Incidence, Prevalence, and Survival of Patients with Idiopathic Pulmonary Fibrosis in the UK.

INTRODUCTION: Recent developments in the care of patients with idiopathic pulmonary fibrosis have the potential to improve survival rates. Population-based estimates of the current disease burden are needed to evaluate the future impact of newly approved therapies. The objective of this study is to describe incidence, prevalence, and survival of idiopathic pulmonary fibrosis patients in the UK. METHODS: Between 2000 and 2012, a patient cohort (N = 9,748,108), identified from Clinical Practice Research Datalink primary care data, was used to identify incident and prevalent cases of idiopathic pulmonary fibrosis-clinical syndrome. Incident cases were followed up to identify deaths. Poisson and Cox regressions were used to calculate incidence rate ratios (IRR) and hazard ratios for mortality, respectively. Adjustments were made for age, gender, and strategic health authority. Survival from diagnosis was estimated using Kaplan-Meier analysis. RESULTS: In total 1491 and 4527 incident cases were identified using narrow and broad idiopathic pulmonary fibrosis-clinical syndrome definitions, respectively. Incidence and prevalence increased during the study. Compared with 2000, a near 80% increase in incidence was observed by 2012 [IRR 1.78 (95% CI 1.50-2.11; broad definition)], despite an observed decrease using the narrow definition [0.50 (0.38-0.65)]. Median survival was 3.0 years (95% CI 2.8-3.1) and 2.7 years (95% CI 2.5-3.0) in broad (n = 2168) and narrow case sets (n = 996), respectively. No significant changes in survival were observed. CONCLUSIONS: Idiopathic pulmonary fibrosis incidence rates have increased since 2000 and survival remains poor. These results provide a benchmark against which the effects of future treatment changes can be measured. FUNDING: InterMune UK and Ireland (now part of F. Hoffman La Roche)

Flow-Based Propagators for the SEQUENCE and Related Global Constraints

We propose new filtering algorithms for the SEQUENCE constraint and some extensions of the SEQUENCE constraint based on network flows. We enforce domain consistency on the SEQUENCE constraint in $O(n^2)$ time down a branch of the search tree. This improves upon the best existing domain consistency algorithm by a factor of $O(\log n)$. The flows used in these algorithms are derived from a linear program. Some of them differ from the flows used to propagate global constraints like GCC since the domains of the variables are encoded as costs on the edges rather than capacities. Such flows are efficient for maintaining bounds consistency over large domains and may be useful for other global constraints.Comment: Principles and Practice of Constraint Programming, 14th International Conference, CP 2008, Sydney, Australia, September 14-18, 2008. Proceeding

Identifying genomic regions for fine-mapping using genome scan meta-analysis (GSMA) to identify the minimum regions of maximum significance (MRMS) across populations

In order to detect linkage of the simulated complex disease Kofendrerd Personality Disorder across studies from multiple populations, we performed a genome scan meta-analysis (GSMA). Using the 7-cM microsatellite map, nonparametric multipoint linkage analyses were performed separately on each of the four simulated populations independently to determine p-values. The genome of each population was divided into 20-cM bin regions, and each bin was rank-ordered based on the most significant linkage p-value for that population in that region. The bin ranks were then averaged across all four studies to determine the most significant 20-cM regions over all studies. Statistical significance of the averaged bin ranks was determined from a normal distribution of randomly assigned rank averages. To narrow the region of interest for fine-mapping, the meta-analysis was repeated two additional times, with each of the 20-cM bins offset by 7 cM and 13 cM, respectively, creating regions of overlap with the original method. The 6–7 cM shared regions, where the highest averaged 20-cM bins from each of the three offsets overlap, designated the minimum region of maximum significance (MRMS). Application of the GSMA-MRMS method revealed genome wide significance (p-values refer to the average rank assigned to the bin) at regions including or adjacent to all of the simulated disease loci: chromosome 1 (p < 0.0001 for 160–167 cM, including D1), chromosome 3 (p-value < 0.0000001 for 287–294 cM, including D2), chromosome 5 (p-value < 0.001 for 0–7 cM, including D3), and chromosome 9 (p-value < 0.05 for 7–14 cM, the region adjacent to D4). This GSMA analysis approach demonstrates the power of linkage meta-analysis to detect multiple genes simultaneously for a complex disorder. The MRMS method enhances this powerful tool to focus on more localized regions of linkage

Methods for detecting gene × gene interaction in multiplex extended pedigrees

Complex diseases are multifactorial in nature and can involve multiple loci with gene × gene and gene × environment interactions. Research on methods to uncover the interactions between those genes that confer susceptibility to disease has been extensive, but many of these methods have only been developed for sibling pairs or sibships. In this report, we assess the performance of two methods for finding gene × gene interactions that are applicable to arbitrarily sized pedigrees, one based on correlation in per-family nonparametric linkage scores and another that incorporates candidate loci genotypes as covariates into an affected relative pair linkage analysis. The power and type I error rate of both of these methods was addressed using the simulated Genetic Analysis Workshop 14 data. In general, we found detection of the interacting loci to be a difficult problem, and though we experienced some modest success there is a clear need to continue developing new methods and approaches to the problem

Methods for detecting gene × gene interaction in multiplex extended pedigrees

Complex diseases are multifactorial in nature and can involve multiple loci with gene × gene and gene × environment interactions. Research on methods to uncover the interactions between those genes that confer susceptibility to disease has been extensive, but many of these methods have only been developed for sibling pairs or sibships. In this report, we assess the performance of two methods for finding gene × gene interactions that are applicable to arbitrarily sized pedigrees, one based on correlation in per-family nonparametric linkage scores and another that incorporates candidate loci genotypes as covariates into an affected relative pair linkage analysis. The power and type I error rate of both of these methods was addressed using the simulated Genetic Analysis Workshop 14 data. In general, we found detection of the interacting loci to be a difficult problem, and though we experienced some modest success there is a clear need to continue developing new methods and approaches to the problem

An ordered subset approach to including covariates in the transmission disequilibrium test

Clinical heterogeneity of a disease may reflect an underlying genetic heterogeneity, which may hinder the detection of trait loci. Consequently, many statistical methods have been developed that allow for the detection of linkage and/or association signals in the presence of heterogeneity

Unmet needs in the treatment of idiopathic pulmonary fibrosis―insights from patient chart review in five European countries

Background: Two antifibrotic drugs, pirfenidone and nintedanib, are approved by the European Medicines Agency and the US Food and Drug Administration for the treatment of idiopathic pulmonary fibrosis (IPF). In this analysis, treatment patterns of European patients with IPF were investigated to understand antifibrotic prescribing and identify unmet needs in IPF treatment practice. Methods: Between February and March 2016, respiratory physicians from France, Germany, Italy, Spain, and the UK participated in an online questionnaire designed to collect information on IPF treatment patterns in patients under their care. Patients were categorized as treated (received approved antifibrotics) or untreated (did not receive approved antifibrotics, but may have received other unapproved therapies). Classification of IPF diagnosis (confirmed/suspected) and severity ('mild'/'moderate'/'severe') for each patient was based on the individual physician's report. Patients' perspectives were not recorded in this study. Results: In total, 290 physicians responded to the questionnaire. Overall, 54% of patients with IPF did not receive treatment with an approved antifibrotic. More patients had a confirmed IPF diagnosis in the treated (84%) versus the untreated (51%) population. Of patients with a confirmed diagnosis, 40% did not receive treatment. The treated population was younger than the untreated population (67 vs 70 years, respectively; p = 0.01), with more frequent multidisciplinary team evaluation (83% vs 57%, respectively; p = 0.01). A higher proportion of untreated patients had forced vital capacity > 80% at diagnosis versus treated patients. Of patients with 'mild' IPF, 71% did not receive an approved antifibrotic versus 41% and 60% of patients with 'moderate' and 'severe' IPF, respectively. Conclusions: Despite the availability of antifibrotic therapies, many European patients with confirmed IPF do not receive approved antifibrotic treatment. Importantly, there appears to be a reluctance to treat patients with 'mild' or 'stable' disease, and instead adopt a 'watch and wait' approach. More education is required to address diagnostic uncertainty, poor understanding of IPF and its treatments, and issues of treatment access. There is a need to increase physician awareness of the benefits associated with antifibrotic treatment across the spectrum of IPF severity

Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: design of a double-blind, randomised, placebo-controlled phase II trial

Introduction: Despite extensive multidisciplinary team (MDT) assessment, some patients have interstitial lung disease (ILD) that is considered unclassifiable (uILD), for which there are currently no approved treatments. This study will assess the efficacy and safety of the antifibrotic pirfenidone in treating uILD. Methods and analysis: This double-blind, randomised, placebo-controlled phase II trial is enrolling adults with fibrosing ILD, including uILD that fulfils proposed research criteria for interstitial pneumonia with autoimmune features (IPAF), that cannot be classified with moderate or high confidence to any category of ILD following MDT discussion. Study participants must have >10% fibrosis on high-resolution CT scan within the previous 12 months, forced vital capacity (FVC) ≥45% and diffusing capacity of the lung for carbon monoxide ≥30% of predicted values. Study participants will be randomised to receive 801 mg pirfenidone or placebo three times daily for 24 weeks. The efficacy of pirfenidone vs placebo will be assessed by daily measurement of FVC using a handheld spirometer over the treatment period. Other functional parameters, patient-reported outcomes, samples for biomarker analysis and safety endpoints will be collected. Additionally, the study will assess the efficacy and safety of pirfenidone with and without concomitant mycophenolate mofetil treatment and in study participants with or without IPAF. Ethics and dissemination: This trial is being conducted in accordance with the International Conference on Harmonisation E6 guideline for Good Clinical Practice, Declaration of Helsinki and local laws for countries in which the research is conducted

Nalbuphine Tablets for Cough in Patients with Idiopathic Pulmonary Fibrosis

BACKGROUND There are no approved therapies for cough in patients with idiopathic pulmonary fibrosis (IPF). In this small crossover trial we administered nalbuphine extended-release tablets (NAL ER) as a potential cough therapy for such patients. METHODS This randomized, double-blind, placebo-controlled, crossover trial involved two 22-day treatment periods (NAL ER!placebo and placebo!NAL ER) separated by a 2-week washout period. NAL ER was started at a dose of 27 mg once daily and was titrated up to 162 mg twice daily at day 16. The primary end point was percent change from baseline in hourly daytime objective cough frequency as measured by an electronic cough monitor. The daytime period was defined as the patient-reported time of awakening and bedtime. Secondary end points included change in objective 24-hour cough frequency, changes in cough frequency, cough severity, and breathlessness, per patient-reported outcomes. RESULTS A total of 41 patients were randomly assigned and received one or more doses of study medication. There was a 75.1% reduction in daytime objective cough frequency during the NAL ER treatment period versus the placebo treatment period of 22.6%, a 52.5 percentage point placebo-adjusted decrease from baseline (P<0.001) at day 21. There was a 76.1% (95% confidence interval, 83.1 to 69.1) decrease in the 24-hour objective cough frequency with NAL ER, versus a 25.3% (43.9 to 6.7) decrease with placebo, a 50.8 percentage point placebo-adjusted change. Nausea, fatigue, constipation, and dizziness were more common with NAL ER than with placebo. CONCLUSIONS In this short-term crossover trial, NAL ER reduced cough in individuals with IPF. Larger and longer trials are needed to assess the impact on cough versus drug adverse effects. (Funded by Trevi Therapeutics; ClinicalTrials.gov number, NCT04030026.