Discriminatory Properties of Quality-Adjusted Life Year Based Cost-Effectiveness Analyses for Patients With Disabilities: A Duchenne Muscular Dystrophy Case Study.

OBJECTIVES: Quality-adjusted life years (QALYs) have been challenged as a measure of benefit for people with disabilities, particularly for those in low-utility health states or with irreversible disability. This study examined the impact of a QALY-based assessment on the price for a hypothetical treatment for Duchenne muscular dystrophy (DMD), a progressive, genetic neuromuscular disease. METHODS: A previously published, 5-state model, which analyzed treatments for early ambulatory (EA) DMD patients, was replicated, validated, and adapted to include early nonambulatory (ENA) DMD patients. The model was used to assess a QALY-based threshold price (maximum cost-effective price) for a hypothetical treatment for 13-year-old ENA and 5-year-old EA patients (initial health states with lower and higher utility, respectively). All inputs were replicated including willingness-to-pay thresholds of $50 000 to $200 000/QALY. RESULTS: In contrast to EA patients, ENA patients had a 98% modeled decline in QALY-based threshold price at a willingness-to-pay of $150 000/QALY or higher, despite equal treatment benefit (delayed progression/death). At $100 000/QALY or lower, net nontreatment costs exceeded health benefits, implying any treatment for ENA patients would not be considered cost-effective, even at $0 price, including an indefinite pause in disease progression. CONCLUSIONS: For certain severe, disabling conditions, traditional approaches are likely to conclude that treatments are not cost-effective at any price once a patient progresses to a disabled health state with low utility value. These findings elucidate theoretical/ethical concerns regarding potential discriminatory properties of traditional QALY assessments for people with disabilities, particularly those who have lost ambulation or have other physical limitations.

The impact of genotype on outcomes in individuals with Duchenne muscular dystrophy: A systematic review.

Duchenne muscular dystrophy (DMD) is associated with progressive muscle weakness, loss of ambulation (LOA), and early mortality. In this review we have synthesized published data on the clinical course of DMD by genotype. Using a systematic search implemented in Medline and Embase, 53 articles were identified that describe the clinical course of DMD, with pathogenic variants categorizable by exon skip or stop-codon readthrough amenability and outcomes presented by age. Outcomes described included those related to ambulatory, cardiac, pulmonary, or cognitive function. Estimates of the mean (95% confidence interval) age at LOA ranged from 9.1 (8.7-9.6) years among 90 patients amenable to skipping exon 53 to 11.5 (9.5-13.5) years among three patients amenable to skipping exon 8. Although function worsened with age, the impact of genotype was less clear for other outcomes (eg, forced vital capacity and left ventricular ejection fraction). Understanding the distribution of pathogenic variants is important for studies in DMD, as this research suggests major differences in the natural history of disease. In addition, specific details of the use of key medications, including corticosteroids, antisense oligonucleotides, and cardiac medications, should be reported.

Factors associated with the health-related quality of life among people with Duchenne muscular dystrophy: a study using the Health Utilities Index (HUI).

BACKGROUND: Data on health state utility in Duchenne muscular dystrophy (DMD) are few. This study estimated mean utility values by age, ambulatory status and over time, and investigated which aspects of health-related quality-of-life (HRQoL) are most strongly associated with utility in DMD. METHODS: Data from placebo-treated ambulant boys with DMD with exon 51 skip amenable mutations, (NCT01254019), were included. Ambulatory function assessments were conducted at baseline and every 12 weeks for the trial duration. Family member proxies completed the Health Utility Index (HUI) at baseline, 24 and 48 weeks; and HUI3 and HUI2 utility values were summarized. Changes in HUI attribute level over time, and predictors of changes in utility, were explored. RESULTS: Sixty-one boys (mean [range] age of 8.0 [5-16] years) were included in the analysis. Mean baseline utilities were 0.82 (HUI3) and 0.87 (HUI2); and utilities were 0.35 (HUI3) and 0.55 (HUI2) after loss of ambulation (LOA, where applicable). Over the follow-up period mean utility declined more among the older versus younger boys. Pain accounted for the highest proportion of variability (42%) in change in HUI3 utility from baseline to week 48, while for HUI2, self-care (39%) did. After LOA, change in ambulation levels explained 88% of the decline in mean HUI3 utility and change in mobility levels explained 66% of the decline in mean HUI2 utility. CONCLUSIONS: Utility values among this sample were higher than previously published estimates. In younger boys utility remained relatively stable, but older boys and those losing ambulation experienced important declines over follow-up.

Characterizing health state utilities associated with Duchenne muscular dystrophy: a systematic review.

BACKGROUND: Preferences for health states for Duchenne muscular dystrophy (DMD) are necessary to assess costs and benefits of novel therapies. Because DMD progression begins in childhood, the impact of DMD on health-related quality-of-life (HRQoL) affects preferences of both DMD patients and their families. The objective of this review was to synthesize published evidence for health state utility from the DMD patient and caregiver perspectives. METHODS: A systematic review was performed using MEDLINE and Embase, according to best practices. Data were extracted from studies reporting DMD patient or caregiver utilities; these included study and patient characteristics, health states considered, and utility estimates. Quality appraisal of studies was performed. RESULTS: From 888 abstracts, eight publications describing five studies were identified. DMD utility estimates were from preference-based measures presented stratified by ambulatory status, ventilation, and age. Patient (or patient-proxy) utility estimates ranged from 0.75 (early ambulatory DMD) to 0.05 (day-and-night ventilation). Caregiver utilities ranged from 0.87 (for caregivers of adults with DMD) to 0.71 (for caregivers of predominantly childhood patients). Both patient and caregiver utilities trended lower with higher disease severity. Variability in utilities was observed based on instrument, respondent type, and country. Utility estimates for health states within non-ambulatory DMD are under reported; nor were utilities for DMD-related health states such as scoliosis or preserved upper limb function identified. CONCLUSION: Published health state utilities document the substantial HRQoL impacts of DMD, particularly with disease progression. Additional research in patient utilities for additional health states, particularly in non-ambulatory DMD patients, is warranted.

Liver-specific case fatality due to chronic hepatitis C virus infection: a systematic review.

Despite reports that mortality is increasing, overall case fatality due to hepatitis C virus (HCV) is thought to be low. Given the variability in published rates, we aimed to synthesize estimates of liver-specific case fatality and all-cause mortality in chronic HCV according to follow-up duration, sustained viral response (SVR) to treatment, and liver disease severity. A systematic review was conducted of studies published in English from 2003 to 2013, reporting liver-specific case fatality estimates from HCV-infected samples. Thirty-five eligible articles were identified; 26 also presented estimates of all-cause mortality. Among community-based samples, liver-specific case fatality ranged from 0.3% over 5.7 years to 9.2% over 8.2 years of follow-up; and of all-cause mortality, from 4.0% over 5.7 years, to 23.0% over 8.2 years of follow-up. Estimates were higher among clinic-based samples and those with more severe liver disease. Among treated patients achieving SVR, liver-specific case fatality was low: up to 1.4% over 11.5 years of follow-up among samples with any severity of liver disease. Estimates were higher among those without SVR: up to 14.0% over 10 years of followup among samples with any severity of liver disease, and higher still among samples with more severe liver disease. The proportion of deaths attributable to liver-specific causes ranged from 55 to 85% among those with severe liver disease. Published estimates of fatality are high among certain populations of chronic HCV patients, with liver-specific causes being an important contributor. Understanding current HCV mortality rates is important for quantifying the total burden of HCV disease.

A population-based study of childhood respiratory morbidity after severe lower respiratory tract infections in early childhood.

OBJECTIVES: To estimate the risk of childhood chronic respiratory morbidity among those hospitalized for severe lower respiratory tract infection (LRTI) in early childhood, and to determine whether severe LRTI is an independent predictor. STUDY DESIGN: The population-based Régie de l'Assurance Maladie du Québec datasets were used to identify LRTI hospitalizations before age 2 years in a birth cohort from 1996-1997 and a comparison cohort of children without an LRTI hospitalization. The incidence rate and incidence rate ratio of chronic respiratory morbidity before age 10 years were calculated, and multivariable logistic regression was performed to estimate the impact of LRTI hospitalization on chronic respiratory morbidity. Population-attributable risks of chronic respiratory morbidity due to severe LRTI were estimated, and similar analyses were performed for respiratory syncytial virus LRTI. RESULTS: Among the birth cohort, 7104 patients (4.9%) were hospitalized for LRTI before age 2 years. By age 10 years, 52.5% of the LRTI cohort and 27.9% of the nonhospitalized cohort had developed chronic respiratory morbidity; the incidence rate ratio was 1.81 (95% CI, 1.76-1.86) for males and 1.91 (95% CI, 1.84-1.99) for females. The OR for chronic respiratory morbidity based on LRTI hospitalization before age 2 years was 2.79 (95% CI, 2.66-2.93). The population-attributable risk of chronic respiratory morbidity due to any LRTI was approximately 25%, and that for respiratory syncytial virus LRTI was similar. CONCLUSIONS: Hospitalization of young children for LRTIs is associated with two-fold increased risk of childhood chronic respiratory morbidity, demonstrating the ongoing impact of LRTI in infancy.

Current Challenges of Using Patient-Level Claims and Electronic Health Record Data for the Longitudinal Evaluation of Duchenne Muscular Dystrophy Outcomes.

INTRODUCTION: Insurance claims data and electronic health records (EHRs) have been used to characterize Duchenne muscular dystrophy (DMD) in real-world populations. The ability to assess patient-level DMD disease progression within insurance claims or EHR data infrastructures is unknown. Insurance claims and EHR data were comprehensively examined for availability and reliability of DMD outcomes that describe functional status and disease progression at the individual patient level over time. METHODS: MarketScan Commercial and Medicaid claims, and EHR-linked Clarivate open claims datasets were examined for data measuring 54 previously identified DMD-relevant outcomes in patients with DMD. Each outcome was assigned to one of five categories: functional and clinical events, clinical measures, biomarkers, functional measures, or patient-reported outcomes (PROs). Patients were identified using published coding algorithms. Annual 5-year attrition and data availability for each outcome was determined. The ability to distinguish disease severity and identify test results was also considered where applicable. RESULTS: A total of 1964 (MarketScan Commercial), 2007 (MarketScan Medicaid), and 10,639 (Clarivate) patients were identified. At 5 years, 31.7%, 35.1%, and 59.1% of patients remained in MarketScan Commercial, MarketScan Medicaid, and Clarivate, respectively. Claims were available for five of six functional and clinical events, with 45.5% (MarketScan Commercial), 48.0% (Clarivate), and 48.5% (MarketScan Medicaid) of patients with ≥ 1 claim for the most frequently identified clinical event (cardiomyopathy diagnosis). No data were available to describe frequency of wheelchair use or loss of ambulation. Very limited EHR data (≤ 2% of patients) were available to indicate tests were ordered for clinical measures, biomarkers, or functional assessments. No PRO notes or scores were observed. Data existed for inferring disease severity (e.g., hospitalization for cardiomyopathy); however, it was not apparent whether these events were incident. CONCLUSION: Insurance claims and EHR-linked open claims data are of limited utility for holistically evaluating the progression and burden of DMD in individual patients.

Duchenne muscular dystrophy is a fatal disease that weakens muscles and causes loss of function over time. The timing of symptoms varies across individuals, making it important for doctors to closely monitor them. Although billing data from medical practices have been used to understand how Duchenne muscular dystrophy progresses at the population level, how well these data can document disease progression over time in individuals is unclear. This study examined data submitted by healthcare providers to insurers and electronic health records used to track patients' medical histories to see what information is available about known clinical and functional outcomes for Duchenne muscular dystrophy. Some information was available about major events experienced by patients with Duchenne muscular dystrophy, like heart problems and breathing difficulties. However, these data were limited to more advanced stages of Duchenne muscular dystrophy and did not reveal when these events first occurred or how severe they were. Information about whether ordered tests were performed was limited, with even less information available for test results. There were no data reported by patients themselves available in the datasets. The limitations of data submitted to insurers and from electronic health records in describing the clinical and functional outcomes of Duchenne muscular dystrophy make it difficult to understand individuals' medical history. Other data sources, particularly from tests measuring patient function done in the doctor's office or patient-reported outcomes, may exist but are not transferred to insurer data infrastructures.

Observing the Clinical Course of Duchenne Muscular Dystrophy in Medicaid Real-World Healthcare Data.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a rare, severe progressive neuromuscular disease. Health insurance claims allow characterization of population-level real-world outcomes, based on observed healthcare resource use. An analysis of data specific to those with Medicaid insurance is presently unavailable. The objective was to describe the real-world clinical course of DMD based on claims data from Medicaid-insured individuals in the USA. METHODS: Individuals with DMD were identified from the MarketScan Multi-State Medicaid datasets (2013-2018). Diagnosis and procedure codes from healthcare claims were used to characterize the occurrence of DMD-relevant clinical observations; categories were scoliosis, cardiovascular-related, respiratory and severe respiratory-related, and neurologic/neuropsychiatric. Age-restricted analyses were conducted to focus on the ages at which DMD-relevant clinical observations were more likely to be captured, and to better understand the impact of both age and follow-up time. RESULTS: Of 2007 patients with DMD identified, median (interquartile range) age at index was 14 (9-20) years, and median follow-up was 3.1 (1.6-4.7) years. Neurologic and neuropsychiatric observations were most frequently identified, among 49.3% of the cohort; followed by cardiovascular (48.5%), respiratory (38.1%), scoliosis (36.3%), and severe respiratory (25.0%). Prevalence estimates for each category were higher when analyzed within age-restricted subgroups; and increased as follow-up time increased. CONCLUSIONS: This study is the first to use diagnosis and procedure codes from real-world Medicaid claims to document the clinical course in DMD. Findings were consistent with previously published estimates from commercially insured populations and clinical registries; and contribute to the expanding body of real-world evidence around clinical progression of patients with DMD.

Comparing Preferences for Disease Profiles: A Discrete Choice Experiment from a US Societal Perspective.

OBJECTIVES: There is increasing interest in expanding the elements of value to be considered when making health policy decisions. To help inform value frameworks, this study quantified preferences for disease attributes in a general public sample and examined which combination of attributes (disease profiles) are considered most important for research and treatment. METHODS: A discrete choice experiment (DCE) was conducted in a US general population sample, recruited through online consumer panels. Respondents were asked to select one of a set of health conditions they believed to be most important, characterized by attributes defined by a previous qualitative study: onset age; cause of disease; life expectancy; caregiver requirement; symptom burden (characterized by the Health Utilities Index with varying levels of ambulation independence, dexterity limitations, and degree of pain and discomfort); and disease prevalence. A fractional factorial DCE design was implemented using R, and 60 choice sets were generated (separated into blocks of 10 per participant). Data were analyzed using a mixed-logit regression model, and results used to assess the likelihood of preferring disease profiles. Based on individual attribute preferences, overall preferences for disease profiles, including a profile aligned with Duchenne muscular dystrophy (DMD), were compared. RESULTS: Fifty-two percent of respondents (n = 537) were female, and 70.6% were aged 18-54 years. Attributes considered most important were those related to life expectancy (odds ratio [OR], 95% confidence interval [CI] 1.88 [1.56-2.27] for a 50% reduction in remaining life expectancy vs no impact), and symptom burden (OR [95% CI] 1.84 [1.47-2.31] for severe vs mild burden). Greater importance was also found for pediatric onset, caregiver requirement, and diseases affecting more people. As an example of disease profile preferences, a DMD-like pediatric inherited disease with 50% reduction in life expectancy, extensive caregiver requirement, severe symptom burden, and 1:5000 prevalence had 2.37-fold higher odds of being selected as important versus an equivalent disease with adult onset and no life expectancy reduction. CONCLUSIONS: Of disease attributes included in this DCE, respondents valued higher prevalence of disease, life expectancy and symptom burden as most important for prioritizing research and treatment. Based on expressed attribute preferences, a case study of an inherited pediatric disease involving substantial reductions to length and quality of life and requiring caregiver support has relatively high odds of being identified as important compared to diseases reflecting differing attribute profiles. These findings can help inform expansions of value frameworks by identifying important attributes from the societal perspective.

Elevated risk of asthma after hospitalization for respiratory syncytial virus infection in infancy.

Severe respiratory syncytial virus (RSV) infection in infancy is associated with substantial morbidity worldwide; whether it is a risk factor for childhood asthma is contentious. A systematic review of 28 articles was conducted, summarizing estimates of asthma risk after RSV hospitalization during infancy. Prevalence estimates of asthma, among those hospitalized for RSV in infancy, were from 8% to 63%, 10% to 92%, and 37%, at ages <5, 5 to 11, and ≥ 12 years, respectively. These rates were higher than those among non-hospitalized comparisons. The attributable risk of asthma due to RSV ranged from 13% to 22% and from 11% to 27% among children aged ≤ 5 and aged 5 to 11, respectively, and was 32% among children ≥ 12 years of age. Overall, 59% of asthma prevalence estimates from those previously hospitalized for RSV exceeded 20%, compared to only 6% of non-hospitalized comparison estimates. Despite variability in asthma prevalence estimates after RSV-related hospitalization, available data suggest a link between severe RSV infection in infancy and childhood asthma.

The risk of mortality among young children hospitalized for severe respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) is the leading cause of childhood morbidity. Although also an important cause of childhood mortality worldwide, the impact of key risk factors has not been established. A systematic review of 34 articles reporting case fatality rates in young children hospitalized for severe RSV LRTI, according to the presence of underlying RSV risk factors, was conducted. The weighted mean case fatality rate was 1.2% (range, 0-8.3%; median, 0%; n = 10) among preterm infants; 5.2% (range, 2.0-37.0%; median, 5.9%; n = 7) among children with CHD; and 4.1% (range, 0-10.5%; median, 7.0%; n = 6) among children with BPD. Case fatality estimates among children not at high risk (n = 6) ranged from 0% to 1.5% (weighted mean, 0.2%; median, 0.0%). Fatality during hospitalization for severe RSV LRTI is rare among children not at high risk, but occurs more commonly among children at higher risk of RSV LRTI.

Assessing the impact of single or short-term administration on a therapy's cost-effectiveness: a hypothetical disease-agnostic model.

AIMS: Assessing the value of single or short-term therapies (SSTs) within traditional cost-effectiveness analyses (CEAs) has been a topic of discussion as the number of SSTs increases, particularly regarding the effect of discounting on valuation. To quantify the impact of discounting in economic evaluations, a CEA of a hypothetical SST and equivalent chronic therapy was conducted using standard methods. MATERIALS AND METHODS: A lifetime Markov model was developed for a hypothetical chronic, progressive disease that could be treated with an SST, chronic therapy, or no novel treatment, termed standard of care (SoC). Incremental cost-effectiveness ratios (ICERs) with quality-adjusted life years (QALYs) comparing SST vs. SoC and an equivalent chronic therapy vs. SoC were assessed from a payer perspective. Both treatments had equal benefits and undiscounted lifetime costs; 3% discounting was applied to costs/benefits in the base case, and the impact of discounting was assessed. RESULTS: In the base case example, both the SST and equivalent chronic therapy vs. SoC had ICERs of $86,000/QALY without discounting. With 3% discounting, the ICER for the SST increased by 116% ($186,000/QALY) while the ICER for the chronic therapy increased by 10% ($95,000/QALY) despite equal clinical benefit. In scenario analyses, the ICER of the SST was consistently higher than the equivalent chronic therapy across a range of assumptions/inputs. Varying the cost/benefit discount rates had a greater impact on the SST. Differences in the ICERs between the therapies increased with increasing life expectancy/time horizon. LIMITATIONS: The simple model structure may not be reflective of acute or more complex diseases. Also, the scenario of perfect equivalency in efficacy and lifetime costs is hypothetical. CONCLUSIONS: This quantitative assessment showed the extent to which SST CEAs are highly sensitive to discounting, resulting in worse value assessments for SSTs than equivalent chronic therapies.

Paving the way for future gene therapies: A case study of scientific spillover from delandistrogene moxeparvovec.

Gene therapies have potential to improve outcomes of severe diseases after only a single administration. Novel therapies are continually being developed using knowledge gained from prior successes, a concept known as scientific spillover. Gene therapy advancement requires extensive development at each stage: preclinical work to create and evaluate vehicles for delivery of the therapy, design of clinical development programs, and establishment of a large-scale manufacturing process. Pioneering gene therapies are generating spillover as investigators confront myriad issues specific to this treatment modality. These include frameworks for construct engineering, dose evaluation, patient selection, outcome assessment, and safety monitoring. Consequently, the benefits of these therapies extend beyond offering knowledge for treating any one disease to establishing new platforms and paradigms that will accelerate advancement of future gene therapies. This impact is even more profound in rare diseases, where developing therapies in isolation may not be possible. This review describes some instances of scientific spillover in healthcare, and specifically gene therapy, using delandistrogene moxeparvovec (SRP-9001), a gene therapy recently approved by the US Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with Duchenne muscular dystrophy with a confirmed mutation in the DMD gene, as a case study.

Patterns of Clinical Progression Among Patients With Autosomal Recessive Limb-Girdle Muscular Dystrophy: A Systematic Review.

OBJECTIVES: As the clinical course of autosomal recessive limb-girdle muscular dystrophy (LGMDR) is highly variable, this study characterized the frequency of loss of ambulation (LOA) among patients by subtype (LGMDR1, LGMDR2, LGMDR3-6, LGMDR9, LGMDR12) and progression to cardiac and respiratory involvement among those with and without LOA. METHODS: Systematic literature review. RESULTS: From 2929 abstracts screened, 418 patients were identified with ambulatory status data (LOA: 265 [63.4%]). Cardiac and/or respiratory function was reported for 142 patients (34.0%; all with LOA). Among these, respiratory involvement was most frequent in LGMDR3-6 (74.1%; mean [SD] age 23.9 [11.0] years) and cardiac in LGMDR9 (73.3%; mean [SD] age 23.7 [17.7] years). Involvement was less common in patients without LOA except in LGMDR9 (71.4% respiratory and 52.4% cardiac). CONCLUSIONS: This study described the co-occurrence of LOA, cardiac, and respiratory involvement in LGMDR and provides greater understanding of the clinical progression of LGMDR.

Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States.

Background: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene therapy that may delay progression of Duchenne muscular dystrophy (DMD), a severe, rare neuromuscular disease caused by DMD gene mutations. Early cost-effectiveness analyses are important to help contextualize the value of gene therapies for reimbursement decision making. Objective: To determine the potential value of delandistrogene moxeparvovec using a cost-effectiveness analysis. Study design: A simulation calculated lifetime costs and equal value of life years gained (evLYG). Inputs included extrapolated clinical trial results and published utilities/costs. As a market price for delandistrogene moxeparvovec has not been established, threshold analyses established maximum treatment costs as they align with value, including varying willingness-to-pay up to $500,000, accounting for severity/rarity. Setting: USA, healthcare system perspective Patients: Boys with DMD Intervention: Delandistrogene moxeparvovec plus standard of care (SoC; corticosteroids) versus SoC alone Main outcome measure: Maximum treatment costs at a given willingness-to-pay threshold Results: Delandistrogene moxeparvovec added 10.30 discounted (26.40 undiscounted) evLYs. The maximum treatment cost was approximately $5 M, assuming $500,000/evLYG. Varying the benefit discount rate to account for the single administration increased the estimated value to #$5M, assuming $500,000/evLYG. Conclusion: In this early economic model, delandistrogene moxeparvovec increases evLYs versus SoC and begins to inform its potential value from a healthcare perspective.

Estimating health state utilities in Duchenne muscular dystrophy using the health utilities index and EQ-5D-5L.

BACKGROUND: The progression of Duchenne muscular dystrophy (DMD) is characterized by loss of ambulation, respiratory insufficiency, cardiomyopathy, and early mortality. DMD profoundly impacts health-related quality-of-life (HRQoL). However, few health state utility data exist; published utilities tend to be derived from small samples for a limited number of health states and are often based on caregiver-reported patient health status. This study estimated utility values for varied clinical and functional health states in DMD, based on patient-reported health status. METHODS: Individuals with DMD in the US aged 12-40 years completed the EQ-5D (5-level) and Health Utilities Index (HUI) preference-based instruments. Based on responses to a clinical questionnaire, participants self-classified into functional health states according to level of lower and upper limb function, use of respiratory support, and presence of cardiomyopathy. Mean [standard deviation (SD)] utility and EQ-5D visual analogue scale (VAS) scores were estimated according to health state; and median (interquartile range) attribute levels calculated to understand which domains of health are most severely affected in DMD. RESULTS: Of 63 males with DMD, mean (SD) age was 19.8 (6.1) years and 11 (17.5%) were ambulatory. Mean (SD) utility values were 0.92 (0.08; HUI2), 0.84 (0.20; HUI3), and 0.84 (0.13; EQ-5D) for ambulatory patients without cardiomyopathy (n = 10). For non-ambulatory patients with moderately impaired upper limb function, night and daytime ventilation without cardiomyopathy, mean (SD) utilities were 0.49 (0.07) for the HUI2, 0.16 (0.15) for the HUI3 and 025 (0.14) for the EQ-5D. Mean (SD) VAS scores for the same health states were 91 (9) and 83 (21), respectively. In addition to impairments in mobility/ambulation, and self-care, attributes like usual activities and pain also showed notable effects of DMD. CONCLUSIONS: In DMD, although a relationship between disease progression and HRQoL is observed, there is large variability in utility within functional health states, and across instruments. Utility values for less severe non-ambulatory health states described by level of upper limb function are novel. These utility values, derived based on direct patient feedback rather than from caregiver report, are relevant to individuals of varying functional statuses and augment scarce DMD-specific utility data.

The evolution of risk factors for respiratory syncytial virus-related hospitalisation in infants born at 32-35 weeks' gestational age: time-based analysis using data from the FLIP-2 study.

AIM: The aim of this study was to examine whether the risk for respiratory syncytial virus (RSV)-related hospitalisation changes through the first year of life in infants of 32-35 weeks' gestational age (wGA). METHODS: Risk factors from the FLIP-2 study (190 cases/4566 age-matched controls) were included in a Cox regression analysis wherein time slices were taken at 1-month intervals from birth. RESULTS: Half of all RSV hospitalisations occurred in the first 68 days after birth, with 56% occurring within 90 days. The time taken for 50% of hospitalisations to occur was 148 days for those born outside the RSV season and 58 days for those born within the season. By 90 days old, 84% of infants born in the season and 20% of those born outside the season were hospitalised. In both groups, hospitalisations occurred ≥5 months after birth. Male sex, smoking whilst pregnant, month of birth, duration of breastfeeding, number of siblings at school, and number of smokers in household all contributed to the risk of RSV hospitalisation beyond the age of 90 days. CONCLUSIONS: The risk of RSV hospitalisation appears to persist to at least 5-6 months old in 32-35 wGA infants, which has implications for the optimal management of disease prevention.

Characterizing the Occurrence of Key Clinical Milestones in Duchenne Muscular Dystrophy in the United States Using Real-World Data.

BACKGROUND: Data on the clinical course of Duchenne muscular dystrophy (DMD) exist from well-characterized clinical cohorts but estimates from real-world populations are fewer. OBJECTIVE: The objective was to estimate the prevalence of key clinical milestones by age, among real-world commercially-insured DMD patients in the United States. METHODS: MarketScan claims (2013-2018) were used to identify males with DMD. The percentages with wheelchair use or experiencing scoliosis, neurologic/neuropsychiatric involvement, cardiomyopathy, and respiratory involvement were tabulated; as were the median (interquartile range [IQR]) ages at first observed occurrence within the claims data. RESULTS: Among DMD patients (n = 1,964), the median (IQR) baseline age was 15 (9-21) years, and median follow-up was 1.7 years. Wheelchair use was observed in 55% of those aged 8 to 13 years at cohort entry; scoliosis, among 38% of those 8 to 10 and 52% of those 11 to 13 years; neurologic/neuropsychiatric involvement, among 41-43% of those 8 to 13 years; respiratory involvement, among 45% of those 14 to 19 years; and cardiomyopathy, among 68% of those 14 to 16 and 58% of those 17 to 19 years. CONCLUSIONS: The prevalence of key clinical milestones across ages was broadly consistent with published findings. Variability in estimates reflect clinical heterogeneity; these contemporary estimates from real-world data help characterize clinical outcomes in DMD.

Societal perspectives on disease and treatment attributes characterizing rare diseases: a qualitative study from the United States.

PURPOSE: Under a societal perspective, disease and treatment attributes that the general public deem important should be considered within value frameworks. The objective was to investigate how members of the general public value attributes beyond health gains and healthcare system expenditures; and better understand their perspectives regarding the importance of attributes typically characterizing rare genetic diseases like Duchenne muscular dystrophy (DMD). METHODS: Qualitative interviews were conducted to elicit feedback on the importance of disease and treatment attributes from general public participants from three US cities. Participants ranked attributes (scale, 1-10) in terms of importance for future research, reported their rationale for ranking, and provided feedback specific to rare diseases. Interview transcripts were coded using NVivo for thematic analysis. RESULTS: The 33 participants (median age, 51 years; 48.5% male) ranked disease severity (mean [median] ranking, 8.7 [9.0]), treatment availability (8.7 [9.0]), and impact on life expectancy (8.4 [9.0]), as most important. The impact on the family, need for equity, and intrinsic value of life were frequently provided rationales. While rare disease as an attribute received a relatively low ranking (6.1 [7.0]), 88% of participants prioritized disease profiles including attributes of severity, health related quality of life (HRQoL) impact, limited lifespan and young age at onset. CONCLUSION: Attributes including disease severity, impact on life expectancy and HRQoL, and treatment availability were all highly important to members of the general public. These findings support the growing evidence regarding the importance of expanding value assessments to include attributes considered important from a societal perspective.

QALYs and ambulatory status: societal preferences for healthcare decision making.

BACKGROUND: This research aimed to review the theoretical and methodological aspects of the quality-adjusted life year (QALY) which give rise to potential for bias against certain patient populations, including those with problems with walking or an inability to walk (ambulatory disabilities), when health technology assessment decisions rely on QALY gain to show cost-effectiveness. Societal preferences for treating ambulatory versus non-ambulatory patients were also investigated. METHODS: We reviewed published literature to identify information on theoretical underpinnings of the QALY, measurement of utilities for QALY assessment, and empirical evidence of societal preferences for the treatment of ambulatory and non-ambulatory patients. RESULTS AND DISCUSSION: Health states which represent mobility impairment and the inability to walk receive low valuation from general public preferences. Non-ambulatory patients, for example those with advanced neuromuscular disease, have lower utilities determined by standardized preference-based measurement (PBM) tools. Any treatment that increases survival but could not restore ambulation would result in lower lifetime QALY gains for non-ambulatory versus ambulatory patients. Treatments could therefore potentially be deemed less cost-effective, or not cost-effective at all for this patient population.Empirical research indicates a societal preference for equal treatment of patients regardless of ambulatory status. The main limitation of our review was the non-systematic approach to evidence search and review, however, given the broad scope of content required to meet the aims of the review, we believe that the targeted approach was appropriate. The evidence presented in this article highlights the need for alternatives to strict QALY-based approaches to prevent avoidable health inequities when determining cost-effectiveness of healthcare interventions for non-ambulatory populations against fixed cost-effectiveness thresholds. An alternative metric, the Equal Value of Life Years Gained (evLYG), has been proposed as a supplementary measure for use alongside the QALY for its potential to alleviate bias against disabled patient populations during the assessment of healthcare treatments.