Top 10 metrics for life science software good practices [version 1; referees: 2 approved]

Metrics for assessing adoption of good development practices are a useful way to ensure that software is sustainable, reusable and functional. Sustainability means that the software used today will be available - and continue to be improved and supported - in the future. We report here an initial set of metrics that measure good practices in software development. This initiative differs from previously developed efforts in being a community-driven grassroots approach where experts from different organisations propose good software practices that have reasonable potential to be adopted by the communities they represent. We not only focus our efforts on understanding and prioritising good practices, we assess their feasibility for implementation and publish them here

A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies

Background: Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients. Methods: We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI. Results: The genetic susceptibility to AAD-quantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p < 2e - 16), and 1.2 SD higher in the young patients compared with the old (p = 3e - 4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies. Conclusions: The PRS performed well for case-control differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity

GWAS for autoimmune Addison's disease identifies multiple risk loci and highlights AIRE in disease susceptibility

Autoimmune Addison’s disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10−8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7–4.3), P = 9.0 × 10−25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35–41% of heritability (h2)

GWAS for autoimmune Addisons disease identifies multiple risk loci and highlights AIRE in disease susceptibility

Autoimmune Addisons disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P&amp;lt;5x10(-8)). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR=3.4 (2.7-4.3), P=9.0x10(-25)) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h(2)). Autoimmune Addisons disease is a rare complex disease, which has not yet been characterized by non-biased genetic studies. Here, the authors perform the first GWAS for the disease, identifying nine loci including two coding variants in the gene Autoimmune Regulator (AIRE).Funding Agencies|Swedish National Infrastructure for Computing (SNIC) through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) [sens2017513]; KG Jebsen Foundation; Research Council of NorwayResearch Council of Norway; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Knut and Alice Wallenberg FoundationKnut &amp; Alice Wallenberg Foundation; Health Authorities of Western Norway; Torsten and Ragnar Soderberg Foundations; Novo Nordisk FoundationNovo Nordisk Foundation; Swedish Society for Medical Research</p