Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants.

PURPOSE: Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice. METHODS: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset. RESULTS: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62. CONCLUSION: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met

Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.

PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain. METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features. RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD). CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity

Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome

BRCA1-associated protein-1 (BAP1) is a recognised tumour suppressor gene. Germline BAP1 pathogenic/likely pathogenic variants are associated with predisposition to multiple tumours, including uveal melanoma, malignant pleural and peritoneal mesothelioma, renal cell carcinoma and specific non-malignant neoplasms of the skin, as part of the autosomal dominant BAP1-tumour predisposition syndrome. The overall lifetime risk for BAP1 carriers to develop at least one BAP1-associated tumour is up to 85%, although due to ascertainment bias, current estimates of risk are likely to be overestimated. As for many rare cancer predisposition syndromes, there is limited scientific evidence to support the utility of surveillance and, therefore, management recommendations for BAP1 carriers are based on expert opinion. To date, European recommendations for BAP1 carriers have not been published but are necessary due to the emerging phenotype of this recently described syndrome and increased identification of BAP1 carriers via large gene panels or tumour sequencing. To address this, the Clinical Guideline Working Group of the CanGene-CanVar project in the United Kingdom invited European collaborators to collaborate to develop guidelines to harmonize surveillance programmes within Europe. Recommendations with respect to BAP1 testing and surveillance were achieved following literature review and Delphi survey completed by a core group and an extended expert group of 34 European specialists including Geneticists, Ophthalmologists, Oncologists, Dermatologists and Pathologists. It is recognised that these largely evidence-based but pragmatic recommendations will evolve over time as further data from research collaborations informs the phenotypic spectrum and surveillance outcomes.</p

The Wake Island Rodent Eradication: Part Success, Part Failure, but Wholly Instructive

Rodent eradications undertaken on tropical islands have had a lower success rate than those attempted in temperate regions. A recent project undertaken to eradicate Rattus tanezumi and R. exulans from the 3 islands comprising Wake Atoll is illustrative. R. tanezumi was successfully removed from all 3 islands. R. exulans was permanently eradicated on Peale Island (95 ha) and temporarily on Wilkes Island (76 ha). R. exulans eradication on Wake Island (525 ha) was unsuccessful and the species has since repopulated Wake Island and recolonized Wilkes Island. We completed a detailed review of the project in an attempt to isolate potential causes of eradication failure. Based on the evidence available, we were not able to positively identify a single factor to explain why R. exulans survived on Wake Island. However, monitoring after the operation points to a sequence of events that comprised delayed mortality amongst a subset of breeding females and the emergence of young rats after bait was no longer readily available. Such an event was likely influenced by an abundance of natural food resources throughout the treatment area, a high density of rats, interspecific competition for toxic bait, and rapid disappearance of bait because of consumption by non-target consumers (land crabs). These factors are common to many tropical islands. We provide recommendations for addressing these factors in a future attempt to remove rats from Wake Atoll

Intellectual disability health content within medical curriculum: an audit of what our future doctors are taught

Background: There is a high burden of unmet health needs for people with intellectual disability. Despite experiencing significantly higher rates of morbidity and mortality compared with the general population, this group faces greater barriers to accessing healthcare. While increasing workplace capacity is one way to reduce this inequitable access, previous research indicates a scarcity of undergraduate teaching in intellectual disability. The aim of the study was to determine the extent and nature of intellectual disability content currently offered within medical degree curricula

Intellectual disability content within tertiary medical curriculum: how is it taught and by whom?

Background: Individuals with intellectual disability experience higher rates of physical and mental health conditions compared with the general population, yet have inequitable access to health care services. Improving the workplace capacity of medical professionals to meet the needs of this population is one way to reduce barriers to care and improve health outcomes. Using diverse pedagogy appropriate to learning outcomes to teach medical students about intellectual disability is a necessary step in improving future workplace capacity. However, there is a lack of research into how, and by whom, medical students are taught about intellectual disability. The aim of this study was to investigate this through an audit of Australian medical school curricula.Methods: The Deans of Australian universities that provide accredited medical degrees (n = 20) were invited by email to participate in a two-phase audit of intellectual disability content in the curricula. Phase 1 (n = 14 schools) involved the Dean's delegate completing a telephone interview or questionnaire regarding medical course structure. If intellectual disability content was identified, a unit coordinator was invited to complete a survey regarding how this content was taught and by whom (Phase 2; n = 12 schools).Results: There was considerable variability across Australian medical schools regarding methods used to teach content about intellectual disability. Didactic teaching methods were most frequently used (62% of units included some form of lecture), but workshops and tutorials were reasonably well represented (34% of units contained one or both). Thirty-six percent of units included two or more teaching methods. Almost all schools (83%) used some problem- and/or enquiry-based learning. Educator backgrounds included medicine, nursing, and allied health. A majority of schools (n = 9, 75%) involved people with intellectual disability designing and teaching content but the extent to which this occurred was inconsistent.Conclusions: Renewing curricula around intellectual disability across all medical schools by introducing varied teaching methods and the inclusion of people with intellectual disability would assist students to develop knowledge, skills, attitudes, and confidence in intellectual disability health. Such renewal offers the potential to reduce barriers to service this population regularly face, thereby improving their health outcomes

Has teaching about intellectual disability healthcare in Australian medical schools improved? A 20-year comparison of curricula audits

BACKGROUND: People with intellectual disability (ID) have multiple and complex health needs, more frequent healthcare episodes, and experience poorer health outcomes. Research conducted two decades ago showed that medical professionals were lacking in the knowledge and skills required to address the complex needs of this patient group. The aim of the current study was to determine whether Australian undergraduate medical schools that offer ID health education content had changed the amount and nature of such teaching over this period. METHODS: Identical or equivalent questionnaire items were compared across eight Australian medical schools that participated in curricula audits conducted in 1995 (referred to as T1) and 2013/14 (T2). The audits were of the nature of the ID content, methods used to teach it, and who taught it. RESULTS: There was no significant difference in the number of hours of compulsory ID content offered to medical students at T2 (total = 158.3 h; median = 2.8 h per ID unit) compared with T1 (total = 171 h; median = 2.5 h). At T2 compared with T1, units with ID content taught in the area of general practice had increased (2 units; 3.6% to 7 units; 16.3%), while decreases were seen in paediatrics (22 units; 40.0% to 10 units; 23.3%) and psychiatry (10 units; 18.2% to 4 units; 9.3%). The number of schools using problem- and/or enquiry-based learning rose to six at T2 from one at T1. Inclusive teaching practices (people with ID develop or deliver content) in compulsory/elective units had increased at T2 (10 units; 23.3%) compared with T1 (6 units; 10.9%), but direct clinical contact with people with ID had decreased (29 units; 52.7% to 11 units; 25.6%). CONCLUSIONS: Overall, little progress has been made to address the gaps in ID education for medical students identified from an audit conducted in 1995. Renewal of ID content in medical curricula is indicated as a key element in efforts to improve workforce capacity in this area and reduce barriers to care, with the aim of reversing the poor health outcomes currently seen for this group