Genomic Insights for Personalized Care: Motivating At-Risk Individuals Toward Evidence-Based Health Practices.

Lung cancer and tobacco use pose significant global health challenges and require a comprehensive translational roadmap for improved prevention strategies. We propose the GREAT care paradigm ( G enomic Informed Care for Motivating High R isk Individuals E ligible for Evidence-b a sed Prevention), which employs polygenic risk scores (PRSs) to stratify disease risk and personalize interventions, such as lung cancer screening and tobacco treatment. We developed PRSs using large-scale multi-ancestry genome-wide association studies and adjusted for genetic ancestry for standardized risk stratification across diverse populations. We applied our PRSs to over 340,000 individuals of diverse ethnic background and found significant odds ratios for lung cancer and difficulty quitting smoking. These findings enable the evaluation of PRS-based interventions in ongoing trials aimed at motivating health behavior changes in high-risk patients. This pioneering approach enhances primary care with genomic insights, promising improved outcomes in cancer prevention and tobacco treatment, and is currently under assessment in clinical trials.

Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification.

BACKGROUND: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. METHODS: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. RESULTS: Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12-3.50, P-value = 4.13 × 10-15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99-2.49, P-value = 5.70 × 10-46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72-0.74). CONCLUSIONS: Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS.

Host genetic variants, Epstein-Barr virus subtypes, and the risk of nasopharyngeal carcinoma: Assessment of interaction and mediation.

Epstein-Barr virus (EBV) and human leukocyte antigen (HLA) polymorphisms are well-known risk factors for nasopharyngeal carcinoma (NPC). However, the combined effects between HLA and EBV on the risk of NPC are unknown. We applied a causal inference framework to disentangle interaction and mediation effects between two host HLA SNPs, rs2860580 and rs2894207, and EBV variant 163364 with a population-based case-control study in NPC-endemic southern China. We discovered the strong interaction effects between the high-risk EBV subtype and both HLA SNPs on NPC risk (rs2860580, relative excess risk due to interaction [RERI] = 4.08, 95% confidence interval [CI] = 2.03-6.14; rs2894207, RERI = 3.37, 95% CI = 1.59-5.15), accounting for the majority of genetic risk effects. These results indicate that HLA genes and the high-risk EBV have joint effects on NPC risk. Prevention strategies targeting the high-risk EBV subtype would largely reduce NPC risk associated with EBV and host genetic susceptibility.

Accurate and efficient estimation of local heritability using summary statistics and the linkage disequilibrium matrix.

Existing SNP-heritability estimators that leverage summary statistics from genome-wide association studies (GWAS) are much less efficient (i.e., have larger standard errors) than the restricted maximum likelihood (REML) estimators which require access to individual-level data. We introduce a new method for local heritability estimation-Heritability Estimation with high Efficiency using LD and association Summary Statistics (HEELS)-that significantly improves the statistical efficiency of summary-statistics-based heritability estimator and attains comparable statistical efficiency as REML (with a relative statistical efficiency >92%). Moreover, we propose representing the empirical LD matrix as the sum of a low-rank matrix and a banded matrix. We show that this way of modeling the LD can not only reduce the storage and memory cost, but also improve the computational efficiency of heritability estimation. We demonstrate the statistical efficiency of HEELS and the advantages of our proposed LD approximation strategies both in simulations and through empirical analyses of the UK Biobank data.

Ensembled best subset selection using summary statistics for polygenic risk prediction.

Polygenic risk scores (PRS) enhance population risk stratification and advance personalized medicine, yet existing methods face a tradeoff between predictive power and computational efficiency. We introduce ALL-Sum, a fast and scalable PRS method that combines an efficient summary statistic-based L 0 L 2 penalized regression algorithm with an ensembling step that aggregates estimates from different tuning parameters for improved prediction performance. In extensive large-scale simulations across a wide range of polygenicity and genome-wide association studies (GWAS) sample sizes, ALL-Sum consistently outperforms popular alternative methods in terms of prediction accuracy, runtime, and memory usage. We analyze 27 published GWAS summary statistics for 11 complex traits from 9 reputable data sources, including the Global Lipids Genetics Consortium, Breast Cancer Association Consortium, and FinnGen, evaluated using individual-level UKBB data. ALL-Sum achieves the highest accuracy for most traits, particularly for GWAS with large sample sizes. We provide ALL-Sum as a user-friendly command-line software with pre-computed reference data for streamlined user-end analysis.

Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium.

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

A new method for multiancestry polygenic prediction improves performance across diverse populations.

Polygenic risk scores (PRSs) increasingly predict complex traits; however, suboptimal performance in non-European populations raise concerns about clinical applications and health inequities. We developed CT-SLEB, a powerful and scalable method to calculate PRSs, using ancestry-specific genome-wide association study summary statistics from multiancestry training samples, integrating clumping and thresholding, empirical Bayes and superlearning. We evaluated CT-SLEB and nine alternative methods with large-scale simulated genome-wide association studies (~19 million common variants) and datasets from 23andMe, Inc., the Global Lipids Genetics Consortium, All of Us and UK Biobank, involving 5.1 million individuals of diverse ancestry, with 1.18 million individuals from four non-European populations across 13 complex traits. Results demonstrated that CT-SLEB significantly improves PRS performance in non-European populations compared with simple alternatives, with comparable or superior performance to a recent, computationally intensive method. Moreover, our simulation studies offered insights into sample size requirements and SNP density effects on multiancestry risk prediction.

Caught in the crossfire: Fears of Chinese-American scientists.

The US global leadership in science and technology has greatly benefitted from immigrants from other countries, most notably from China in the recent decades. However, feeling the pressure of potential federal investigations since the 2018 launch of the China Initiative, scientists of Chinese descent in the United States now face higher incentives to leave the United States and lower incentives to apply for federal grants. Analyzing data pertaining to institutional affiliations of more than 200 million scientific papers, we find a steady increase in the return migration of scientists of Chinese descent from the United States to China. We also conducted a survey of scientists of Chinese descent employed by US universities in tenured or tenure-track positions (n = 1,304), with results revealing general feelings of fear and anxiety that lead them to consider leaving the United States and/or stop applying for federal grants. If the situation is not corrected, American science will likely suffer the loss of scientific talent to China and other countries.

Lung cancer risk discrimination of prediagnostic proteomics measurements compared with existing prediction tools.

BACKGROUND: We sought to develop a proteomics-based risk model for lung cancer and evaluate its risk-discriminatory performance in comparison with a smoking-based risk model (PLCOm2012) and a commercially available autoantibody biomarker test. METHODS: We designed a case-control study nested in 6 prospective cohorts, including 624 lung cancer participants who donated blood samples at most 3 years prior to lung cancer diagnosis and 624 smoking-matched cancer free participants who were assayed for 302 proteins. We used 470 case-control pairs from 4 cohorts to select proteins and train a protein-based risk model. We subsequently used 154 case-control pairs from 2 cohorts to compare the risk-discriminatory performance of the protein-based model with that of the Early Cancer Detection Test (EarlyCDT)-Lung and the PLCOm2012 model using receiver operating characteristics analysis and by estimating models' sensitivity. All tests were 2-sided. RESULTS: The area under the curve for the protein-based risk model in the validation sample was 0.75 (95% confidence interval [CI] = 0.70 to 0.81) compared with 0.64 (95% CI = 0.57 to 0.70) for the PLCOm2012 model (Pdifference = .001). The EarlyCDT-Lung had a sensitivity of 14% (95% CI = 8.2% to 19%) and a specificity of 86% (95% CI = 81% to 92%) for incident lung cancer. At the same specificity of 86%, the sensitivity for the protein-based risk model was estimated at 49% (95% CI = 41% to 57%) and 30% (95% CI = 23% to 37%) for the PLCOm2012 model. CONCLUSION: Circulating proteins showed promise in predicting incident lung cancer and outperformed a standard risk prediction model and the commercialized EarlyCDT-Lung.

Impact of Aneuploidy and Chromosome 9p Loss on Tumor Immune Microenvironment and Immune Checkpoint Inhibitor Efficacy in NSCLC.

INTRODUCTION: Although gene-level copy number alterations have been studied as a potential biomarker of immunotherapy efficacy in NSCLC, the impact of aneuploidy burden and chromosomal arm-level events on immune checkpoint inhibitor (ICI) efficacy in NSCLC is uncertain. METHODS: Patients who received programmed cell death protein 1 or programmed death-ligand 1 (PD-L1) inhibitor at two academic centers were included. Across all 22 chromosomes analyzed, an arm was considered altered if at least 70% of its territory was either gained or deleted. Among nonsquamous NSCLCs which underwent targeted next-generation sequencing, we retrospectively quantified aneuploidy using the adjusted fraction of chromosomal arm alterations (FAA), defined as the number of altered chromosome arms divided by the number of chromosome arms assessed, adjusted for tumor purity. RESULTS: Among 2293 nonsquamous NSCLCs identified, the median FAA increased with more advanced cancer stage and decreased with higher PD-L1 tumor proportion score (TPS) levels (median FAA in TPS < 1%: 0.09, TPS 1%-49%: 0.08, TPS ≥ 50%: 0.05, p < 0.0001). There was a very weak correlation between FAA and tumor mutational burden when taken as continuous variables (R: 0.07, p = 0.0005). A total of 765 advanced nonsquamous NSCLCs with available FAA values were treated with ICIs. With decreasing FAA tertiles, there was a progressive improvement in objective response rate (ORR 15.1% in upper tertile versus 23.2% in middle tertile versus 28.4% in lowest tertile, p = 0.001), median progression-free survival (mPFS 2.5 versus 3.3 versus 4.1 mo, p < 0.0001), and median overall survival (mOS 12.5 versus 13.9 versus 16.4 mo, p = 0.006), respectively. In the arm-level enrichment analysis, chromosome 9p loss (OR = 0.22, Q = 0.0002) and chromosome 1q gain (OR = 0.43, Q = 0.002) were significantly enriched in ICI nonresponders after false discovery rate adjustment. Compared with NSCLCs without chromosome 9p loss (n = 452), those with 9p loss (n = 154) had a lower ORR (28.1% versus 7.8%, p < 0.0001), a shorter mPFS (4.1 versus 2.3 mo, p < 0.0001), and a shorter mOS (18.0 versus 9.6 mo, p < 0.0001) to immunotherapy. In addition, among NSCLCs with high PD-L1 expression (TPS ≥ 50%), chromosome 9p loss was associated with lower ORR (43% versus 6%, p < 0.0001), shorter mPFS (6.4 versus 2.6 mo, p = 0.0006), and shorter mOS (30.2 versus 14.3 mo, p = 0.0008) to immunotherapy compared with NSCLCs without 9p loss. In multivariable analysis, adjusting for key variables including FAA, chromosome 9p loss, but not 1q gain, retained a significant impact on ORR (hazard ratio [HR] = 0.25, p < 0.001), mPFS (HR = 1.49, p = 0.001), and mOS (HR = 1.47, p = 0.003). Multiplexed immunofluorescence and computational deconvolution of RNA sequencing data revealed that tumors with either high FAA levels or chromosome 9p loss had significantly fewer tumor-associated cytotoxic immune cells. CONCLUSIONS: Nonsquamous NSCLCs with high aneuploidy and chromosome 9p loss have a distinct tumor immune microenvironment and less favorable outcomes to ICIs.

Unraveling attributes of COVID-19 vaccine acceptance and uptake in the U.S.: a large nationwide study.

SARS-CoV-2 vaccines are useful tools to combat the Coronavirus Disease 2019 (COVID-19) pandemic, but vaccine reluctance threatens these vaccines' effectiveness. To address COVID-19 vaccine reluctance and ensure equitable distribution, understanding the extent of and factors associated with vaccine acceptance and uptake is critical. We report the results of a large nationwide study in the US conducted December 2020-May 2021 of 36,711 users from COVID-19-focused smartphone-based app How We Feel on their willingness to receive a COVID-19 vaccine. We identified sociodemographic and behavioral factors that were associated with COVID-19 vaccine acceptance and uptake, and we found several vulnerable groups at increased risk of COVID-19 burden, morbidity, and mortality were more likely to be reluctant to accept a vaccine and had lower rates of vaccination. Our findings highlight specific populations in which targeted efforts to develop education and outreach programs are needed to overcome poor vaccine acceptance and improve equitable access, diversity, and inclusion in the national response to COVID-19.

Advanced non-small-cell lung cancer treated with first-line pembrolizumab plus chemotherapy: tumor response dynamics as a marker for survival.

OBJECTIVES: The study investigated tumor burden dynamics on computed tomography (CT) scans in patients with advanced non-small-cell lung cancer (NSCLC) during first-line pembrolizumab plus chemotherapy, to provide imaging markers for overall survival (OS). METHODS: The study included 133 patients treated with first-line pembrolizumab plus platinum-doublet chemotherapy. Serial CT scans during therapy were assessed for tumor burden dynamics during therapy, which were studied for the association with OS. RESULTS: There were 67 responders, with overall response rate of 50%. The tumor burden change at the best overall response ranged from - 100.0% to + 132.1% (median of - 30%). Higher response rates were associated with younger age (p < 0.001) and higher programmed cell death-1 (PD-L1) expression levels (p = 0.01). Eighty-three patients (62%) showed tumor burden below the baseline burden throughout therapy. Using an 8-week landmark analysis, OS was longer in patients with tumor burden below the baseline burden in the first 8 weeks than in those who experienced ≥ 0% increase (median OS: 26.8 vs. 7.6 months, hazard ratio (HR): 0.36, p < 0.001). Tumor burden remained below their baseline throughout therapy was associated with significantly reduced hazards of death (HR: 0.72, p = 0.03) in the extended Cox models, after adjusting for other clinical variables. Pseudoprogression was noted in only one patient (0.8%). CONCLUSIONS: Tumor burden staying below the baseline burden throughout the therapy was predictive of prolonged overall survival in patients with advanced NSCLC treated with first-line pembrolizumab plus chemotherapy, and may be used as a practical marker for therapeutic decisions in this widely used combination regimen. CLINICAL RELEVANCE STATEMENT: The analysis of tumor burden dynamics on serial CT scans in reference to the baseline burden can provide an additional objective guide for treatment decision making in patients treated with first-line pembrolizumab plus chemotherapy for their advanced NSCLC. KEY POINTS: • Tumor burden remaining below baseline burden during therapy predicted longer survival during first-line pembrolizumab plus chemotherapy. • Pseudoprogression was noted in 0.8%, demonstrating the rarity of the phenomenon. • Tumor burden dynamics may serve as an objective marker for treatment benefit to guide treatment decisions during first-line pembrolizumab plus chemotherapy.

Accurate and Efficient Estimation of Local Heritability using Summary Statistics and LD Matrix.

Existing SNP-heritability estimation methods that leverage GWAS summary statistics produce estimators that are less efficient than the restricted maximum likelihood (REML) estimator using individual-level data under linear mixed models (LMMs). Increasing the precision of a heritability estimator is particularly important for regional analyses, as local genetic variances tend to be small. We introduce a new estimator for local heritability, "HEELS", which attains comparable statistical efficiency as REML (\emph{i.e.} relative efficiency greater than 92%) but only requires summary-level statistics -- Z-scores from the marginal association tests plus the empirical LD matrix. HEELS significantly improves the statistical efficiency of the existing summary-statistics-based heritability estimators-- for instance, HEELS produces heritability estimates that are more than 3-fold and 7-times less variable than GRE and LDSC, respectively. Moreover, we introduce a unified framework to evaluate and compare the performance of different LD approximation strategies. We propose representing the empirical LD as the sum of a low-rank matrix and a banded matrix. This approximation not only reduces the storage and memory cost of using the LD matrix, but also improves the computational efficiency of the HEELS estimation. We demonstrate the statistical efficiency of HEELS and the advantages of our proposed LD approximation strategies both in simulations and through empirical analyses of the UK Biobank data.

Clinicopathologic and Genomic Factors Impacting Efficacy of First-Line Chemoimmunotherapy in Advanced NSCLC.

INTRODUCTION: Although programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) blockade in combination with platinum-doublet chemotherapy has become a mainstay of first-line treatment for advanced NSCLC, factors associated with efficacy of chemoimmunotherapy (CIT) are not well characterized. METHODS: In this multicenter retrospective analysis, clinicopathologic and genomic data were collected from patients with advanced NSCLC (lacking sensitizing genomic alterations in EGFR and ALK) and evaluated with clinical outcomes to first-line CIT. RESULTS: Among 1285 patients treated with CIT, a worsening performance status and increasing derived neutrophil-to-lymphocyte ratio in the blood were associated with a significantly reduced objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS). With increasing PD-L1 tumor proportion scores of less than 1%, 1% to 49%, 50% to 89%, and greater than or equal to 90%, there was a progressive improvement in ORR (32.7% versus 37.5% versus 51.6% versus 61.7%, p < 0.001), mPFS (5.0 versus 6.1 versus 6.8 versus 13.0 mo, p < 0.001), and generally mOS (12.9 versus 14.6 versus 34.7 versus 23.1 mo, p = 0.009), respectively. Of 789 NSCLCs with comprehensive genomic data, NSCLCs with a tumor mutational burden (TMB) greater than or equal to the 90th percentile had an improved ORR (53.5% versus 36.4%, p = 0.004), mPFS (10.8 versus 5.5 mo, p < 0.001), and mOS (29.2 versus 13.1 mo, p < 0.001), compared with those with a TMB less than the 90th percentile. In all-comers with nonsquamous NSCLC, the presence of an STK11, KEAP1, or SMARCA4 mutation was associated with significantly worse ORR, mPFS, and mOS to CIT (all p < 0.05); this was also observed in the KRAS-mutant subgroup of NSCLCs with co-occurring mutations in STK11, KEAP1, or SMARCA4 (all p < 0.05). In KRAS wild-type NSCLC, KEAP1 and SMARCA4 mutations were associated with a significantly shorter mPFS and mOS to CIT (all p < 0.05), but STK11 mutation status had no significant impact on mPFS (p = 0.16) or mOS (p = 0.38). CONCLUSIONS: In advanced NSCLC, better patient performance status, low derived neutrophil-to-lymphocyte ratio, increasing PD-L1 expression, a very high TMB, and STK11/KEAP1/SMARCA4 wild-type status are associated with improved clinical outcomes to first-line CIT.

Leveraging a surrogate outcome to improve inference on a partially missing target outcome.

Sample sizes vary substantially across tissues in the Genotype-Tissue Expression (GTEx) project, where considerably fewer samples are available from certain inaccessible tissues, such as the substantia nigra (SSN), than from accessible tissues, such as blood. This severely limits power for identifying tissue-specific expression quantitative trait loci (eQTL) in undersampled tissues. Here we propose Surrogate Phenotype Regression Analysis (Spray) for leveraging information from a correlated surrogate outcome (eg, expression in blood) to improve inference on a partially missing target outcome (eg, expression in SSN). Rather than regarding the surrogate outcome as a proxy for the target outcome, Spray jointly models the target and surrogate outcomes within a bivariate regression framework. Unobserved values of either outcome are treated as missing data. We describe and implement an expectation conditional maximization algorithm for performing estimation in the presence of bilateral outcome missingness. Spray estimates the same association parameter estimated by standard eQTL mapping and controls the type I error even when the target and surrogate outcomes are truly uncorrelated. We demonstrate analytically and empirically, using simulations and GTEx data, that in comparison with marginally modeling the target outcome, jointly modeling the target and surrogate outcomes increases estimation precision and improves power.

FAVOR: functional annotation of variants online resource and annotator for variation across the human genome.

Large biobank-scale whole genome sequencing (WGS) studies are rapidly identifying a multitude of coding and non-coding variants. They provide an unprecedented resource for illuminating the genetic basis of human diseases. Variant functional annotations play a critical role in WGS analysis, result interpretation, and prioritization of disease- or trait-associated causal variants. Existing functional annotation databases have limited scope to perform online queries and functionally annotate the genotype data of large biobank-scale WGS studies. We develop the Functional Annotation of Variants Online Resources (FAVOR) to meet these pressing needs. FAVOR provides a comprehensive multi-faceted variant functional annotation online portal that summarizes and visualizes findings of all possible nine billion single nucleotide variants (SNVs) across the genome. It allows for rapid variant-, gene- and region-level queries of variant functional annotations. FAVOR integrates variant functional information from multiple sources to describe the functional characteristics of variants and facilitates prioritizing plausible causal variants influencing human phenotypes. Furthermore, we provide a scalable annotation tool, FAVORannotator, to functionally annotate large-scale WGS studies and efficiently store the genotype and their variant functional annotation data in a single file using the annotated Genomic Data Structure (aGDS) format, making downstream analysis more convenient. FAVOR and FAVORannotator are available at https://favor.genohub.org.

Daily positive and negative affect during the COVID-19 pandemic.

The COVID-19 pandemic influenced emotional experiences globally. We examined daily positive and negative affect between May/June 2020 and February 2021 (N = 151,049; 3,509,982 observations) using a convenience sample from a national mobile application-based survey that asked for daily affect reports. Four questions were examined: (1) How did people in the United States feel from May/June 2020 to February 2021?; (2) What demographic variables are related to positive and negative affect?; (3) What is the relationship between experienced stressors and daily affect?; and (4) What is the relationship between daily affect and preventive behavior? Positive affect increased, and negative decreased over time. Demographic differences mirrored those from before the pandemic (e.g., younger participants reported more negative and less positive affect). Stressors such as feeling unwell, experiencing COVID-19 symptoms, exposure to COVID-19, and lack of sleep were associated with less positive and more negative affect. Exercising protective behaviors predicted future affect, and affect also predicted future protective behaviors (e.g., less protective behavior when happy but more when grateful and thoughtful). The implications for public health communication were discussed.

Efficient and accurate frailty model approach for genome-wide survival association analysis in large-scale biobanks.

With decades of electronic health records linked to genetic data, large biobanks provide unprecedented opportunities for systematically understanding the genetics of the natural history of complex diseases. Genome-wide survival association analysis can identify genetic variants associated with ages of onset, disease progression and lifespan. We propose an efficient and accurate frailty model approach for genome-wide survival association analysis of censored time-to-event (TTE) phenotypes by accounting for both population structure and relatedness. Our method utilizes state-of-the-art optimization strategies to reduce the computational cost. The saddlepoint approximation is used to allow for analysis of heavily censored phenotypes (>90%) and low frequency variants (down to minor allele count 20). We demonstrate the performance of our method through extensive simulation studies and analysis of five TTE phenotypes, including lifespan, with heavy censoring rates (90.9% to 99.8%) on ~400,000 UK Biobank participants with white British ancestry and ~180,000 individuals in FinnGen. We further analyzed 871 TTE phenotypes in the UK Biobank and presented the genome-wide scale phenome-wide association results with the PheWeb browser.

Differences in set-based tests for sparse alternatives when testing sets of outcomes compared to sets of explanatory factors in genetic association studies.

Set-based association tests are widely popular in genetic association settings for their ability to aggregate weak signals and reduce multiple testing burdens. In particular, a class of set-based tests including the Higher Criticism, Berk-Jones, and other statistics have recently been popularized for reaching a so-called detection boundary when signals are rare and weak. Such tests have been applied in two subtly different settings: (a) associating a genetic variant set with a single phenotype and (b) associating a single genetic variant with a phenotype set. A significant issue in practice is the choice of test, especially when deciding between innovated and generalized type methods for detection boundary tests. Conflicting guidance is present in the literature. This work describes how correlation structures generate marked differences in relative operating characteristics for settings (a) and (b). The implications for study design are significant. We also develop novel power bounds that facilitate the aforementioned calculations and allow for analysis of individual testing settings. In more concrete terms, our investigation is motivated by translational expression quantitative trait loci (eQTL) studies in lung cancer. These studies involve both testing for groups of variants associated with a single gene expression (multiple explanatory factors) and testing whether a single variant is associated with a group of gene expressions (multiple outcomes). Results are supported by a collection of simulation studies and illustrated through lung cancer eQTL examples.

Large-Scale Hypothesis Testing for Causal Mediation Effects with Applications in Genome-wide Epigenetic Studies.

In genome-wide epigenetic studies, it is of great scientific interest to assess whether the effect of an exposure on a clinical outcome is mediated through DNA methylations. However, statistical inference for causal mediation effects is challenged by the fact that one needs to test a large number of composite null hypotheses across the whole epigenome. Two popular tests, the Wald-type Sobel's test and the joint significant test using the traditional null distribution are underpowered and thus can miss important scientific discoveries. In this paper, we show that the null distribution of Sobel's test is not the standard normal distribution and the null distribution of the joint significant test is not uniform under the composite null of no mediation effect, especially in finite samples and under the singular point null case that the exposure has no effect on the mediator and the mediator has no effect on the outcome. Our results explain why these two tests are underpowered, and more importantly motivate us to develop a more powerful Divide-Aggregate Composite-null Test (DACT) for the composite null hypothesis of no mediation effect by leveraging epigenome-wide data. We adopted Efron's empirical null framework for assessing statistical significance of the DACT test. We showed analytically that the proposed DACT method had improved power, and could well control type I error rate. Our extensive simulation studies showed that, in finite samples, the DACT method properly controlled the type I error rate and outperformed Sobel's test and the joint significance test for detecting mediation effects. We applied the DACT method to the US Department of Veterans Affairs Normative Aging Study, an ongoing prospective cohort study which included men who were aged 21 to 80 years at entry. We identified multiple DNA methylation CpG sites that might mediate the effect of smoking on lung function with effect sizes ranging from -0.18 to -0.79 and false discovery rate controlled at level 0.05, including the CpG sites in the genes AHRR and F2RL3. Our sensitivity analysis found small residual correlations (less than 0.01) of the error terms between the outcome and mediator regressions, suggesting that our results are robust to unmeasured confounding factors.