Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

Background: Lung adenocarcinoma (LUAD) among never-smokers is a public health burden especially prevalent in East Asian (EAS) women. Polygenic risk scores (PRSs), which quanefy geneec suscepebility, are promising for straefying risk, yet have mainly been developed in European (EUR) populaeons. We developed and validated single-and mule-ancestry PRSs for LUAD in EAS never-smokers, using the largest available genome-wide associaeon study (GWAS) dataset. Methods: We used GWAS summary staesecs from both EAS (8,002 cases; 20,782 controls) and EUR (2,058 cases; 5,575 controls) populaeons, as well as independent EAS individual level data. We evaluated several PRSs approaches: a single-ancestry PRS using 25 variants that reached genome-wide significance (PRS-25), a genome-wide Bayesian based approach (LDpred2), and a mule-ancestry approach that models geneec correlaeons across ancestries (CT-SLEB). PRS performance was evaluated based on the associaeon with LUAD and AUC values. We then esemated the lifeeme absolute risk of LUAD (age 30-80) and projected the AUC at different sample sizes using EAS-derived effect-size distribueon and heritability esemates. Findings: The CT-SLEB PRS showed a strong associaeon with LUAD risk (odds raeo=1.71, 95% confidence interval (CI): 1.61, 1.82) with an AUC of 0.640 (95% CI: 0.629, 0.653). Individuals in the 95 th percenele of the PRS had an esemated 6.69% lifeeme absolute risk of LUAD. Comparison of LUAD risk between individuals in the highest and lowest 20% PRS quaneles revealed a 3.92-fold increase. Projeceon analyses indicated that achieving an AUC of 0.70, which approaches the maximized prediceon poteneal of the PRS given the esemated geneec variance, would require a future study encompassing 55,000 EAS LUAD cases with a 1:10 case-control raeo. Interpretations: Our study underscores the poteneal of mule-ancestry PRS approaches to enhance LUAD risk straeficaeon in never-smokers, parecularly in EAS populaeons, and highlights the necessary scale of future research to uncover the geneec underpinnings of LUAD.

Wasm-iCARE: a portable and privacy-preserving web module to build, validate, and apply absolute risk models.

Objectives: Absolute risk models estimate an individual's future disease risk over a specified time interval. Applications utilizing server-side risk tooling, the R-based iCARE (R-iCARE), to build, validate, and apply absolute risk models, face limitations in portability and privacy due to their need for circulating user data in remote servers for operation. We overcome this by porting iCARE to the web platform. Materials and Methods: We refactored R-iCARE into a Python package (Py-iCARE) and then compiled it to WebAssembly (Wasm-iCARE)-a portable web module, which operates within the privacy of the user's device. Results: We showcase the portability and privacy of Wasm-iCARE through 2 applications: for researchers to statistically validate risk models and to deliver them to end-users. Both applications run entirely on the client side, requiring no downloads or installations, and keep user data on-device during risk calculation. Conclusions: Wasm-iCARE fosters accessible and privacy-preserving risk tools, accelerating their validation and delivery.

Polygenic Risk Score, Environmental Tobacco Smoke, and Risk of Lung Adenocarcinoma in Never-Smoking Women in Taiwan.

Importance: Estimating absolute risk of lung cancer for never-smoking individuals is important to inform lung cancer screening programs. Objectives: To integrate data on environmental tobacco smoke (ETS), a known lung cancer risk factor, with a polygenic risk score (PRS) that captures overall genetic susceptibility, to estimate the absolute risk of lung adenocarcinoma (LUAD) among never-smokers in Taiwan. Design, Setting, and Participants: The analyses were conducted in never-smoking women in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma, a case-control study. Participants were recruited between September 17, 2002, and March 30, 2011. Data analysis was performed from January 17 to July 15, 2022. Exposures: A PRS was derived using 25 genetic variants that achieved genome-wide significance (P < 5 × 10-8) in a recent genome-wide association study, and ETS was defined as never exposed, exposed at home or at work, and exposed at home and at work. Main Outcomes and Measures: The Individualized Coherent Absolute Risk Estimator software was used to estimate the lifetime absolute risk of LUAD in never-smoking women aged 40 years over a projected 40-year span among the controls by using the relative risk estimates for the PRS and ETS exposures, as well as age-specific lung cancer incidence rates for never-smokers in Taiwan. Likelihood ratio tests were conducted to assess an additive interaction between the PRS and ETS exposure. Results: Data were obtained on 1024 women with LUAD (mean [SD] age, 59.6 [11.4] years, 47.9% ever exposed to ETS at home, and 19.5% ever exposed to ETS at work) and 1024 controls (mean [SD] age, 58.9 [11.0] years, 37.0% ever exposed to ETS at home, and 14.3% ever exposed to ETS at work). The overall average lifetime 40-year absolute risk of LUAD estimated using PRS alone was 2.5% (range, 0.6%-10.3%) among women never exposed to ETS. When integrating both ETS and PRS data, the estimated absolute risk was 3.7% (range, 0.6%-14.5%) for women exposed to ETS at home or work and 5.3% (range, 1.2%-12.1%) for women exposed to ETS at home and work. A super-additive interaction between ETS and the PRS (P = 6.5 × 10-4 for interaction) was identified. Conclusions and Relevance: This study found differences in absolute risk of LUAD attributed to genetic susceptibility according to levels of ETS exposure in never-smoking women. Future studies are warranted to integrate these findings in expanded risk models for LUAD.

Wasm-iCARE: a portable and privacy-preserving web module to build, validate, and apply absolute risk models.

Objective: Absolute risk models estimate an individual's future disease risk over a specified time interval. Applications utilizing server-side risk tooling, such as the R-based iCARE (R-iCARE), to build, validate, and apply absolute risk models, face serious limitations in portability and privacy due to their need for circulating user data in remote servers for operation. Our objective was to overcome these limitations. Materials and Methods: We refactored R-iCARE into a Python package (Py-iCARE) then compiled it to WebAssembly (Wasm-iCARE): a portable web module, which operates entirely within the privacy of the user's device. Results: We showcase the portability and privacy of Wasm-iCARE through two applications: for researchers to statistically validate risk models, and to deliver them to end-users. Both applications run entirely on the client-side, requiring no downloads or installations, and keeps user data on-device during risk calculation. Conclusions: Wasm-iCARE fosters accessible and privacy-preserving risk tools, accelerating their validation and delivery.

Moving Toward Findable, Accessible, Interoperable, Reusable Practices in Epidemiologic Research.

Data sharing is essential for reproducibility of epidemiologic research, replication of findings, pooled analyses in consortia efforts, and maximizing study value to address multiple research questions. However, barriers related to confidentiality, costs, and incentives often limit the extent and speed of data sharing. Epidemiological practices that follow Findable, Accessible, Interoperable, Reusable (FAIR) principles can address these barriers by making data resources findable with the necessary metadata, accessible to authorized users, and interoperable with other data, to optimize the reuse of resources with appropriate credit to its creators. We provide an overview of these principles and describe approaches for implementation in epidemiology. Increasing degrees of FAIRness can be achieved by moving data and code from on-site locations to remote, accessible ("Cloud") data servers, using machine-readable and nonproprietary files, and developing open-source code. Adoption of these practices will improve daily work and collaborative analyses and facilitate compliance with data sharing policies from funders and scientific journals. Achieving a high degree of FAIRness will require funding, training, organizational support, recognition, and incentives for sharing research resources, both data and code. However, these costs are outweighed by the benefits of making research more reproducible, impactful, and equitable by facilitating the reuse of precious research resources by the scientific community.

Breast Cancer Risk in Women from Ghana Carrying Rare Germline Pathogenic Mutations.

BACKGROUND: Risk estimates for women carrying germline mutations in breast cancer susceptibility genes are mainly based on studies of European ancestry women. METHODS: We investigated associations between pathogenic variants (PV) in 34 genes with breast cancer risk in 871 cases [307 estrogen receptor (ER)-positive, 321 ER-negative, and 243 ER-unknown] and 1,563 controls in the Ghana Breast Health Study (GBHS), and estimated lifetime risk for carriers. We compared results with those for European, Asian, and African American ancestry women. RESULTS: The frequency of PV in GBHS for nine breast cancer genes was 8.38% in cases and 1.22% in controls. Relative risk estimates for overall breast cancer were: (OR, 13.70; 95% confidence interval (CI), 4.03-46.51) for BRCA1, (OR, 7.02; 95% CI, 3.17-15.54) for BRCA2, (OR, 17.25; 95% CI, 2.15-138.13) for PALB2, 5 cases and no controls carried TP53 PVs, and 2.10, (0.72-6.14) for moderate-risk genes combined (ATM, BARD1, CHEK2, RAD51C, RAD52D). These estimates were similar to those previously reported in other populations and were modified by ER status. No other genes evaluated had mutations associated at P < 0.05 with overall risk. The estimated lifetime risks for mutation carriers in BRCA1, BRCA2, and PALB2 and moderate-risk genes were 18.4%, 9.8%, 22.4%, and 3.1%, respectively, markedly lower than in Western populations with higher baseline risks. CONCLUSIONS: We confirmed associations between PV and breast cancer risk in Ghanaian women and provide absolute risk estimates that could inform counseling in Ghana and other West African countries. IMPACT: These findings have direct relevance for breast cancer genetic counseling for women in West Africa.

Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

The Association of Vitamin D Deficiency and Incident Frailty in Older Women: The Role of Cardiometabolic Diseases.

OBJECTIVES: Evidence suggests vitamin D deficiency is associated with developing frailty. However, cardiometabolic factors are related to both conditions and may confound and/or mediate the vitamin D-frailty association. We aimed to determine the association of vitamin D concentration with incidence of frailty, and the role of cardiometabolic diseases (cardiovascular disease, diabetes, hyperlipidemia, hypertension) in this relationship. DESIGN: Prospective longitudinal cohort study (7 visits from 1994-2008). SETTING: Baltimore, Maryland. PARTICIPANTS: Three hundred sixty-nine women from the Women's Health and Aging Study II aged 70-79 years, free of frailty at baseline. MEASUREMENTS: Serum circulating 25-hydroxyvitamin D (25[OH]D) concentration was assessed at baseline and categorized as: <10; 10-19.9; 20-29.9; and ≥30 ng/mL. Frailty incidence was determined based on presence of three or more criteria: weight loss, low physical activity, exhaustion, weakness, and slowness. Cardiometabolic diseases were ascertained at baseline. Analyses included Cox regression models adjusted for key covariates. RESULTS: Incidence rate of frailty was 32.2 per 1,000 person-years in participants with 25(OH)D < 10 ng/mL, compared to 12.9 per 1,000 person-years in those with 25(OH)D ≥ 30 ng/mL (mean follow-up = 8.5 ± 3.7 years). In cumulative incidence analyses, those with lower 25(OH)D exhibited higher frailty incidence, though differences were non-significant (P = .057). In regression models adjusted for demographics, smoking, and season, 25(OH)D < 10 ng/mL (vs ≥30 ng/mL) was associated with nearly three-times greater frailty incidence (hazard ratio (HR) = 2.77, 95% CI = 1.14, 6.71, P = .02). After adjusting for BMI, the relationship of 25(OH)D < 10 ng/mL (vs ≥30 ng/mL) with incident frailty persisted, but was attenuated after further accounting for cardiometabolic diseases (HR = 2.29, 95% CI = 0.92, 5.69, P = .07). CONCLUSION: Low serum vitamin D concentration is associated with incident frailty in older women; interestingly, the relationship is no longer significant after accounting for the presence of cardiometabolic diseases. Future studies should explore mechanisms to explain this relationship.