Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism That Increases Risk of Docetaxel-Induced Neuropathy

Purpose: Discovery of SNPs that predict a patient\u27s risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy. Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy. Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10−8, adjusted P = 5.88 × 10−7). siRNA knockdown of VAC14 in stem cell–derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P \u3c 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001). Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR

Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer.

Purpose: Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCSs). Experimental Design: TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived, and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt\u27s electronic health database (BioVU) and the CALGB 90401 trial. Results: Eight sensory items formed a subscale with good internal consistency (Cronbach α = 0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year, 1.06; P= 2 × 10−9), smoking (OR, 1.54; P = 0.004), excess drinking (OR, 1.83; P = 0.007), and hypertension (OR, 1.61; P = 0.03). CisIPN was correlated with lower self-reported health (OR, 0.56; P = 2.6 × 10−9) and weight gain adjusted for years since treatment (OR per Δkg/m2, 1.05; P = 0.004). PrediXcan identified lower expressions of MIDN and RPRD1B, and higher THEM5expression as associated with CisIPN (P value for each \u3c 5 × 10−6) with replication of RPRD1Bmeeting significance criteria (Fisher combined P = 0.0089). Conclusions: CisIPN is associated with age, modifiable risk factors, and genetically determined expression level of RPRD1B. Further study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN. Clin Cancer Res; 23(19); 5757–68. ©2017 AACR

Determining the Genetic Component of Protein Levels Using TWAS

The central dogma of biology describes how an individual\u27s genome contributes to their unique phenotypes: genes encoded in DNA get transcribed into mRNA molecules, which get translated into proteins. Nevertheless, the path from genotype to phenotype is not straightforward, and unraveling the specific molecular mechanisms by which a genotype results in a phenotype is particularly challenging. Multi-omics approaches seek to combat this issue by integrating a variety of omics data into genetic analyses. The combination of genome-wide association studies, which calculate associations between SNPs and traits, transcriptome-wide association studies, which calculate associations between transcripts and traits, and expression quantitative trait loci, which identify SNPs associated with varying expression levels, can help further elucidate causative variants with respect to a phenotype. This project aims at bringing another omics relationship into the fold - associations between transcripts and protein levels by performing TWAS for proteins using protein level data from individuals in the Trans-Omics for Precision Medicine cohort and predicted expression levels from the PrediXcan software, calculated with Genotype-Tissue Expression Project expression models

Leveraging Cataloging and Collection Development Expertise to Improve OER Discovery

While there is ongoing improvement in some of the larger open educational resources (OER) search engines, librarians sending emails to listservs asking “anyone know of OER on this topic?” and keeping old-fashioned reading lists of valuable OER are common occurrences. Compared to searching for books in a library catalog or scholarly articles in a research database, finding OER wherever they may be is challenging even for librarians, not to mention instructional faculty. The reason is technical: subpar and variable metadata in OER search engines leads to difficulties searching, capturing, and sharing data across repositories. In other words, the current lack of robust, descriptive metadata for OER results in fewer access points. Thus, OER are comparatively hard to find. Bibliographic control for purposes of information storage and retrieval is something librarians are experts in, but we have not shared our methods with the Open Education community yet. So far, the majority of library advocates for OER have been reference and instruction librarians, as well as library directors. This is great, and we need them to continue to champion OER creation and adoption, but the Open Education movement needs technical services librarians to step forward and apply their cataloging and systems administration expertise to streamline access to the sprawling landscape of OER content; our profession would do well to share our collection development expertise as well. To this end, Clare Sobotka, Reference Assistant at Linn-Benton Community College (LBCC), Holly Wheeler, Library Cataloging and Metadata Specialist at Mt. Hood Community College (MHCC), and Heather White, Library Technical Services & OER Coordinator, along with their colleagues, have started to experiment with creating collection development policies and MARC records for OER. Ultimately, they hope for the development of a metadata schema that is shared between the Open Education and library communities and is mapped to MARC and RDA, to improve both catalog records and OER search engines across the web

Genetic and environmental variation impact transferability of polygenic risk scores

Even when polygenic risk scores (PRSs) are trained in African ancestral populations, Kamiza and colleagues showed that genetic and environmental variation within sub-Saharan African populations impacts prediction performance, highlighting the challenges of clinical implementation of PRSs for risk assessment

Proteome Association Studies in Populations of Diverse Ancestries

Most GWAS have been conducted in populations of European ancestries, but these results do not reflect the global population or replicate well in non-European populations. Additionally, investigating traits at the proteome level may provide more insight to biological mechanisms than at the genome level. Using data from the TOPMed consortium, we have built protein models to perform PWAS using S-PrediXcan in published multiethnic GWAS data from the PAGE study (Wojcik et al 2019). This output reveals significant associations between genes and a variety of complex traits in non-European populations

ONBOARDING FACULTY MEMBERS TO BE SUCCESSFUL WITHIN THE RESEARCH ENTERPRISE: MAKING A CASE FOR CHANGING BEST PRACTICES

The overall purpose of this study is finding ways to improve the faculty onboarding process. There are specific issues that new research faculty must overcome in order to be contributing members to their university, students, research lab, and field of study. Issues such as managing workflow, complying with internal university/institution policy and external sponsor policy (federal or non-federal) are a few examples of the problems facing research faculty. Failure to properly onboard faculty members has the potential for serious non-compliance consequences. The overall study design consisted of previously surveyed faculty and research administrators to understand the issues with current systems and w changes were needed to improve the process. Additionally, industry professionals and literature were examined in an effort to find the best solution. Analysis and feedback from examining these groups illustrated the need for a robust onboarding option given the complex nature of the Faculty Researcher job type. This updated system consisting of a hybrid method utilizing online and in-person training would onboard faculty during the initial phase and used throughout their professional development within the university/institution

A meta-analysis to establish the construct validity and normative values of the Pain Catastrophising Scale

Introduction: Outcome measures in clinical psychology tend to be developed in an ad-hoc way, with psychological constructs added to theoretical understanding without formal evaluation of their validity and relationship with existing constructs. Pain catastrophising is an example of a construct with no proven differentiation from other pain-related cognitions. The Pain Catastrophising Scale (PCS) is widely used and several theories exist regarding its theoretical basis and causal relationship with pain outcomes. Aims: This thesis aims to establish psychometric properties for the PCS from a wide and varied population; to assess the sensitivity of the scale and create norms for pain types; and assess the construct validity of pain catastrophising. Method: A systematic review was conducted to collect baseline PCS scores from research studies since its development in 1995 to the present day. Meta-analysis including multivariate regression explored variables influencing pain catastrophising. Correlations between the PCS and other measures were used to evaluate the construct validity of pain catastrophising. Results: Good internal reliability (α=.92, 95% CI .91-.93) and test-retest reliability scores (Spearman correlation coefficient=.88, 95% CI .83-.93) were found for the PCS. Participants’ pain type was highly related to PCS scores, with those with generalized pain scoring highest. No significant effects of age or gender were found. Language of the PCS affected PCS scores. Study type influenced PCS scores, but was confounded with pain diagnosis, with controlled trials more likely than quasi-experimental studies to recruit clinical samples. Divergent validity of the construct of pain catastrophising was tentatively supported by limited data. Discussion: Within the limits of available data, the use of the PCS is supported as a valid and reliable measure. Pain catastrophising varies depending on the pain type and intensity experienced. Further research is recommended to clarify the construct validity of pain catastrophising through consistent use of outcome measures