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

Investigating the Potential Contribution of Patient Rating Sites to Hospital Supervision: Exploratory Results From an Interview Study in the Netherlands

Background: Over the last decades, the patient perspective on health care quality has been unconditionally integrated into quality management. For several years now, patient rating sites have been rapidly gaining attention. These offer a new approach toward hearing the patient's perspective on the quality of health care. Objective: The aim of our study was to explore whether and how patient reviews of hospitals, as reported on rating sites, have the potential to contribute to health care inspector's daily supervision of hospital care. Methods: Given the unexplored nature of the topic, an interview study among hospital inspectors was designed in the Netherlands. We performed 2 rounds of interviews with 10 senior inspectors, addressing their use and their judgment on the relevance of review data from a rating site. Results: All 10 Dutch senior hospital inspectors participated in this research. The inspectors initially showed some reluctance to use the major patient rating site in their daily supervision. This was mainly because of objections such as worries about how representative they are, subjectivity, and doubts about the relevance of patient reviews for supervision. However, confrontation with, and assessment of, negative reviews by the inspectors resulted in 23% of the reviews being deemed relevant for risk identification. Most inspectors were cautiously positive about the contribution of the reviews to their risk identification. Conclusions: Patient rating sites may be of value to the risk-based supervision of hospital care carried out by the Health Care Inspectorate. Health care inspectors do have several objections against the use of patient rating sites for daily supervision. However, when they are presented with texts of negative reviews from a hospital under their supervision, it appears that most inspectors consider it as an additional source of information to detect poor quality of care. Still, it should always be accompanied and verified by other quality and safety indicators. More research on the value and usability of patient rating sites in daily hospital supervision and other health settings is neede