Participant Experience with Protocol Research Kidney Biopsies in the Kidney Precision Medicine Project.

BACKGROUND: Kidney biopsies are procedures commonly performed in clinical nephrology and are increasingly used in research. In this study we aimed to evaluate the experiences of participants who underwent research kidney biopsies in the Kidney Precision Medicine Project (KPMP). METHODS: KPMP research participants with acute kidney injury (AKI) or chronic kidney disease (CKD) were enrolled at nine recruitment sites in the United States between September 2019 to January 2023. At 28 days post-biopsy, participants were invited to complete a survey to share their experiences, including: motivation to participate in research; comprehension of informed consent; pain and anxiety during and after the biopsy procedure; overall satisfaction with KPMP participation; and impact of the study on their lives. The survey was developed in collaboration with the KPMP Community Engagement Committee and the Institute of Translational Health Sciences at the University of Washington. RESULTS: 111 participants completed the survey, 23 enrolled for AKI and 88 for CKD. Median age was 61 (IQR 48-67) years, 43% were women, 28% were Black, and 18% were of Hispanic ethnicity. Survey respondents most commonly joined KPMP to help future patients (59%). The consent form was understood by 99% and 97% recognized their important role in the study. Pain during the biopsy was reported by 50%, at a median level of 1 (IQR 0-3) on a 0-10 scale. Anxiety during the biopsy was described by 64% at a median level of 3 (IQR 1-5) on a 0-10 scale. More than half conveyed that KPMP participation impacted their diet, physical activity, and how they think about kidney disease. CONCLUSIONS: KPMP survey respondents were most commonly motivated to participate in research protocol kidney biopsies by altruism, with excellent understanding of the informed consent process.

Exploring various polygenic risk scores for skin cancer in the phenomes of the Michigan genomics initiative and the UK Biobank with a visual catalog: PRSWeb.

Polygenic risk scores (PRS) are designed to serve as single summary measures that are easy to construct, condensing information from a large number of genetic variants associated with a disease. They have been used for stratification and prediction of disease risk. The primary focus of this paper is to demonstrate how we can combine PRS and electronic health records data to better understand the shared and unique genetic architecture and etiology of disease subtypes that may be both related and heterogeneous. PRS construction strategies often depend on the purpose of the study, the available data/summary estimates, and the underlying genetic architecture of a disease. We consider several choices for constructing a PRS using data obtained from various publicly-available sources including the UK Biobank and evaluate their abilities to predict not just the primary phenotype but also secondary phenotypes derived from electronic health records (EHR). This study was conducted using data from 30,702 unrelated, genotyped patients of recent European descent from the Michigan Genomics Initiative (MGI), a longitudinal biorepository effort within Michigan Medicine. We examine the three most common skin cancer subtypes in the USA: basal cell carcinoma, cutaneous squamous cell carcinoma, and melanoma. Using these PRS for various skin cancer subtypes, we conduct a phenome-wide association study (PheWAS) within the MGI data to evaluate PRS associations with secondary traits. PheWAS results are then replicated using population-based UK Biobank data and compared across various PRS construction methods. We develop an accompanying visual catalog called PRSweb that provides detailed PheWAS results and allows users to directly compare different PRS construction methods.

Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-wide Study: Results from The Michigan Genomics Initiative.

Health systems are stewards of patient electronic health record (EHR) data with extraordinarily rich depth and breadth, reflecting thousands of diagnoses and exposures. Measures of genomic variation integrated with EHRs offer a potential strategy to accurately stratify patients for risk profiling and discover new relationships between diagnoses and genomes. The objective of this study was to evaluate whether polygenic risk scores (PRS) for common cancers are associated with multiple phenotypes in a phenome-wide association study (PheWAS) conducted in 28,260 unrelated, genotyped patients of recent European ancestry who consented to participate in the Michigan Genomics Initiative, a longitudinal biorepository effort within Michigan Medicine. PRS for 12 cancer traits were calculated using summary statistics from the NHGRI-EBI catalog. A total of 1,711 synthetic case-control studies was used for PheWAS analyses. There were 13,490 (47.7%) patients with at least one cancer diagnosis in this study sample. PRS exhibited strong association for several cancer traits they were designed for, including female breast cancer, prostate cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, and thyroid cancer. Phenome-wide significant associations were observed between PRS and many non-cancer diagnoses. To differentiate PRS associations driven by the primary trait from associations arising through shared genetic risk profiles, the idea of "exclusion PRS PheWAS" was introduced. Further analysis of temporal order of the diagnoses improved our understanding of these secondary associations. This comprehensive PheWAS used PRS instead of a single variant.

The College of American Pathologists Biorepository Accreditation Program: Results from the First 5 Years.

The College of American Pathologists (CAP) developed the Biorepository Accreditation Program (BAP) in 2012. This program integrates best practices from the International Society for Biological and Environmental Biorepositories, the National Cancer Institute, the Organisation for Economic Cooperation and Development, the Center for Medicare and Medicaid Services, and the CAP Laboratory Accreditation Program. The goal of this elective program is to provide requirements for standardization in biorepository processes that will result in high-quality specimens that can be used to support research, drug discovery, and personalized medicine. CAP uses a peer inspection model to ensure the inspectors have proper expertise and to promote educational efforts through information sharing. Lead inspectors are comprised of pathologists, PhDs, and managers of biorepositories and they are often supported by CAP staff inspectors. Accreditation is a 3-year continuous cycle of quality with a peer inspection occurring at the start of year 1 and a self-inspection and CAP desk assessment at the start of year 2 and 3. At this time 53 biorepositories are fully CAP BAP accredited and 13 are in the process of obtaining accreditation. There are currently 273 established standards with requirement lists customized based on the scope of activities performed by a biorepository. A total of 90 inspections were completed between May 2012 and December 2016. Sixty-one were initial inspections and 29 were reinspections. A total of 527 deficiencies were identified in the areas of Equipment/Instrumentation (22%), Information Technology (18%), Specimen Handling and QC (15%), Quality Management (16%), Personnel (11%), Safety (10%), Facilities (6%), and Regulatory (2%). Assessment of common deficiencies identifies areas of focus for continuous improvement and educational opportunities. Overall success of the program is high based on the current enrollment of 66 biorepositories, anecdotal participant feedback and increasing national recognition of the BAP in federal documents.

Ty1 insertions in intergenic regions of the genome of Saccharomyces cerevisiae transcribed by RNA polymerase III have no detectable selective effect.

The retrotransposon Ty1 of Saccharomyces cerevisiae inserts preferentially into intergenic regions in the vicinity of RNA polymerase III-transcribed genes. It has been suggested that this preference has evolved to minimize the deleterious effects of element transposition on the host genome, and thus to favor their evolutionary survival. This presupposes that such insertions have no selective effect. However, there has been no direct test of this hypothesis. Here we construct a series of strains containing single Ty1 insertions in the vicinity of tRNA genes, or in the rDNA cluster on chromosome XII, which are otherwise isogenic to strain 337, containing zero Ty1 elements. Competition experiments between 337 and the strains containing single Ty1 insertions revealed that in all cases, the Ty1 insertions have no selective effect in rich medium. These results are thus consistent with the hypothesis that the insertion site preference of Ty1 elements has evolved to minimize the deleterious effects of transposition on the host genome.

Evolution in Saccharomyces cerevisiae: identification of mutations increasing fitness in laboratory populations.

Since the publication of the complete sequence of the genome of Saccharomyces cerevisiae, a number of comprehensive investigations have been initiated to gain insight into cellular function. The focus of these studies has been to identify genes essential for survival in specific environments or those that when mutated cause gross phenotypic defects in growth. Here we describe Ty1-based mutational approaches designed to identify genes, which when mutated generate evolutionarily significant phenotypes causing small but positive increments on fitness. As expected, Ty1 mutations with a positive fitness effect were in the minority. However, mutations in two loci, one inactivating FAR3 and one upstream of CYR1, identified in evolving populations, were shown to have small but significantly positive fitness effects.