Assessing the impact of grief on quality of life, work productivity, and health outcomes for parents bereaved from SMA: A study protocol.

BACKGROUND: U.S. cost-effectiveness recommendations suggest that analyses should include all costs and effects relevant to the decision problem [1]. However, in many diseases, including spinal muscular atrophy (SMA), few studies have evaluated bereaved family outcomes after a child has died, neglecting potential impacts on their health-related quality of life (HRQoL), work productivity, and mental health. Additionally, grief-related outcomes are rarely included in economic evaluations. This manuscript outlines the protocol of a study that will estimate the HRQoL, work functioning, and mental health of bereaved parents of children with SMA type 1 to determine how outcomes vary based on parent's sex and the time since a child's death. METHODS: This study will involve two phases. In Phase 1, we will conduct a literature review to identify prior research that has measured how parental grief impacts HRQoL, work productivity, and mental health. We will also interview four bereaved parents of children with SMA type 1, stratified by parent sex and time since their child's death, and analyze findings using a thematic analysis. In Phase 2, we will develop a survey draft based on Phase 1 findings. Parents bereaved from SMA type 1 will review our survey draft and we will revise the survey based on their feedback. We will send a cross-sectional survey to approximately 880 parents bereaved from SMA type 1. We will analyze findings from the survey to investigate whether the severity of grief symptoms is correlated with HRQoL, productivity, depression and anxiety symptom severity. We will also evaluate whether the mean scores of grief and each of the outcomes vary significantly when stratified by parent sex and the time since the child's death. DISCUSSION: Our results will provide preliminary information on how parental grief can impact HRQoL, productivity, and mental health outcomes over time. Increasing the availability of family outcomes data will potentially assist organizations performing health economic evaluations, such as the Institute of Clinical and Economic Review (ICER) in the U.S. This research will also help to inform the development of future economic guidelines on this topic.

Developing Criteria for Health Economic Quality Evaluation Tool.

OBJECTIVES: Because existing publication guidelines and checklists have limitations when used to assess the quality of cost-effectiveness analysis, we developed a novel quality assessment tool for cost-effectiveness analyses, differentiating methods and reporting quality and incorporating the relative importance of different quality attributes. METHODS: We defined 15 quality domains from a scoping review and identified 72 methods and reporting quality attributes (36 each). After designing a best-worst scaling survey, we fielded an online survey to researchers and practitioners to estimate the relative importance of the attributes in February 2021. We analyzed the survey data using a sequential conditional logit model. The final tool included 48 quality attributes deemed most important for assessing methods and reporting quality (24 each), accompanied by a free and web-based scoring system. RESULTS: A total of 524 participants completed the methodology section, and 372 completed both methodology and reporting sections. Quality attributes pertaining to the "modeling" and "data inputs and evidence synthesis" domains were deemed most important for methods quality, including "structure of the model reflects the underlying condition and intervention's impact" and "model validation is conducted." Quality attributes pertaining to "modeling" and "Intervention/comparator(s)" domains were considered most important for reporting quality, including "model descriptions are detailed enough for replication." Despite its growing prominence, "equity considerations" were not deemed as important as other quality attributes. CONCLUSIONS: The Criteria for Health Economic Quality Evaluation tool allows users to differentiate methods and reporting as well as quantifies the relative importance of quality attributes. Alongside other considerations, it could help assess and improve the quality of cost-effectiveness evidence to inform value-based decisions.

Family Spillover Effects: Are Economic Evaluations Misrepresenting the Value of Healthcare Interventions to Society?

The societal impacts of health interventions are seldom incorporated into health economic evaluations, including the impact that illness can have on informal or unpaid caregivers and other family members (i.e., "family spillover effects"). Previous research has demonstrated that by excluding family spillover effects, the value of health interventions may be underestimated on average. In this commentary, we discuss how the inclusion of spillover effects influences how we value interventions and, given the extent to which caregiver/family effects are largely not captured or known, propose ways in which these data could be more systematically collected or estimated and used by researchers. These recommendations include prioritizing data collection alongside clinical trials and patient registries, engaging expert opinion panels, and developing mapping algorithms for estimating caregiver/family utility values from non-preference-based caregiver health-related quality-of-life measures and/or from patient preference-based measures.

Key drivers of family-level utility of pediatric genomic sequencing: a qualitative analysis to support preference research.

Given that pediatric genomic sequencing (GS) may have implications for the health and well-being of both the child and family, a clearer understanding of the key drivers of the utility of GS from the family perspective is needed. The purpose of this study is to explore what is important to caregivers of pediatric patients regarding clinical GS, with a focus on family-level considerations. We conducted semi-structured interviews with caregivers (n = 41) of pediatric patients who had been recommended for or completed GS that explored the scope of factors caregivers considered when deciding whether to pursue GS for their child. We analyzed the qualitative data in multiple rounds of coding using thematic analysis. Caregivers raised important family-level considerations, in addition to those specifically for their child, which included wanting the best chance at good quality of life for the family, the ability to learn about family health, the impact on the caregiver's well-being, privacy concerns among family members, and the cost of testing to the family. We developed a framework of key drivers of utility consisting of four domains that influenced caregivers' decision making: underlying values, perceived benefits, perceived risks, and other pragmatic considerations regarding GS. These findings can inform measurement approaches that better capture the utility of pediatric GS for families and improve assessments of the value of clinical GS.

Psychometric Performance of the SF-6D Quality of Life Measure in an Outpatient Population with Bipolar Disorder.

BACKGROUND: Bipolar disorder is among the top 10 causes of disability worldwide. The Short-Form Six-Dimension (SF-6D) is a frequently used measure of preference-based health-related quality of life (HRQOL). However, this measure's psychometric performance has not been tested in outpatient patients with bipolar disorder. AIMS OF THE STUDY: This study assessed the psychometric properties of the SF-6D, including convergent validity, known-groups validity, and responsiveness. METHODS: We examined convergent validity between the SF-6D and four condition-specific measures of functioning (LIFE-RIFT), life satisfaction (QLESQ), depressive symptoms (MADRS), and manic symptoms (YMRS). We used known-groups validity tests to compare the SF-6D health utility values estimated for patients in different clinical states, including depression, mania, hypomania, and recovered. We assessed the responsiveness of the SF-6D by comparing the sensitivity of the SF-6D utility values to longitudinal changes in the four condition-specific measures during the same period of time. We conducted all analyses using data from 2,627 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) clinical trial. RESULTS: The SF-6D demonstrated moderate (0.3-0.7) convergence with the LIFE-RIFT, QLESQ, and MADRS measures. Convergence with the manic symptoms measure (YMRS) was weak (<0.3). For known-groups validity, the SF-6D distinguished the recovered state from the three symptomatic clinical states. For responsiveness, the measure did not show floor or ceiling effects. The SF-6D utility value increased when mental health improved, with a small ES of 0.3 over the 1-year period, which was comparable to the four condition-specific measures. DISCUSSION: The SF-6D demonstrated moderate convergent validity, moderate responsiveness, and it can distinguish the differences between known-groups that had been identified in literature. The SF-6D may be a suitable measure of preference-based HRQOL for patients with bipolar disorder, but caution is needed due to its lower convergence with the YMRS mania scale. LIMITATIONS: The subsample of patients in manic episode was small, which may reduce the reliability of study findings regarding this specific clinical state. In terms of generalizability, the STEP-BD study sample is based on patients who received treatment in bipolar specialty clinics affiliated with academic medical centers, which may be different from other outpatient clinics. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: The mean health utility value for patients with hypomania is significantly lower than the mean value for recovered patients. This finding emphasizes the importance of treating hypomania. IMPLICATION FOR HEALTH POLICIES: This study validates an existing approach toward generating health utility values for bipolar disorder. These utility values can be used to create quality-adjusted life years (QALYs), which are the most commonly used measure of health benefit in cost-effectiveness studies. IMPLICATIONS FOR FURTHER RESEARCH: Studies with larger samples of patients with mania are needed to study measures of health utility in this patient population.

Incentivizing Drug Development in Serious Mental Illness.

Serious mental illness (SMI) imposes a significant burden on individuals and society. Individuals living with SMI have worse expected health, education, and career outcomes during their lifetime. Although treatments exist, pharmaceutical innovation in this area has lagged many other disease areas, despite an important need for new treatments. This report describes barriers that have hindered innovation and the development of new drugs for SMI, including science and research, regulatory, and health system barriers. To address these barriers, this report presents policies that may incentivize investment in this area.

Trends in Author-Reported Cost-Effectiveness Thresholds in the United States from 1995 to 2018: Implications for Discount Rates.

BACKGROUND: Decisions based on cost-effectiveness analyses (CEAs) using equal discount rates for health and cost outcomes are consistent with using a constant cost-effectiveness threshold over time. We sought to analyze trends in author-reported cost per quality-adjusted life-year (QALY) thresholds from CEAs published for the US setting over 24 y to retrospectively assess whether the recommended equal discount rates for costs and health were consistent with trends in the CEA literature. METHODS: We used the Tufts CEA Registry to assess whether author-reported cost-effectiveness thresholds changed in CEAs published for the US setting between 1995 and 2018 and back-calculated the implied discount rate for health based on these trends for inflation-adjusted cost-effectiveness thresholds and an annual discount rate for costs of 3%. RESULTS: We found 1995 CEAs published for the US setting and found that average nominal and inflation-adjusted cost-effectiveness thresholds increased over that time period. The discount rate for health would need to equal 2.43% to 2.48% (depending on the subset of CEAs analyzed) to be consistent with the observed trends in inflation-adjusted author-reported cost-effectiveness thresholds. We also found that restricting our analysis to currency years between 1995 and 2014 would result in a back-calculated discount rate for health of 2.99% to 3.28%. CONCLUSIONS: We found that CEA researchers have implicitly assumed that inflation-adjusted cost-effectiveness thresholds in the United States have been increasing over time (1995-2018), which is inconsistent with the recommended and prevailing choice of equal discount rates for health and cost outcomes. Our results are sensitive to the cutoff year used in the analysis. HIGHLIGHTS: We show visually and through equations that the recommended and prevailing practice of using equal discount rates for cost and health outcomes in cost-effectiveness analyses (CEAs) logically implies a constant inflation-adjusted cost-effectiveness threshold over time.Using data from the Tufts CEA Registry, we found that author-reported cost-effectiveness thresholds used in CEAs published for the US setting with currency years between 1995 and 2018 increased over time (both with and without adjustment for inflation).Assuming an annual discount rate for costs equal to 3%, the discount rate for health would need to equal approximately 2.5% to preserve consistency across decisions taken at different dates given the observed trends in inflation-adjusted author-reported cost-effectiveness thresholds.This finding depends on the cutoff year used in the analysis (data from currency years 1995-2014 would support use of equal discount rates, whereas data after 2014 would suggest a sharper trend toward increasing cost-effectiveness thresholds).

Addressing Challenges to Alternative Payment Models for New Alzheimer's Disease Therapies for US Commercial Payers.

Commercial payers that ultimately decide to cover aducanumab or other Alzheimer's disease therapies may require innovative payment tools to minimize their financial risk given the uncertain benefits and high cost of such treatments. Drawing on the published evidence, we propose two different types of payment models applicable to disease-modifying therapies in Alzheimer's disease, and suggest four strategies to overcome challenges in their implementation. Such strategies range from developing best practices for outcome measurement in Alzheimer's disease, investing in infrastructure to collect real-world data, increasing representativeness of registry data in Alzheimer's disease, and integrating the diagnostic, treatment, and payment landscape. These important steps could make access to emerging therapies in Alzheimer's disease more sustainable in the long term, and could serve as a blueprint for better access to novel therapies in other indications in the future.

Cost-effectiveness of exome and genome sequencing for children with rare and undiagnosed conditions.

PURPOSE: This study aimed to estimate the cost-effectiveness of exome sequencing (ES) and genome sequencing (GS) for children. METHODS: We modeled costs, diagnoses, and quality-adjusted life years (QALYs) for diagnostic strategies for critically ill infants (aged <1 year) and children (aged <18 years) with suspected genetic conditions: (1) standard of care (SOC) testing, (2) ES, (3) GS, (4) SOC followed by ES, (5) SOC followed by GS, (6) ES followed by GS, and (7) SOC followed by ES followed by GS. We calculated the 10-year incremental cost per additional diagnosis, and lifetime incremental cost per QALY gained, from a health care perspective. RESULTS: First-line GS costs $15,048 per diagnosis vs SOC for infants and $27,349 per diagnosis for children. If GS is unavailable, ES represents the next most efficient option compared with SOC ($15,543 per diagnosis for infants and $28,822 per diagnosis for children). Other strategies provided the same or fewer diagnoses at a higher incremental cost per diagnosis. Lifetime results depend on the patient's assumed long-term prognosis after diagnosis. For infants, GS ranged from cost-saving (vs all alternatives) to $18,877 per QALY (vs SOC). For children, GS (vs SOC) ranged from $119,705 to $490,047 per QALY. CONCLUSION: First-line GS may be the most cost-effective strategy for diagnosing infants with suspected genetic conditions. For all children, GS may be cost-effective under certain assumptions. ES is nearly as efficient as GS and hence is a viable option when GS is unavailable.

Herd Immunity Effects in Cost-Effectiveness Analyses among Low- and Middle-Income Countries.

BACKGROUND: Herd immunity (HI) is a key benefit of vaccination programs, but the effects are not routinely included in cost-effectiveness analyses (CEAs). OBJECTIVE: This study investigated how the inclusion of HI in CEAs may influence the reported value of immunizations in low- and middle-income countries (LMICs) and illustrated the implications for COVID-19 immunization. METHODS: We reviewed immunization CEAs published from 2000 to 2018 focusing on LMICs using data from the Tufts Medical Center CEA Registries. We investigated the proportion of studies that included HI, the methods used, and the incremental cost-effectiveness ratios (ICERs) reported. When possible, we evaluated how ICERs would change with and without HI. RESULTS: Among the 243 immunization CEAs meeting inclusion criteria, 44 studies (18%) included HI. Of those studies, 11 (25%) used dynamic transmission models, whereas the remainder used static models. Sixteen studies allowed for ICER calculations with and without HI (n = 48 ratios). The inclusion of HI always resulted in more favorable ratios. In 20 cases (42%), adding HI decreased the ICERs enough to cross at least one or more common cost-effectiveness benchmarks for LMICs. Among pneumococcal vaccination studies, including HI in the analyses decreased seven of 24 ICERs enough to cross at least one cost-effectiveness benchmark. CONCLUSION: The full value of immunization may be underestimated without considering a scenario in which HI is achieved. Given the evidence in pneumococcal CEAs, COVID-19 vaccine value assessments should aim to show ICERs with and without HI to inform decision-making in LMICs.

Developmental Behavioral Pediatrician Perspectives on Decision-Making in Early Treatment Planning for Children with Autism Spectrum Disorder.

OBJECTIVE: Providers of children with autism spectrum disorder (hereafter "autism") report higher levels of shared decision-making during initial diagnostic and treatment planning visits than observed. The goal of this study was to qualitatively explore this discrepancy by investigating provider perceptions of the parent-provider decision-making process in early treatment planning and the role for parents in this process. METHODS: We conducted semistructured qualitative interviews with developmental behavioral pediatricians (DBPs; n = 15) to investigate how they approach early treatment planning with parents. We analyzed participant characteristics using descriptive statistics. Interviews were audio-recorded, transcribed, and independently coded by 2 researchers until consensus was reached. Analyses were conducted using a modified grounded theory framework. RESULTS: DBPs reported that their primary role during early treatment planning was to provide diagnostic clarification and that parents' primary role was to learn as much as they can about autism. Most DBPs wanted treatment planning to be collaborative, and perceived that parents had the same preference but might not have the knowledge or skills to effectively participate. DBPs identified additional barriers that influence the extent to which they engage parents in the collaborative decision-making and provided recommendations for enhancing the process. CONCLUSION: DBPs are proponents of collaborative treatment planning between parents and providers; however, there are many obstacles that prevent this. Strategies such as decision tools or aids and larger systemic reforms are necessary to support DBPs and parents in this process.

The cost-effectiveness of treatments for attention deficit-hyperactivity disorder and autism spectrum disorder in children and adolescents: a systematic review.

Economic evaluations can help decision makers identify what services for children with neurodevelopmental disorders provide best value-for-money. The aim of this paper is to review the best available economic evidence to support decision making for attention deficit-hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children and adolescents. We conducted a systematic review of economic evaluations of ADHD and ASD interventions including studies published 2010-2020, identified through Econlit, Medline, PsychINFO, and ERIC databases. Only full economic evaluations comparing two or more options, considering both costs and consequences were included. The quality of the studies was assessed using the Drummond checklist. We identified ten studies of moderate-to-good quality on the cost-effectiveness of treatments for ADHD and two studies of good quality of interventions for ASD. The majority of ADHD studies evaluated pharmacotherapy (n = 8), and two investigated the economic value of psychosocial/behavioral interventions. Both economic evaluations for ASD investigated early and communication interventions. Included studies support the cost-effectiveness of behavioral parenting interventions for younger children with ADHD. Among pharmacotherapies for ADHD, different combinations of stimulant/non-stimulant medications for children were cost-effective at willingness-to-pay thresholds reported in the original papers. Early intervention for children with suspected ASD was cost-effective, but communication-focused therapy for preschool children with ASD was not. Prioritizing more studies in this area would allow decision makers to promote cost-effective and clinically effective interventions for this target group.

Quantifying the Burden of Hyperphagia in Prader-Willi Syndrome Using Quality-Adjusted Life-years.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare disease associated with cognitive impairment, hypotonia, hyperphagia (an insatiable hunger), and obesity. Therapies that target hyperphagia are in development, but understanding the value of these therapies to inform patient-focused drug development (PFDD) requires valid data on disease burden. We estimated disease burden by measuring and comparing quality-adjusted life-years (QALYs) for 3 PWS health states relevant to current PFDD initiatives. METHODS: Time trade-off (TTO) and a visual analog scale (VAS) were used to elicit PWS caregivers' values for 3 fixed health states for a standardized patient described with (1) untreated PWS, (2) PWS with controlled obesity, and (3) PWS with controlled obesity and hyperphagia. We excluded participants who left at least 1 TTO or VAS question blank or incomplete (noncompleters) and respondents who reported the same answer for all TTO scenarios (nontraders). The remaining group of respondents (traders) were used for all primary analyses. We assessed validity and bias of QALY estimates by comparing differences in health state valuations, treatment priorities, and characteristics among respondents who did and did not complete the TTO. RESULTS: A total of 458 respondents completed the survey, including 226 traders, 93 nontraders, and 139 noncompleters. Traders valued untreated PWS at 0.69 QALYs, PWS with controlled obesity at 0.79 QALYs, and controlled hyperphagia/obesity at 0.91 QALY (P < 0.01 for differences among health state values). Reported VAS ratings were similar for traders versus nontraders for untreated PWS (38.64 vs 38.95, P = 0.89) and PWS with controlled obesity (57.36 vs 55.14, P = 0.35) but varied for PWS with controlled obesity and hyperphagia (70.70 vs 64.46, P = 0.02). Exclusion of noncompleters did not introduce obvious bias because traders and noncompleters were similar in treatment priorities and characteristics. The exclusion of nontraders did not meaningfully alter mean or distribution of valuations. CONCLUSIONS: This study found that avoiding hyperphagia decreases the burden of PWS and that these results are robust, even once imposing strict inclusion criteria. Use of fixed health states to estimate QALYs addresses many of the complexities of measuring disease burden in rare and pediatric conditions, indicating the potential value of this approach to inform premarket decision makers in identifying outcome importance.

Family-level impact of genetic testing: integrating health economics and ethical, legal, and social implications.

Tweetable abstract Health economics and ELSI can be better integrated to consider the family impacts of genetic and genomic testing.

Shared Decision-Making During Initial Diagnostic and Treatment Planning Visits for Children with Autism Spectrum Disorder.

OBJECTIVE: Although shared decision-making (SDM) can improve patient engagement, adherence, and outcomes, evidence on the use of SDM within the context of autism spectrum disorder (ASD) initial diagnosis and treatment planning remains limited. The goal of this study was to objectively assess the occurrence of SDM in these visits and to compare this assessment with parent and provider perceptions of SDM in the same encounter. METHODS: After audio-recording and transcribing initial clinical visits between parents (n = 22) and developmental behavioral pediatricians (n = 6) discussing the diagnosis of ASD and treatment options, we used the OPTION5 Item scale to assess the occurrence of SDM. Afterward, parents and providers completed the OPTION5 Item, and parents also participated in a semistructured qualitative interview. Analysis consisted of descriptive statistics for OPTION5 Item scores and a modified grounded theory framework for interviews. RESULTS: Low levels of SDM were observed, with 41% of visits having no elements of SDM. On average, visits scored 1.1 of a possible 20 points on the OPTION5 Item scale for SDM. By contrast, parents and providers indicated on the OPTION5 Item scale that providers made a "moderate" to "skilled" effort to engage parents in SDM. Qualitative interviews with parents were consistent with their OPTION5 Item ratings. CONCLUSION: The level of SDM determined by parent and provider reports was higher than the level of SDM determined by objective observation using a standard validated rating method. The findings reinforce the need for further research into barriers and facilitators of SDM methods and outcomes within ASD.

Healthcare Costs of Pediatric Autism Spectrum Disorder in the United States, 2003-2015.

Published healthcare cost estimates for children with autism spectrum disorder (ASD) vary widely. One possible contributor is different methods of case ascertainment. In this study, ASD case status was determined using two sources of parent reports among 45,944 children ages 3-17 years in the Medical Expenditure Panel Survey (MEPS) linked to the National Health Interview Survey (NHIS) Sample Child Core questionnaire. In a two-part regression model, the incremental annual per-child cost of ASD relative to no ASD diagnosis was $3930 (2018 US dollars) using ASD case status from the NHIS Child Core and $5621 using current-year ASD case status from MEPS. Both estimates are lower than some published estimates but still represent substantial costs to the US healthcare system.

A Population-Based Survey of the Workplace Costs for Caregivers of Persons With Treatment-Resistant Depression Compared With Other Health Conditions.

OBJECTIVE: To describe caregiving work outcomes and related indirect (ie, productivity) and direct (ie, caregiving hours and expenses) costs. METHODS: A national, population-based survey to identify employed caregivers assisting a person with treatment-resistant depression (TRD) and a comparison group of employed caregivers assisting others (No TRD). RESULTS: Screening identified 169 TRD caregivers and 1070 No TRD caregivers providing 23.3 and 14.6 mean weekly caregiving hours, respectively. Adjusted annual indirect cost estimates were $11,121 for caregivers of TRD and $7761 for caregivers in the No TRD group (P ≤ 0.0001). At-work productivity loss (presenteeism) was the largest component. Adjusted annual direct cost estimates were $29,805 for caregivers of TRD and $20,642 for caregivers in the No TRD group (P ≤ 0.0001). CONCLUSIONS: TRD exacts a toll on caregivers and their employers exceeding that for other caregivers.