reported daytime sleepiness (OR: 4.08; 95% CI, 1.44–11.61; p = .008), and accelerator-derived sleep duration (OR: 0.73; 95% CI, 0.54–0.98; p = .036) and sleep efficiency (OR: 0.54; 95% CI, 0.36–0.80; p = .002) on DR. Conclusions STs may have a potential causal role for DR. Attention should be paid to the STs of patients for better prevention and treatment of DR.
Nature genetics · 2015
Lars G Fritsche、Wilmar Igl、Jessica N Cooke Bailey 等
Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
medRxiv · 2025
J. Hu、M. Lupton、E. Byrne 等
Background: Anxiety disorders show striking sex differences in prevalence, symptoms, and clinical characteristics, shaping how they manifest and are experienced. Methods: This study investigated the genetic basis of these differences using sex-specific genome-wide association studies (GWAS). GWAS were conducted separately in females (47,054 cases, 57,027 controls) and males (23,819 cases, 55,030 controls) within the UK Biobank. Functional annotation, sex-specific polygenic scores (PGS), and genetic correlations were performed to assess genetic differences and functional implications. Results: In females, 10 lead SNPs were significantly associated with anxiety, compared to four in males. Among these, three lead SNPs in females and two in males demonstrated significantly different effect sizes across sexes. In addition, SNP-based heritability estimates were significantly different and gene-based tests and functional prioritization identified different genes associated with anxiety in females and males. However, whole-genome analyses, including genetic correlations across sexes and PGS predictions, revealed no significant genetic differences between the sexes. Sex combined GWAS of several traits showed a trend toward sex differences with anxiety in genetic correlation analysis. Sex-specific GWAS on waist-to-hip ratio (WHR) adjusted for BMI enabled separate genetic correlation analyses with anxiety, revealing significant sex differences that were not observed in the combined GWAS. Conclusions: This study is the first sex-specific GWAS of anxiety. While the overall genetic architecture of anxiety is largely shared between sexes, our findings reveal distinct sex-specific genetic associations and correlations, highlighting the value of analysing the sexes separately to uncover genetic signals that may be masked in sex-combined samples.
为什么值得关注
编辑短评邻近 SNP 的因果效应并不独立，同一调控单元内倾向负相关；该模式由稳定选择下的连锁掩蔽产生，打破了遗传力分析里 SNP 效应独立的经典假设，会让高功能区域遗传力被高估。