Validation of GenProb-T1D and its clinical utility for differentiating types of diabetes in a biobank from a US healthcare system.

Atypical diabetes with overlapping clinical features of type 1 (T1D) and type 2 (T2D) is common and challenging diagnostically and for implementing effective treatment. Here, we validate a recently reported genetic probability of type 1 diabetes (GenProb-T1D) from the UK Biobank (UKB) for differentiating type 1 diabetes and type 2 diabetes in a diabetes patient cohort from a healthcare system-based biobank in the USA. Among 3,363 diabetes patients, we confirmed the performance of GenProb-T1D in differentiating typical type 1 diabetes vs type 2 diabetes.

Personalized medicine in a community health system: the NorthShore experience.

Genomic and personalized medicine implementation efforts have largely centered on specialty care in tertiary health systems. There are few examples of fully integrated care systems that span the healthcare continuum. In 2014, NorthShore University HealthSystem launched the Center for Personalized Medicine to catalyze the delivery of personalized medicine.

Cancer-associated thrombosis by cancer sites and inherited factors in a prospective population-based cohort.

Cancer-associated thrombosis (CAT) is common and associated with mortality. We estimated CAT rate by cancer sites and inherited factors among cancer patients from the UK Biobank (N =70,406). The 12-month CAT rate after cancer diagnosis was 2.

Refining Risk for Alzheimer's Disease Among Heterozygous APOEɛ4 Carriers.

In a large population-based cohort, we show not all heterozygous APOEɛ4 carriers are at increased risk for Alzheimer's disease (AD); a significantly higher AD proportion was only found for ɛ3/ɛ4, not ɛ2/ɛ4. Among ɛ3/ɛ4 carriers (24% in the cohort), the AD proportion differed considerably by polygenic risk score (PRS). In particular, the AD proportion was lower than the entire cohort for subjects in the bottom 20-percentile PRS and was higher than that of homozygous ɛ4 carriers for subjects at the top 5th-percentile PRS.

Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2.

Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.

Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies.

Association of Reported Candidate Monogenic Genes With Lung Cancer Risk.

Introduction/background: Published studies on association of germline monogenic genes and lung cancer risk were inconsistent. Our objective is to assess the validity of reported candidate monogenic genes for their association with lung cancer.

Materials And Methods: A systematic review of published papers prior to August 2022 was performed first to identify all genes where germline mutations were associated with lung cancer risk.

Reliability of Ancestry-specific Prostate Cancer Genetic Risk Score in Four Racial and Ethnic Populations.

Background: Reliability of prostate cancer (PCa) genetic risk score (GRS), that is, the concordance between its estimated risk and observed risk, is required for genetic testing at the individual level. Reliability data are lacking for non-European racial/ethnic populations, which hinders its clinical use and exacerbates racial disparity.

Objective: To calibrate PCa ancestry-specific GRS in four racial/ethnic populations.

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers.

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation.

Effect Modification by Social Determinants of Pharmacogenetic Medication Interactions on 90-Day Hospital Readmissions within an Integrated U.S. Healthcare System.

The present study builds on our prior work that demonstrated an association between pharmacogenetic interactions and 90-day readmission. In a substantially larger, more diverse study population of 19,999 adults tracked from 2010 through 2020 who underwent testing with a 13-gene pharmacogenetic panel, we included additional covariates to evaluate aggregate contribution of social determinants and medical comorbidity with the presence of identified gene-x-drug interactions to moderate 90-day hospital readmission (primary outcome). Univariate logistic regression analyses demonstrated that strongest associations with 90 day hospital readmissions were the number of medications prescribed within 30 days of a first hospital admission that had Clinical Pharmacogenomics Implementation Consortium (CPIC) guidance (CPIC medications) (5+ CPIC medications, odds ratio (OR) = 7.

Inherited risk assessment and its clinical utility for predicting prostate cancer from diagnostic prostate biopsies.

Background: Many studies on prostate cancer (PCa) germline variants have been published in the last 15 years. This review critically assesses their clinical validity and explores their utility in prediction of PCa detection rates from prostate biopsy.

Methods: An integrative review was performed to (1) critically synthesize findings on PCa germline studies from published papers since 2016, including risk-associated single nucleotide polymorphisms (SNPs), polygenic risk score methods such as genetic risk score (GRS), and rare pathogenic mutations (RPMs); (2) exemplify the findings in a large population-based cohort from the UK Biobank (UKB); (3) identify gaps for implementing inherited risk assessment in clinic based on experience from a healthcare system; (4) evaluate available GRS data on their clinical utility in predicting PCa detection rates from prostate biopsies; and (5) describe a prospective germline-based biopsy trial to address existing gaps.

Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction.

The integration of personalized medicine into health systems: progress and a path forward.

Tweetable abstract Fueled by technological advancements and the integration efforts of many pioneer health systems, personalized medicine is now being clinically implemented at measurable but incomplete levels system-wide.

Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study.

Background: The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders.

Implementing Primary Care Mediated Population Genetic Screening Within an Integrated Health System.

Introduction: Genetic screenings can have a large impact on enabling personalized preventive care. However, this can be limited by the primary use of medical history-based screenings in determining care. The purpose of this study was to understand the impact of DNA10K, a population-based genetic screening program mediated by primary care physicians within an integrated health system to emphasize its contribution to preventive healthcare.

Observed evidence for guideline-recommended genes in predicting prostate cancer risk from a large population-based cohort.

Background: Germline testing for prostate cancer (PCa) is now recommended by the National Comprehensive Cancer Network. While multi-gene testing has been proposed, evidence for their association with PCa risk is not well established.

Methods: We tested associations of pathogenic/likely pathogenic mutations in 10 guideline-recommended genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, MLH1, MSH2, MSH6, PMS2, and HOXB13) with PCa risk in the UK Biobank, a population-based cohort.

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Purpose: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS and CBC risk.

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies.

Patient-Reported Outcomes and Experiences with Population Genetic Testing Offered Through a Primary Care Network.

To explore patient experiences in a large-scale primary care-based, preemptive genetic testing program. Patients who received genetic results from the initiative were invited to participate in an online survey 3 weeks postresult disclosure. A 6-month follow-up survey was sent to assess changes over time.

Calibration of polygenic risk scores is required prior to clinical implementation: results of three common cancers in UKB.

Background: SNP-based polygenic risk scores have recently been adopted in the clinic for risk assessment of some common diseases. Their validity is supported by a consistent trend between their and disease risk in populations. However, for clinical use at the individual level, the reliability of is necessary considering they are directly used to calculate remaining lifetime risk.

Cystic fibrosis F508del carriers and cancer risk: Results from the UK Biobank.

Cystic fibrosis (CF) carriers carrying one defective copy of a CFTR germline mutation are common in the general population. A recent study reported associations of CF carriers with risk for cancers of digestive organs and pancreatic cancer. In the current study, we assessed associations of CFTR F508del carriers with the risk for 54 types of cancers in the UK Biobank, a large population-based study.