A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Trends in absolute and relative educational inequalities in four modifiable ischaemic heart disease risk factors: repeated cross-sectional surveys from the Nord-Trøndelag Health Study (HUNT) 1984–2008

<p>Abstract</p> <p>Background</p> <p>There has been an overall decrease in incident ischaemic heart disease (IHD), but the reduction in IHD risk factors has been greater among those with higher social position. Increased social inequalities in IHD mortality in Scandinavian countries is often referred to as the Scandinavian “public health puzzle”. The objective of this study was to examine trends in absolute and relative educational inequalities in four modifiable ischaemic heart disease risk factors (smoking, diabetes, hypertension and high total cholesterol) over the last three decades among Norwegian middle-aged women and men.</p> <p>Methods</p> <p>Population-based, cross-sectional data from The Nord-Trøndelag Health Study (HUNT): HUNT 1 (1984–1986), HUNT 2 (1995–1997) and HUNT 3 (2006–2008), women and men 40–59 years old. Educational inequalities were assessed using the Slope Index of Inequality (SII) and The Relative Index of Inequality (RII).</p> <p>Results</p> <p>Smoking prevalence increased for all education groups among women and decreased in men. Relative and absolute educational inequalities in smoking widened in both genders, with significantly higher absolute inequalities among women than men in the two last surveys. Diabetes prevalence increased in all groups. Relative inequalities in diabetes were stable, while absolute inequalities increased both among women (p = 0.05) and among men (p = 0.01). Hypertension prevalence decreased in all groups. Relative inequalities in hypertension widened over time in both genders. However, absolute inequalities in hypertension decreased among women (p = 0.05) and were stable among men (p = 0.33). For high total cholesterol relative and absolute inequalities remained stable in both genders.</p> <p>Conclusion</p> <p>Widening absolute educational inequalities in smoking and diabetes over the last three decades gives rise to concern. The mechanisms behind these results are less clear, and future studies are needed to assess if educational inequalities in secondary prevention of IHD are larger compared to educational inequalities in primary prevention of IHD. Continued monitoring of IHD risk factors at the population level is therefore warranted. The results emphasise the need for public health efforts to prevent future burdens of life-style-related diseases and to avoid further widening in socioeconomic inequalities in IHD mortality in Norway, especially among women.</p

Psychotherapy Research Needs Theory. Outline for an Epistemology of the Clinical Exchange

This paper provides an analysis of a basic assumption grounding the clinical research: the ontological autonomy of psychotherapy—based on the idea that the clinical exchange is sufficiently distinguished from other social objects (i.e. exchange between teacher and pupils, or between buyer and seller, or interaction during dinner, and so forth). A criticism of such an assumption is discussed together with the proposal of a different epistemological interpretation, based on the distinction between communicative dynamics and the process of psychotherapy— psychotherapy is a goal-oriented process based on the general dynamics of human communication. Theoretical and methodological implications are drawn from such a view: It allows further sources of knowledge to be integrated within clinical research (i.e. those coming from other domains of analysis of human communication); it also enables a more abstract definition of the psychotherapy process to be developed, leading to innovative views of classical critical issues, like the specific-nonspecific debate. The final part of the paper is devoted to presenting a model of human communication—the Semiotic Dialogical Dialectic Theory–which is meant as the framework for the analysis of psychotherapy