Bayesian approach to determining penetrance of pathogenic SDH variants.

BACKGROUND: Until recently, determining penetrance required large observational cohort studies. Data from the Exome Aggregate Consortium (ExAC) allows a Bayesian approach to calculate penetrance, in that population frequencies of pathogenic germline variants should be inversely proportional to their penetrance for disease. We tested this hypothesis using data from two cohorts for succinate dehydrogenase subunits A, B and C (SDHA-C) genetic variants associated with hereditary pheochromocytoma/paraganglioma (PC/PGL). METHODS: Two cohorts were 575 unrelated Australian subjects and 1240 unrelated UK subjects, respectively, with PC/PGL in whom genetic testing had been performed. Penetrance of pathogenic SDHA-C variants was calculated by comparing allelic frequencies in cases versus controls from ExAC (removing those variants contributed by The Cancer Genome Atlas). RESULTS: Pathogenic SDHA-C variants were identified in 106 subjects (18.4%) in cohort 1 and 317 subjects (25.6%) in cohort 2. Of 94 different pathogenic variants from both cohorts (seven in SDHA, 75 in SDHB and 12 in SDHC), 13 are reported in ExAC (two in SDHA, nine in SDHB and two in SDHC) accounting for 21% of subjects with SDHA-C variants. Combining data from both cohorts, estimated lifetime disease penetrance was 22.0% (95% CI 15.2% to 30.9%) for SDHB variants, 8.3% (95% CI 3.5% to 18.5%) for SDHC variants and 1.7% (95% CI 0.8% to 3.8%) for SDHA variants. CONCLUSION: Pathogenic variants in SDHB are more penetrant than those in SDHC and SDHA. Our findings have important implications for counselling and surveillance of subjects carrying these pathogenic variants.

DEFLATE compression algorithm corrects for overestimation of phylogenetic diversity by Grantham approach to single-nucleotide polymorphism classification.

Improvements in speed and cost of genome sequencing are resulting in increasing numbers of novel non-synonymous single nucleotide polymorphisms (nsSNPs) in genes known to be associated with disease. The large number of nsSNPs makes laboratory-based classification infeasible and familial co-segregation with disease is not always possible. In-silico methods for classification or triage are thus utilised. A popular tool based on multiple-species sequence alignments (MSAs) and work by Grantham, Align-GVGD, has been shown to underestimate deleterious effects, particularly as sequence numbers increase. We utilised the DEFLATE compression algorithm to account for expected variation across a number of species. With the adjusted Grantham measure we derived a means of quantitatively clustering known neutral and deleterious nsSNPs from the same gene; this was then used to assign novel variants to the most appropriate cluster as a means of binary classification. Scaling of clusters allows for inter-gene comparison of variants through a single pathogenicity score. The approach improves upon the classification accuracy of Align-GVGD while correcting for sensitivity to large MSAs. Open-source code and a web server are made available at https://github.com/aschlosberg/CompressGV.

Early social distancing policies in Europe, changes in mobility & COVID-19 case trajectories: Insights from Spring 2020.

BACKGROUND: Social distancing have been widely used to mitigate community spread of SARS-CoV-2. We sought to quantify the impact of COVID-19 social distancing policies across 27 European counties in spring 2020 on population mobility and the subsequent trajectory of disease. METHODS: We obtained data on national social distancing policies from the Oxford COVID-19 Government Response Tracker and aggregated and anonymized mobility data from Google. We used a pre-post comparison and two linear mixed-effects models to first assess the relationship between implementation of national policies and observed changes in mobility, and then to assess the relationship between changes in mobility and rates of COVID-19 infections in subsequent weeks. RESULTS: Compared to a pre-COVID baseline, Spain saw the largest decrease in aggregate population mobility (~70%), as measured by the time spent away from residence, while Sweden saw the smallest decrease (~20%). The largest declines in mobility were associated with mandatory stay-at-home orders, followed by mandatory workplace closures, school closures, and non-mandatory workplace closures. While mandatory shelter-in-place orders were associated with 16.7% less mobility (95% CI: -23.7% to -9.7%), non-mandatory orders were only associated with an 8.4% decrease (95% CI: -14.9% to -1.8%). Large-gathering bans were associated with the smallest change in mobility compared with other policy types. Changes in mobility were in turn associated with changes in COVID-19 case growth. For example, a 10% decrease in time spent away from places of residence was associated with 11.8% (95% CI: 3.8%, 19.1%) fewer new COVID-19 cases. DISCUSSION: This comprehensive evaluation across Europe suggests that mandatory stay-at-home orders and workplace closures had the largest impacts on population mobility and subsequent COVID-19 cases at the onset of the pandemic. With a better understanding of policies' relative performance, countries can more effectively invest in, and target, early nonpharmacological interventions.

Impacts of social distancing policies on mobility and COVID-19 case growth in the US.

Social distancing remains an important strategy to combat the COVID-19 pandemic in the United States. However, the impacts of specific state-level policies on mobility and subsequent COVID-19 case trajectories have not been completely quantified. Using anonymized and aggregated mobility data from opted-in Google users, we found that state-level emergency declarations resulted in a 9.9% reduction in time spent away from places of residence. Implementation of one or more social distancing policies resulted in an additional 24.5% reduction in mobility the following week, and subsequent shelter-in-place mandates yielded an additional 29.0% reduction. Decreases in mobility were associated with substantial reductions in case growth two to four weeks later. For example, a 10% reduction in mobility was associated with a 17.5% reduction in case growth two weeks later. Given the continued reliance on social distancing policies to limit the spread of COVID-19, these results may be helpful to public health officials trying to balance infection control with the economic and social consequences of these policies.

Data security in genomics: A review of Australian privacy requirements and their relation to cryptography in data storage.

The advent of next-generation sequencing (NGS) brings with it a need to manage large volumes of patient data in a manner that is compliant with both privacy laws and long-term archival needs. Outside of the realm of genomics there is a need in the broader medical community to store data, and although radiology aside the volume may be less than that of NGS, the concepts discussed herein are similarly relevant. The relation of so-called "privacy principles" to data protection and cryptographic techniques is explored with regards to the archival and backup storage of health data in Australia, and an example implementation of secure management of genomic archives is proposed with regards to this relation. Readers are presented with sufficient detail to have informed discussions - when implementing laboratory data protocols - with experts in the fields.