Interdisciplinary and Transferable Concepts in Bioinformatics Education: Observations and Approaches From a UK MSc Course

Bioinformatics is a highly interdisciplinary subject, with substantial and growing influence in health, environmental science and society, and is utilised by scientists from many diverse academic backgrounds. Education in bioinformatics therefore necessitates effective development of skills in interdisciplinary collaboration, communication, ethics, and critical analysis of research, in addition to practical and technical skills. Insights from bioinformatics training can additionally inform developing education in the tightly aligned and emerging disciplines of data science and artificial intelligence. Here, we describe the design, implementation, and review of a module in a UK MSc-level bioinformatics programme attempting to address these goals for diverse student cohorts. Reflecting the philosophy of the field and programme, the module content was designed either as “diversity-addressing”—working toward a common foundation of knowledge—or “diversity-exploiting”—where different student viewpoints and skills were harnessed to facilitate student research projects “greater than the sum of their parts.” For a universal introduction to technical concepts, we combined a mixed lecture/immediate computational practical approach, facilitated by virtual machines, creating an efficient technical learning environment praised in student feedback for building confidence among cohorts with diverse backgrounds. Interdisciplinary group research projects where diverse students worked on real research questions were supervised in tandem with interactive contact time covering transferable skills in collaboration and communication in diverse teams, research presentation, and ethics. Multi-faceted feedback and assessment provided a constructive alignment with real peer-reviewed bioinformatics research. We believe that the inclusion of these transferable, interdisciplinary, and critical concepts in a bioinformatics course can help produce rounded, experienced graduates, ready for the real world and with many future options in science and society. In addition, we hope to provide some ideas and resources to facilitate such inclusion.publishedVersio

Heterogeneity of germline variants in high risk breast and ovarian cancer susceptibility genes in India

Breast and ovarian cancers now account for one in three cancers in Indian women and their incidence is rising. Major differences in the clinical presentation of breast and ovarian cancers exist between India and the United Kingdom. For example, Indian patients with breast cancer typically present a decade earlier than in the UK. Reasons for this could be multifactorial, including differences in underlying biology, environmental risks, and other systematic factors including access to screening. One possible explanation lies in variable incidence or penetrance of germline mutations in genes such as BRCA1 and BRCA2. We performed a methodical database and literature review to investigate the prevalence and spectrum of high-risk cancer susceptibility genes in Indian patients with breast and ovarian cancers. We identified 148 articles, but most studies were small, with inconsistent inclusion criteria and based on heterogeneous technologies, so that mutation frequency could not be reliably ascertained. Data were also often lacking on penetrance, histopathology, and survival outcomes. After filtering out unsuitable studies, only 13 remained, comprising 1028 patients. Large-scale research studies are urgently needed to determine mutation prevalence, spectra, and clinico-pathological features, and hence derive guidelines for screening, treatment, and prevention specific to the Indian population

Candidate gene variant effects on language disorders in Robinson Crusoe Island

Robinson Crusoe Island is a geographically and socially isolated settlement located over 600km west of the Port of Valparíso, Chile. An unusually high incidence (30%) of the Chilean equivalent of developmental language disorder (TEL) has been reported in Islander children, with 90% of these affected children found to be direct descendants of a pair of original founder-brothers, therefore strongly suggesting a shared genetic basis. Here we utilise whole-genome sequencing to investigate potential underlying variants in a panel of thirty-four genes known to play a role in language disorders, in seven TEL affected and ten unaffected islanders. We use this targeted approach to look for rare, shared variants that may underlie the diagnosis of TEL in a Mendelian genetic model. We go on to test whether the overall burden of rare variants is enriched in individuals affected by TEL or with Islanders related to the founder-brother lineage. In the absence of explanatory rare variants, we further investigate these candidate genes within a complex model of inheritance, where inheriting a small number of moderate impact common variants may increase susceptibility of developing TEL. We examine if any variants segregate with affection status or with founder-brother-related status, and therefore may increase risk of developing a language disorder. Finally, we perform a pooled, gene-based tests to evaluate relationships between combined variation across candidate genes and TEL affection status. Here we report a comprehensive examination of genes directly implicated in language-related mechanisms to identify ‘low hanging fruit’ of causative monogenic Mendelian variants, and complex association model of increased susceptibility in developmental language disorder found on Robinson Crusoe Island

External replication of urinary bladder cancer prognostic polymorphisms in the UK Biobank

Introduction: Multiple studies have reported genetic associations with prognostic outcomes of urinary bladder cancer. However, the lack of replication of these associations prohibits establishing further evidence-based research directions. Moreover, there is a lack of independent bladder cancer patient samples that contain prognostic measures, making genetic replication analyses even more challenging. Materials and Methods: We have identified 1,534 eligible patients and used data on Hospital Episode Statistics in the UK Biobank to model variables of otherwise non-collected events on bladder cancer recurrence and progression. Data on survival was extracted from the Death Registry. We have used SNPTEST software to replicate previously reported genetic associations with bladder cancer recurrence (N = 69), progression (N = 23), survival (N = 53), and age at the time of diagnosis (N = 20). Results: Using our algorithm, we have identified 618 recurrence and 58 UBC progression events. In total, there were 209 deaths (106 UBC-specific). In replication analyses, eight SNPs have reached nominal statistical significance (p <0.05). Rs2042329 (CWC27) for UBC recurrence; rs804256, rs4639, and rs804276 (in/close to NEIL2) for NMIBC recurrence; rs2293347 (EGFR) for UBC OS; rs3756712 (PDCD6) for NMIBC OS; rs2344673 (RGS5) for MIBC OS, and rs2297518 (NOS2) for UBC progression. However, none have remained significant after adjustments for multiple comparisons. Discussion: External replication in genetic epidemiology is an essential step to identify credible findings. In our study, we identify potential genetic targets of higher interest for UBC prognosis. In addition, we propose an algorithm for identifying UBC recurrence and progression using routinely-collected data on patient interventions

Genome-wide association study for tumour stage, grade, size, and age at diagnosis of non-muscle-invasive bladder cancer

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) causes a considerable health burden due to the high recurrence and progression rates. Past studies have identified multiple candidate loci associated with NMIBC prognosis, albeit lacking validation. Moreover, scarce reports exist on genetic susceptibility to independent prognostic predictors of NMIBC, such as stage or grade. OBJECTIVE: To investigate genetic associations with NMIBC tumour and patient characteristics at the time of diagnosis. DESIGN, SETTING, AND PARTICIPANTS: A sample of 653 NMIBC cases comes from the Bladder Cancer Prognosis Programme. Replication of the significant findings was conducted in the Nijmegen Bladder Cancer Study cohort (N=1470). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A genome-wide association study (GWAS) was carried out for outcomes of tumour size (as a continuous variable in centimetres), stage (Tis and T1 vs Ta), grade (G3 vs G2 and G1), and age (as continuous [years] and dichotomous [70.2 yr as a cut-off] variables). RESULTS AND LIMITATIONS: Significant (p<5E-08) associations (N=61) with tumour size, stage, grade, and age were identified in the GWAS discovery stage. None of the variants were independently significantly associated in the replication cohort. A meta-analysis of both cohorts suggests that rs180940944 (13q13.3 locus, NBEA) was associated with tumour size as a continuous variable (ss=0.9cm, p=2.92E-09). However, other single nucleotide polymorphisms in this region did not show evidence of association in the meta-analysis. CONCLUSIONS: Our study suggests that rs180940944 (NBEA) is associated with an increased NMIBC tumour size at the time of diagnosis. Given study limitations, further replication is essential to validate the finding. PATIENT SUMMARY: The current study reports on a genome-wide association study on non-muscle-invasive bladder cancer tumour and patient characteristics. We suggest that NBEA gene might be associated with increased tumour size at the time of diagnosis. The result must be replicated to establish validity