The human gene connectome as a map of short cuts for morbid allele discovery

High-throughput genomic data reveal thousands of gene variants per patient, and it is often difficult to determine which of these variants underlies disease in a given individual. However, at the population level, there may be some degree of phenotypic homogeneity, with alterations of specific physiological pathways underlying the pathogenesis of a particular disease. We describe here the human gene connectome (HGC) as a unique approach for human Mendelian genetic research, facilitating the interpretation of abundant genetic data from patients with the same disease, and guiding subsequent experimental investigations. We first defined the set of the shortest plausible biological distances, routes, and degrees of separation between all pairs of human genes by applying a shortest distance algorithm to the full human gene network. We then designed a hypothesis-driven application of the HGC, in which we generated a Toll-like receptor 3-specific connectome useful for the genetic dissection of inborn errors of Toll-like receptor 3 immunity. In addition, we developed a functional genomic alignment approach from the HGC. In functional genomic alignment, the genes are clustered according to biological distance (rather than the traditional molecular evolutionary genetic distance), as estimated from the HGC. Finally, we compared the HGC with three state-of-the-art methods: String, FunCoup, and HumanNet. We demonstrated that the existing methods are more suitable for polygenic studies, whereas HGC approaches are more suitable for monogenic studies. The HGC and functional genomic alignment data and computer programs are freely available to noncommercial users from http://lab.rockefeller.edu/casanova/HGC and should facilitate the genome-wide selection of disease-causing candidate alleles for experimental validation.     

Systems for evaluation of new drugs in the United Kingdom

The cost of drugs represents 10% of the National Health Service (NHS) budget in the UK and this fraction is increasing. Because the NHS is centrally funded and because there is a budgetary limit, prioritization in health care is required. The National Institute for Clinical Excellence in England and Wales and the Health Technology Board for Scotland have been established with the aim (among others) of ensuring that the NHS secures maximum health gain from available resources by focusing on treatments with clear evidence of cost effectiveness. Reconciling the interests of those responsible for financing the service with the interests of patients and other concerned parties might prove difficult. Copyright © 2001 John Wiley & Sons, Ltd.     

Ethics and value strategies used in prioritizing mental health services in Oregon

The authors describe the ethical considerations underlying the inclusion of mental health services into a prioritizedhealth care system. The Oregon Health Plan is a process for defining and delivering basic health services to an entire state. As the plan was developed, the mental health community needed to decide whether or not to participate in the process and, if so, how. Lengthy discussions among mental health consumers, family members, and providers led to a strategy that emphasized the integration of mental health and chemical dependency services into a comprehensive and universal health care program. This approach appears to have achieved relative parity for mental health.     

Medical ethics – new horizons

Abstract. The medical ethics of Hippocrates are no longer sufficient in a society with changing social attitudes and, especially, rapidly developing medical technologies. This Minisymposium is the third in a series of three, dealing with Medical Journals (J Intern Med 1992; 231 : 99–102) and their central role in the distribution of new medical knowledge, bringing them into close contact with Scientific misconduct in medical research (J Intern Med 1994; 235 : 103–35) and Medical ethics (this Minisymposium). The contents of the three Minisymposia are of importance not only to those dealing with medical journals but to all physicians – regardless of whether they are involved in research or in patient care – and to all others involved in health care. The Minisymposium gives a brief history of the development of research ethics, widens the scope of medical ethics and discusses its transcultural aspects. From a more practical standpoint the two last articles deal with the problem of who makes the decisions for whom, and when to stop treatment – both with relevance to one of the most important problems of medicine today: prioritization. The reader should note the difference between ‘medical ethics’, which is the wider concept, and ‘research ethics’, which deal specifically with the relation between the researcher and her/his patient or volunteer.     

Impact of a National system for waitlist prioritization: the experience with NIKE and cataract surgery in Sweden

Purpose: To evaluate waiting times for first‐eye cataract surgery in Sweden following widespread adoption of the Nationell Indikationsmodell for Kataraktextraktion (NIKE) tool for prioritizing patients for cataract surgery. Methods: Waiting times for all first‐eye cataract surgeries in Sweden in 2009–2011 were identified from the Swedish National Cataract Register. Waiting times were compared according to demographic, clinical and NIKE indication group for surgery. Multivariate logistic regression modelling was used to determine factors associated with waiting times less than the 3‐month Government guarantee period. Results: There were 141 070 first‐eye cataract surgeries in 2009 to 2011; an annual increase of around 6%. Over the study period, mean waiting times decreased across all NIKE groups. The proportion waiting <3 months for surgery also increased across all NIKE groups. Surgery within 3 months of waitlisting was more likely for patients with a NIKE 1 indication classification (most need for surgery), in later years, male patients, younger patients and patients with a preoperative visual acuity in the better eye worse than 6/24. Conclusions: Prioritizing patients for cataract surgery using NIKE reduces waiting times for those with the greatest need.     

Comprehensive interrogation of gene lists from genome-scale cancer screens with oncoEnrichR

Genome-scale screening experiments in cancer produce long lists of candidate genes that require extensive interpretation for biological insight and prioritization for follow-up studies. Interrogation of gene lists frequently represents a significant and time-consuming undertaking, in which experimental biologists typically combine results from a variety of bioinformatics resources in an attempt to portray and understand cancer relevance. As a means to simplify and strengthen the support for this endeavor, we have developed oncoEnrichR, a flexible bioinformatics tool that allows cancer researchers to comprehensively interrogate a given gene list along multiple facets of cancer relevance. oncoEnrichR differs from general gene set analysis frameworks through the integration of an extensive set of prior knowledge specifically relevant for cancer, including ranked gene-tumor type associations, literature-supported proto-oncogene and tumor suppressor gene annotations, target druggability data, regulatory interactions, synthetic lethality predictions, as well as prognostic associations, gene aberrations and co-expression patterns across tumor types. The software produces a structured and user-friendly analysis report as its main output, where versions of all underlying data resources are explicitly logged, the latter being a critical component for reproducible science. We demonstrate the usefulness of oncoEnrichR through interrogation of two candidate lists from proteomic and CRISPR screens. oncoEnrichR is freely available as a web-based service hosted by the Galaxy platform ( https://oncotools.elixir.no ), and can also be accessed as a stand-alone R package ( https://github.com/sigven/oncoEnrichR ).     

A fully‐automated event‐based variant prioritizing solution to the CAGI5 intellectual disability gene panel challenge

Recent applications of gene panel sequencing analysis have significantly helped with identifying genetic causes for inherited diseases. However, large amounts of candidate variants remain a major challenge for prioritizing, often requiring arbitrary cutoffs in multiple steps. In addition, existing tools often prioritize a list of promising candidates that require much manual work to evaluate. To this end, we designed an automated, basically cutoff‐free scoring scheme named Context and Hereditary Event based Scoring Scheme (CHESS), that scores all possible inheritance events in each gene, by taking into consideration phenotypes, genotypes, and how the manual prioritization works. We applied CHESS to the Critical Assessment of Genome Interpretation 5 intellectual disability panel challenge, to assign clinical phenotypes to patients based on gene panel sequencing data. Through this blind testing, CHESS proved to be a leading and useful tool for genetic diagnosis in a research setting. Further analyses showed that precise phenotype terms played an important role in variant prioritization and that multiple etiologies may exist for some patients. CHESS also successfully identified many of the causal, putative and contributing variants. In the postchallenge analysis, we showed that our best submission performed slightly better than the predictions made by a state‐of‐the‐art tool. We believe that CHESS can provide aid to this and many other diagnostic scenarios.     

Increasing phenotypic annotation improves the diagnostic rate of exome sequencing in a rare neuromuscular disorder

Phenotype‐based filtering and prioritization contribute to the interpretation of genetic variants detected in exome sequencing. However, it is currently unclear how extensive this phenotypic annotation should be. In this study, we compare methods for incorporating phenotype into the interpretation process and assess the extent to which phenotypic annotation aids prioritization of the correct variant. Using a cohort of 29 patients with congenital myasthenic syndromes with causative variants in known or newly discovered disease genes, exome data and the Human Phenotype Ontology (HPO)‐coded phenotypic profiles, we show that gene‐list filters created from phenotypic annotations perform similarly to curated disease‐gene virtual panels. We use Exomiser, a prioritization tool incorporating phenotypic comparisons, to rank candidate variants while varying phenotypic annotation. Analyzing 3,712 combinations, we show that increasing phenotypic annotation improved prioritization of the causative variant, from 62% ranked first on variant alone to 90% with seven HPO annotations. We conclude that any HPO‐based phenotypic annotation aids variant discovery and that annotation with over five terms is recommended in our context. Although focused on a constrained cohort, this provides real‐world validation of the utility of phenotypic annotation for variant prioritization. Further research is needed to extend this concept to other diseases and more diverse cohorts.