Application of a policy framework for the public funding of drugs for rare diseases

BACKGROUND: In many countries, decisions about the public funding of drugs are preferentially based on the results of randomized trials. For truly rare diseases, such trials are not typically available, and approaches by public payers are highly variable. In view of this, a policy framework intended to fairly evaluate these drugs was developed by the Drugs for Rare Diseases Working Group (DRDWG) at the request of the Ontario Public Drug Programs. OBJECTIVE: To report the initial experience of applying a novel evaluation framework to funding applications for drugs for rare diseases. METHODS: Retrospective observational cohort study. MEASURES: Clinical effectiveness, costs, funding recommendations, funding approval. KEY RESULTS: Between March 2008 and February 2013, eight drugs were evaluated using the DRDWG framework. The estimated average annual drug cost per patient ranged from 28,000 to 1,200,000 Canadian dollars (CAD). For five drugs, full evaluations were completed, specific funding recommendations were made by the DRDWG, and funding was approved after risk-sharing agreements with the manufacturers were negotiated. For two drugs, the disease indications were determined to be ineligible for consideration. For one drug, there was insufficient natural history data for the disease to provide a basis for recommendation. For the five drugs fully evaluated, 32 patients met the predefined eligibility criteria for funding, and five were denied based on predefined exclusion criteria. CONCLUSIONS: The framework improved transparency and consistency for evaluation and public funding of drugs for rare diseases in Ontario. The evaluation process will continue to be iteratively refined as feedback on actual versus expected clinical and economic outcomes is incorporated. © 2014 Society of General Internal Medicine

Childhood onset of Scheie syndrome, the attenuated form of mucopolysaccharidosis I

Scheie syndrome is the most attenuated and rarest form of mucopolysaccharidosis type I (MPS I), an inherited lysosomal storage disorder. Only small patient series have previously been reported. Using natural history data from the uniquely large population of 78 Scheie patients enrolled in the MPS I Registry, we characterized the onset and prevalence of clinical manifestations and explored reasons for delayed diagnosis of the disease. Median patient age was 17.5 years; 46% of the patients were male, and 88% were Caucasian. Of 25 MPS I-related clinical features, cardiac valve abnormalities, joint contractures, and corneal clouding were each reported by >80% and all three by 53% of patients. Carpal tunnel syndrome, hernia, coarse facial features, and hepatomegaly were each reported by >50% of patients. Age at onset of the clinical features varied widely between individuals, but the median age at onset was 3 years for hernia and between 5 and 12 years for most features, including coarse facial features, hepatomegaly, joint contractures, bone deformities, cardiac valve abnormalities, cognitive impairment, and corneal clouding. Carpal tunnel syndrome, cardiomyopathy, and myelopathy arose more commonly during adolescence or adulthood. Delays up to 47 years intervened between symptom onset and disease diagnosis, and the longest delays were associated with later age at symptom onset and symptom onset before 1980. In summary, Scheie syndrome usually emerges during childhood, and recognition of attenuated MPS I requires awareness of the multisystemic disease manifestations and their diverse presentation. Given the availability of etiologic treatment, prompt diagnosis is important

Kepler Data Release 4 Notes

The Data Analysis Working Group have released long and short cadence materials, including FFIs and Dropped Targets for the Public. The Kepler Science Office considers Data Release 4 to provide "browse quality" data. These notes have been prepared to give Kepler users of the Multimission Archive at STScl (MAST) a summary of how the data were collected and prepared, and how well the data processing pipeline is functioning on flight data. They will be updated for each release of data to the public archive and placed on MAST along with other Kepler documentation, at http://archive.stsci.edu/kepler/documents.html. Data release 3 is meant to give users the opportunity to examine the data for possibly interesting science and to involve the users in improving the pipeline for future data releases. To perform the latter service, users are encouraged to notice and document artifacts, either in the raw or processed data, and report them to the Science Office

Treatment of axial spondyloarthritis with biologic and targeted synthetic DMARDs: British Society for Rheumatology guideline scope

Pharmacological management has advanced considerably since the 2015 British Society for Rheumatology axial spondyloarthritis (axSpA) guideline to incorporate new classes of biologic DMARDs (bDMARDs, including biosimilars), targeted synthetic DMARDs (tsDMARDs) and treatment strategies such as drug tapering. The aim of this guideline is to provide an evidence-based update on pharmacological management of adults with axSpA (including AS and non-radiographic axSpA) using b/tsDMARDs. This guideline is aimed at health-care professionals in the UK who care directly for people with axSpA, including rheumatologists, rheumatology specialist nurses, allied health professionals, rheumatology specialty trainees and pharmacists; people living with axSpA; and other stakeholders, such as patient organizations and charities

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Evidence-based Kernels: Fundamental Units of Behavioral Influence

This paper describes evidence-based kernels, fundamental units of behavioral influence that appear to underlie effective prevention and treatment for children, adults, and families. A kernel is a behavior–influence procedure shown through experimental analysis to affect a specific behavior and that is indivisible in the sense that removing any of its components would render it inert. Existing evidence shows that a variety of kernels can influence behavior in context, and some evidence suggests that frequent use or sufficient use of some kernels may produce longer lasting behavioral shifts. The analysis of kernels could contribute to an empirically based theory of behavioral influence, augment existing prevention or treatment efforts, facilitate the dissemination of effective prevention and treatment practices, clarify the active ingredients in existing interventions, and contribute to efficiently developing interventions that are more effective. Kernels involve one or more of the following mechanisms of behavior influence: reinforcement, altering antecedents, changing verbal relational responding, or changing physiological states directly. The paper describes 52 of these kernels, and details practical, theoretical, and research implications, including calling for a national database of kernels that influence human behavior

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers