Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Evaluating remission of type 2 diabetes using a metabolic intervention including fixed-ratio insulin degludec and liraglutide: A randomized controlled trial.

AIM: To evaluate the effect on type 2 diabetes remission of short-term intensive metabolic intervention consisting of frequent dietary, exercise and diabetes management coaching, metformin and fixed-ratio insulin degludec/liraglutide. METHODS: In a multicentre open-label randomized controlled trial, insulin-naïve participants within 5 years of diabetes diagnosis were assigned to a 16-week remission intervention regimen or standard care, and followed for relapse of diabetes and sustained remission for an additional year after stopping glucose-lowering drugs. RESULTS: A total of 159 participants aged 57 ± 10 years, with diabetes duration 2.6 ± 1.5 years, body mass index 33.5 ± 6.5 kg/m2, and glycated haemoglobin (HbA1c) level 53 ± 7 mmol/mol were randomized and analysed (79 intervention, 80 control). At the end of the 16-week intervention period, compared to controls, intervention participants achieved lower HbA1c levels (40 ± 4 vs. 51 ± 7 mmol/mol; p < 0.0001), and lost more weight (3.3 ± 4.4% vs. 1.9 ± 3.0%; p = 0.02). There was a lower hazard of diabetes relapse overall in the intervention group compared to controls (hazard ratio 0.63, 95% confidence interval [CI] 0.45, 0.88; p = 0.007), although this was not sustained over time. Remission rates in the intervention group were not significantly higher than in the control group at 12 weeks (17.7% vs. 12.5%, relative risk [RR] 1.42, 95% CI 0.67, 3.00; p = 0.36) or at 52 weeks (6.3% vs. 3.8%, RR 1.69, 95% CI 0.42, 6.82) following the intervention period. CONCLUSIONS: An intensive remission-induction intervention including fixed-ratio insulin degludec/liraglutide reduced the risk of type 2 diabetes relapse within 1 year without sustained remission.

The Clinician-reported Genetic testing Utility InDEx (C-GUIDE): Preliminary evidence of validity and reliability.

PURPOSE: Demonstrating the clinical utility of genetic testing is fundamental to clinical adoption and reimbursement, but standardized definitions and measurement strategies for this construct do not exist. The Clinician-reported Genetic testing Utility InDEx (C-GUIDE) offers a novel measure to fill this gap. This study assessed its validity and inter-rater reliability. METHODS: Genetics professionals completed C-GUIDE after disclosure of test results to patients. Construct validity was assessed using regression analysis to measure associations between C-GUIDE and global item scores as well as potentially explanatory variables. Inter-rater reliability was assessed by administering a vignette-based survey to genetics professionals and calculating Krippendorff's α. RESULTS: On average, a 1-point increase in the global item score was associated with an increase of 3.0 in the C-GUIDE score (P < .001). Compared with diagnostic results, partially/potentially diagnostic and nondiagnostic results were associated with a reduction in C-GUIDE score of 9.5 (P < .001) and 10.2 (P < .001), respectively. Across 19 vignettes, Krippendorff's α was 0.68 (95% CI: 0.63-0.72). CONCLUSION: C-GUIDE showed acceptable validity and inter-rater reliability. Although further evaluation is required, C-GUIDE version 1.2 can be useful as a standardized approach to assess the clinical utility of genetic testing.

Trio genome sequencing for developmental delay and pediatric heart conditions: A comparative microcost analysis.

PURPOSE: Genome sequencing (GS) can aid clinical management of multiple pediatric conditions. Insurers require accurate cost information to inform funding and implementation decisions. The objective was to compare the laboratory workflows and microcosts of trio GS testing in children with developmental delay (DD) and in children with cardiac conditions. METHODS: Cost items related to each step in trio GS (child and 2 parents) for both populations were identified and measured. Program costs over 5 years were estimated. Probabilistic and deterministic analyses were conducted. RESULTS: The mean cost per trio GS was CAD$6634.11 (95% CI = 6352.29-6913.40) for DD and CAD$8053.10 (95% CI = 7699.30-8558.10) for cardiac conditions. The 5-year program cost was CAD$28.11 million (95% CI = 26.91-29.29) for DD and CAD$5.63 million (95% CI = 5.38-5.98) for cardiac conditions. Supplies constituted the largest cost component for both populations. The higher cost per sample for the population with cardiac conditions was due to the inclusion of pharmacogenomics, higher bioinformatics labor costs, and a more labor intensive case review. CONCLUSION: This analysis indicated important variation in trio GS workflow and costs between pediatric populations in a single institution. Enhanced understanding of the clinical utility and costs of GS can inform harmonization and implementation decision-making.

Two randomized controlled trials for colorectal cancer screening invitations developed using a behavioral science approach.

The effectiveness of behaviorally informed, targeted invitations to standard invitations and to no invitation (control arm, primary analysis) were compared in the context of an organized colorectal cancer (CRC) screening program. Two multi-arm, pragmatic randomized controlled trials in men (arms: male-specific, unisex, standard invitation, or no invitation) and in women (arms: unisex, standard invitation, or no invitation), were conducted in Ontario, Canada. Eligible persons aged 50-74, due for CRC screening, were randomized. Primary and secondary outcomes were completion of the guaiac fecal occult blood test (gFOBT) and uptake of any colorectal test, respectively, within 5 months of mailing. Impact of invitation type was assessed using logistic regression. Letters were mailed to 75,810 men and women; 38,673 males and 34,453 females were included in the analyses. Men who received the male-specific letter were most likely to screen with gFOBT compared to controls (odds ratio (OR) 7·24, 95% CI: 5·77, 9·09), followed by those receiving the unisex letter (OR 6·75, 95% CI: 5·37, 8·47) and the standard letter (OR 5·99, 95% CI: 4·76, 7·53). Women who received the unisex letter were most likely to be screened with gFOBT compared to controls (OR 7·07, 95% CI: 5·83, 8·59), followed by those receiving the standard letter (OR 6·76, 95% CI: 5·56, 8·21). In both trials, the findings were similar for the secondary outcome. Mailed invitations were effective for both men and women. With greater targeting using the behaviorally informed invitations, the magnitude of benefit relative to no invitation appeared to increase. (ClinicalTrials.gov, NCT02364895).

Patterns, trends and methodological associations in the measurement and valuation of childhood health utilities.

PURPOSE: To systematically assess patterns and temporal changes in the measurement and valuation of childhood health utilities and associations between methodological factors. METHODS: Studies reporting childhood health utilities using direct or indirect valuation methods, published by June 2017, were identified through PubMed, Embase, Web of Science, PsycINFO, EconLit, CINAHL, Cochrane Library and PEDE. The following were explored: patterns in tariff application; linear trends in numbers of studies/samples and paediatric cost-utility analyses (CUAs) and associations between them; changes in proportions of studies/samples within characteristic-based categories over pre-specified periods; impact of National Institute for Health and Care Excellence (NICE) guidance on primary UK research and associations between valuation method, age and methodological factors. RESULTS: 335 studies with 3974 samples covering all ICD-10 chapters, 23 valuation methods, 12 respondent types and 42 countries were identified by systematic review. 34.0% of samples using indirect methods compatible with childhood applied childhood-derived tariffs. There was no association between numbers of studies/samples and numbers of CUAs. Compared to 1990-2008, 2009-June 2017 saw a significant fall in the proportion of studies using case series; significant compositional changes across ICD-10 chapters and significantly higher sample proportions using childhood-specific and adult-specific indirect valuation methods, and based on pre-adolescents, self-assessment, self-administration and experienced health states. NICE guidance was weakly effective in promoting reference methods. Associations between valuation method, age and methodological factors were significant. CONCLUSION: 1990-2017 witnessed significant changes in primary research on childhood health utilities. Health technology assessment agencies should note the equivocal effect of methodological guidance on primary research.

A microcosting and cost-consequence analysis of clinical genomic testing strategies in autism spectrum disorder.

PurposeWhole-exome (WES) and whole-genome sequencing (WGS) increase the diagnostic yield in autism spectrum disorder (ASD) compared to chromosomal microarray (CMA), but there have been no comprehensive cost analyses. The objective was to perform such an assessment of CMA, WES, and WGS and compare the incremental cost per additional positive finding in hypothetical testing scenarios.MethodsFive-year patient and program costs were estimated from an institutional perspective. WES and WGS estimates were based on HiSeq 2500 with an additional WGS estimate for HiSeq X platforms. Parameter uncertainty was assessed with probabilistic and deterministic sensitivity analysis.ResultsThe cost per ASD sample was CAD$1,655 (95% CI: 1,611; 1,699) for WES, CAD$2,851 (95% CI: 2,750; 2,956) for WGS on HiSeq X, and CAD$5,519 (95% CI: 5,244; 5,785) on HiSeq 2500, compared to CAD$744 (95% CI 714, 773) for CMA. The incremental cost was over CAD$25,000 per additional positive finding if CMA was replaced by newer technology.ConclusionWhile costs for WES and WGS remain high, future reductions in material and equipment costs, and increased understanding of newly discovered variants and variants of unknown significance will lead to improved value.

Evaluation of Recall and Reminder Letters on Retention Rates in an Organized Cervical Screening Program.

OBJECTIVE: It is key for women to return to screening at regular intervals to ensure the effectiveness of early detection and protective effects of the Pap test. A correspondence program was initiated in Ontario in 2013 to implement a recall and reminder letter sent to women 2.9 years from their prior normal Pap test. This study sought to evaluate the impact of the recall letter and reminder on retention rates for cervical screening. METHODS: A cohort study with a historical control was carried out with an exposed group, defined as women receiving a letter for recall in the week of November 21-27, 2013, and a non-exposed, control arm of women who did not receive the letter but who would have been eligible for correspondence in the same time period in 2012. RESULTS: The study population comprised 5182 women in the exposed group and 4223 women in the non-exposed group. Women receiving the letter were more likely to return to screening, with an aOR of 1.82 (95% CI 1.66-1.99). Other significant factors included being registered with a Patient Enrolment Model family physician and having a series of prior Pap tests in the past screening history. CONCLUSION: A correspondence program benefits the retention of women in organized cervical screening programs.

EQ-5D-derived health utilities and minimally important differences for chronic health conditions: 2011 Commonwealth Fund Survey of Sicker Adults in Canada.

PURPOSE: The purpose of the study is to estimate the EQ-5D-derived health utilities associated with selected chronic conditions (hypertension, heart disease, arthritis, asthma or COPD, cancer, diabetes, chronic back pain, and anxiety or depression) and to estimate minimally important differences (MID) based on the Commonwealth Fund Survey of Sicker Adults in Canada. METHODS: We used a cross-sectional survey of 3765 sick adults in Canada conducted in 2011 by the Commonwealth Fund. Health utilities were calculated for the entire sample and for each of the eight chronic health conditions. An ordinary least squares regression was used to estimate the utility decrement associated with these conditions with and without adjustment for socio-demographic factors. The MIDs were estimated using the anchor- and distribution-based methods. RESULTS: The adjusted utility decrement varied from 0.028 (95 % confidence interval (CI) -0.049, -0.008) for diabetes to 0.124 (95 % CI -0.142, -0.105) for anxiety or depression. The anchor-based MID for the entire group was 0.044 (95 % CI 0.025, 0.062), and the distribution-based MID for the entire group was 0.091. The condition-specific MIDs using the distribution-based method ranged from 0.089 for cancer to 0.108 for asthma or COPD. CONCLUSIONS: The MID estimated by the distribution-based method was larger than the MID estimated by the anchor-based method, indicating that the choice of method matters. The impact of arthritis, anxiety or depression, and chronic back pain on health utility was substantial, all exceeding or approximating the MID estimated using either anchor- or distribution-based methods.

Chronic ischemic lesions and presence of patent foramen ovale in young adults with embolic stroke of undetermined source: Results of the young ESUS patient registry.

BACKGROUND: Chronic ischemic lesions (CILs) are frequent findings in patients with acute ischemic stroke, but their phenotypes and relevance in young adults with embolic stroke of undetermined source (Y-ESUS) remains uncertain. We aimed to compare Y-ESUS patients with CIL to those without CIL and assessed the association of CIL and its phenotypes with the presence of patent foramen ovale (PFO). METHODS: This prospective longitudinal, multicenter cohort study enrolled consecutive patients 50 years and younger with ESUS from October 2017 to October 2019 in 41 stroke research centers in 13 countries. Local investigators adjudicated presence and phenotypes of CIL on routine brain imaging (either magnetic resonance imaging (MRI) or computed tomography (CT)). RESULTS: Overall, 535 patients were enrolled (mean age = 40.4 (standard deviation (SD) = 7.3) years, 238 (44%) female). CILs were present in 76/534 (14.2%) patients with a median count CIL count of 1.0 (interquartile range (IQR) = 1-2), 42/76 (55%) had at least one cortical phenotype and 38/76 (50%) at least one non-cortical phenotype. Y-ESUS with CIL were less often female (32% vs 47% in non-CIL Y-ESUS), were older (mean 43 vs 40 years), had more often hypertension (42% vs 19%), diabetes (17% vs 7%), and hyperlipidemia (34% vs 18%). CIL Y-ESUS were independently associated with lower stroke recurrence (relative risk (RR) = 0.17 (0.05-0.61)). In Y-ESUS with PFO, CILs were less frequent in probable pathogenic PFO than with probable non-pathogenic PFO (6.1% vs 30% p< 0.001). CONCLUSION: One in seven Y-ESUS patients has additional CIL. CILs were associated with several vascular risk factors, lower probability of a pathogenic PFO, and lower stroke recurrence.

Why it is so challenging to perform economic evaluations of interventions in autism and what to do about it.

Economic evaluation is used to determine the optimal provision of services and programs under budget constraints and to inform public and private payer funding decisions. To maximize value-for-money in the design and delivery of programs and services for persons with autism spectrum disorder (ASD), it's essential to generate high-quality economic evidence to inform budget allocation. There is a paucity however, of economic evaluations of interventions for ASD. This is due in part to challenges in conducting economic evaluations in this population and the lack of guidance on suitable approaches. These challenges are related to the inherent heterogeneity of the autistic population; establishing short- and long-term effectiveness; measurement of costs and the availability of valid instruments for collecting economic data; the appropriateness of outcomes for use in economic evaluation; and achieving statistical power. This commentary addresses a lack of awareness and needed guidance on these issues by discussing the challenges and providing recommendations for how economic evaluations in ASD could be improved to generate high-quality evidence for program funding decision-making.

Measuring the association between behavioural services and outcomes in young children with autism spectrum disorder.

BACKGROUND: Children with autism spectrum disorder (ASD) receive a wide range of services. AIMS: To examine the association between behavioural services received by children with ASD between ages 2 and 5 years and outcomes during primary school years. METHODS: A total of 414 preschool-aged children diagnosed with ASD were enrolled at five Canadian sites and were assessed within four months of diagnosis (T1), six months later (T2), 12 months later (T3), at school entry (T4), and then annually (T5-T8) to 11 years of age. The association between the receipt of behavioural services during T1 to T3 and T8 outcomes related to adaptive behaviour and behavioural problems was modelled using linear regressions adjusted for immigrant status, family income, child's age at diagnosis, site, sex assigned at birth, and baseline (T1) outcome. RESULTS: Children who received behavioural services during at least one time period from T1 to T3 did not have significantly different outcomes at T8 than children who did not receive any behavioural services. IMPLICATIONS: Pre-school use of behavioural services was not found to affect outcomes during later childhood. Numerous challenges accompany studies of the association between pre-school service use and later outcomes in a heterogeneous ASD sample. Recommendations for study design are provided.

Protocol for a Prospective, Observational Cost-effectiveness Analysis of Returning Secondary Findings of Genome Sequencing for Unexplained Suspected Genetic Conditions.

PURPOSE: Although costly, genome-wide sequencing (GWS) detects an extensive range of variants, enhancing our ability to diagnose and assess risk for an increasing number of diseases. In addition to detecting variants related to the indication for testing, GWS can detect secondary variants in BRCA1, BRCA2, and other genes for which early intervention may improve health. As the list of secondary findings grows, there is increased demand for surveillance and management by multiple specialists, adding pressure to constrained health care budgets. Secondary finding testing is actively debated because some consider it opportunistic screening for future health risks that may not manifest. Given the economic implications of secondary finding testing and follow-up and its unproven clinical utility, the objective is to assess the incremental cost-effectiveness of secondary finding ascertainment per case detected and per unit of improved clinical utility in families of children with unexplained suspected genetic conditions undergoing clinical GWS. METHODS: Those undergoing trio genome or exome sequencing are eligible for the study. Positive secondary finding index cases will be matched to negative controls (1:2) based on age group, primary result(s) type, and clinical indication. During the 2-year study, 71 cases and 142 matched controls are expected. Health service use will be collected in patients and 1 adult family member every 6 months. The per-child and per-dyad total cost will be determined by multiplying use of each resource by a corresponding unit price and summing all cost items. Costs will be estimated from the public and societal payer perspectives. The mean cost per child and per dyad for secondary finding-positive and secondary finding-negative groups will be compared statistically. If important demographic differences are observed between groups, ordinary least-squares regression, log transformation, or other nonparametric technique will be used to compare adjusted mean costs. The ratio of the difference in mean cost to the secondary finding yield will be used to estimate incremental cost-effectiveness. In secondary analyses, effectiveness will be estimated using the number of clinical management changes due to secondary findings or the Clinician-Reported Genetic Testing Utility Index (C-GUIDE) score, a validated measure of clinical utility. Sensitivity analysis will be undertaken to assess the robustness of the findings to variation in key parameters. IMPLICATIONS: This study generates key evidence to inform clinical practice and funding allocation related to secondary finding testing. The inclusion of family members and a new measure of clinical utility represent important advancements in economic evaluation in genomics.

Comparing genome sequencing technologies to improve rare disease diagnostics: a protocol for the evaluation of a pilot project, Genome-wide Sequencing Ontario.

BACKGROUND: Genome-wide sequencing has emerged as a promising strategy for the timely diagnosis of rare diseases, but it is not yet available as a clinical test performed in Canadian diagnostic laboratories. We describe the protocol for evaluating a 2-year pilot project, Genome-wide Sequencing Ontario, to offer high-quality clinical genome-wide sequencing in Ontario, Canada. METHODS: The Genome-wide Sequencing Ontario protocol was codesigned by the Ontario Ministry of Health, the Hospital for Sick Children in Toronto and the Children's Hospital of Eastern Ontario in Ottawa. Enrolment of a prospective cohort of patients began on Apr. 1, 2021. Eligible cases with blood samples available for the index case and both parents (i.e., trios) are randomized to receive exome sequencing or genome sequencing. We will collect patient-level data and ascertain costs associated with the laboratory workflow for exome sequencing and genome sequencing. We will compare point estimates for the diagnostic utility and timeliness of exome sequencing and genome sequencing, and we will determine an incremental cost-effectiveness ratio (expressed as the incremental cost of genome sequencing versus exome sequencing per additional patient with a causal variant detected). INTERPRETATION: Findings from this work will provide robust evidence for the diagnostic utility, cost-effectiveness and timeliness of exome sequencing and genome sequencing, and will be disseminated via academic publications and policy briefs. Findings will inform provincial and cross-provincial policy related to the long-term organization, delivery and reimbursement of clinical-grade genome diagnostics for rare disease.

Determining accurate costs for genomic sequencing technologies-a necessary prerequisite.

Genome sequencing (GS) is increasingly being translated into clinical practice and is a technology characterized by a complex multi-step workflow. Funding decisions for GS would be aided by formal economic evaluation of GS platforms, but these analyses require detailed costing. This article addresses the importance of and challenges associated with costing GS using a GS microcosting project in autism spectrum disorder as an illustrative example.

Family Spillover Effects in Pediatric Cost-Utility Analyses.

BACKGROUND: Childhood illness can impose significant costs and health strains on family members, but these are not routinely captured by pediatric economic evaluations. This review investigated how family "spillover effects" related to costs and health outcomes are considered in pediatric cost-utility analyses (CUAs). METHODS: We reviewed pediatric CUAs published between 2000 and 2015 using the Tufts Medical Center Cost-effectiveness Analysis (CEA) Registry and the Pediatric Economic Database Evaluation (PEDE) Registry. We selected studies conducted from the societal perspective and included in both registries. We investigated how frequently family spillover was incorporated into analyses, and how the inclusion of spillover health effects and costs changed CUA results. RESULTS: We found 142 pediatric CUAs meeting inclusion criteria. Of those, 105 (72%) considered either family spillover costs (n = 98 time costs, n = 33 out-of-pocket costs, n = 2 caregiver healthcare costs) or health outcomes (n = 15). Twenty-four studies included 43 pairs of incremental cost-effectiveness ratios (ICERs) with and without spillover. In 19 pairs of ICERs, adding spillover changed the ICER enough to cross a common cost-effectiveness threshold (i.e., $50,000/QALY, $100,000/QALY, $150,000/QALY; values are in 2016 US$). Incorporating spillover generally made interventions more cost-effective (n = 18; 42%), or did not change CUA results enough to cross a threshold (n = 24; 56%). Including family spillover reduced ICERs by 31% ($40,000/QALY) on average. CONCLUSION: Most pediatric CUAs conducted from a societal perspective include family costs but fewer include family health effects. Inclusion of family spillover effects tends to make CUA results more favorable. Future pediatric CUAs should aim to more fully incorporate the family burden of illness.

Types of Services and Costs of Programs for Preschoolers with Autism Spectrum Disorder Across Sectors: A Comparison of Two Canadian Provinces.

This study measured resource utilization and costs for pre-school autism spectrum disorder (ASD)-related services in community-based sectors from multiple payer perspectives in two Canadian provinces, Nova Scotia (NS) and New Brunswick (NB), during the 12 months prior to and following the start of early intensive behavioural intervention (EIBI). The results indicate significant differences between NB and NS in utilization of services and costs to families, public sector and society. Differences can be attributed to variation in EIBI delivery models and may also be influenced by differences in diagnostic assessment practices. The study results provide resource utilization rates and costs which could be used in future economic evaluations and to inform policy making to improve outcomes for children with ASD.

Comparing the 1-year impact of preschool autism intervention programs in two Canadian provinces.

Autism spectrum disorder (ASD) is associated with early differences in children's social interactions, communication, and play/interests. In many countries, considerable resources are invested in early intensive behavioral intervention (EIBI) programs for children with ASD, which aim to build adaptive skills and prevent or treat problem behavior. However, these programs vary widely in structure and delivery. Research evidence supports the efficacy of EIBI, but large knowledge gaps remain about the effectiveness of publicly funded EIBI programs. With policy-makers as formal research partners, we compared children's progress over 1 year in public preschool programs in adjacent Canadian provinces, New Brunswick (NB) and Nova Scotia (NS). In NB, children received up to 20 hr/week of comprehensive EIBI in a publicly funded, privately provided program. In NS, children received up to 15 hr/week of Pivotal Response Treatment and Positive Behavior Support delivered through the publicly funded healthcare system. In this observational parallel cohort study, we collected parent-reported data on 298 NB preschoolers (76.5% boys) and 221 NS preschoolers (86.9% boys) at EIBI start and 1 year later. Multilevel analysis revealed significant differences at baseline: NS children were older, with lower adaptive functioning and more severe ASD symptoms than NB children. Despite these pre-treatment differences that favor NB, children in both provinces showed similar adaptive functioning gains and reductions of maladaptive behavior. No changes were seen in mean ASD symptom severity in either province over time. Results highlight the value of evaluating interventions in their implementation contexts, and have important implications for devising optimal ASD policy. Autism Research 2019, 12: 667-681. © 2019 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: We need to know more about the impact of different forms of early intensive behavioral intervention (EIBI) for young children with autism spectrum disorder (ASD). We showed that preschoolers with ASD gained important skills while in public EIBI programs in two Canadian provinces. We also saw that differences in how EIBI programs are structured and characteristics of children who are served may affect outcomes. For these reasons, policy making requires evidence that fits the local context.

A Systematic Review and Meta-analysis of Childhood Health Utilities.

BACKGROUND: A common feature of most reviews or catalogues of health utilities has been their focus on adult health states or derivation of values from adult populations. More generally, utility measurement in or on behalf of children has been constrained by several methodological concerns. The objective of this study was to conduct the first comprehensive systematic review and meta-analysis of primary utility data for childhood conditions and descriptors, and to determine the effects of methodological factors on childhood utilities. METHODS: The review followed PRISMA guidelines. PubMed, Embase, Web of Science, PsycINFO, EconLit, CINAHL and Cochrane Library were searched for primary studies reporting health utilities for childhood conditions or descriptors using direct or indirect valuation methods. The Paediatric Economic Database Evaluation (PEDE) Porject was also searched for cost-utility analyses with primary utility values. Mean or median utilities for each of the main samples were catalogued, and weighted averages of utilities for each health condition were estimated, by valuation method. Mixed-effects meta-regression using hierarchical linear modeling was conducted for the most common valuation methods to estimate the utility decrement for each health condition category relative to general childhood population health, as well as the independent effects of methodological factors. RESULTS: The literature searches resulted in 272 eligible studies. These yielded 3,414 utilities when all sub-groups were considered, covering all ICD-10 chapters relevant to childhood health, 19 valuation methods, 12 respondent types, 8 modes of administration, and data from 36 countries. A total of 1,191 utility values were obtained when only main study samples were considered, and these were catalogued by health condition or descriptor, and methodological characteristics. 1,073 mean utilities for main samples were used for fixed-effects meta-analysis by health condition and valuation method. Mixed-effects meta-regressions estimated that 53 of 76 ICD-10 delineated health conditions, valued using the HUI3, were associated with statistically significant utility decrements relative to general population health, whereas 38 of 57 valued using a visual analog scale (VAS) were associated with statistically significant VAS decrements. For both methods, parental proxy assessment was associated with overestimation of values, whereas adolescents reported lower values than children under 12 y. VAS responses were more heavily influenced by mode of administration than the HUI3. CONCLUSION: Utilities and their associated distributions, as well as the independent contributions of methodological factors, revealed by this systematic review and meta-analysis can inform future economic evaluations within the childhood context.

Care and cost consequences of pediatric whole genome sequencing compared to chromosome microarray.

The clinical use of whole-genome sequencing (WGS) is expected to alter pediatric medical management. The study aimed to describe the type and cost of healthcare activities following pediatric WGS compared to chromosome microarray (CMA). Healthcare activities prompted by WGS and CMA were ascertained for 101 children with developmental delay over 1 year. Activities following receipt of non-diagnostic CMA were compared to WGS diagnostic and non-diagnostic results. Activities were costed in 2016 Canadian dollars (CDN). Ongoing care accounted for 88.6% of post-test activities. The mean number of lab tests was greater following CMA than WGS (0.55 vs. 0.09; p = 0.007). The mean number of specialist visits was greater following WGS than CMA (0.41 vs. 0; p = 0.016). WGS results (diagnostic vs. non-diagnostic) modified the effect of test type on mean number of activities (p < 0.001). The cost of activities prompted by diagnostic WGS exceeded $557CDN for 10% of cases. In complex pediatric care, CMA prompted additional diagnostic investigations while WGS prompted tailored care guided by genotypic variants. Costs for prompted activities were low for the majority and constitute a small proportion of total test costs. Optimal use of WGS depends on robust evaluation of downstream care and cost consequences.