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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.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.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.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.

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.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).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.

Children with autism spectrum disorder (ASD) receive a wide range of services.To examine the association between behavioural services received by children with ASD between ages 2 and 5 years and outcomes during primary school years.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.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.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.

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.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.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).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.

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.

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).

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.

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.

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.

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. Electronic supplementary material The online version of this article (10.1007/s11136-019-02121-z) contains supplementary material, which is available to authorized users.

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.

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.

Economic evaluations conducted in children have unique features compared to adults. Important developments in pediatric economic evaluation in recent years include new options for valuing health states for cost-utility analysis (CUA) and shifting child health priorities. The Pediatric Economic Database Evaluation (PEDE) project includes a comprehensive database of pediatric health economic evaluations published since 1980. The objective of this scoping review was to identify trends over time in the use of CUA and other analytic techniques, and the therapeutic areas chosen for study. Areas covered: Medical and grey literature were searched, key characteristics were extracted, frequencies were tabulated and cross-tabulations were performed. Differences between early (1980 and 1999) and late (2000 and 2014) periods were assessed using a chi-squared statistic. Of the 2,776 pediatric economic evaluations published between 1980 and 2014, substantially more were cost-effectiveness analyses (CEAs) and CUAs than cost benefit analyses and cost minimization analyses (63.9 and 24.9% versus 7.6 and 3.6%, respectively). This pattern was consistent regardless of the type of intervention, disease or age group studied. A trend toward higher proportions of CUAs and CEAs was evident in the later period (X

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. 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. 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. 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.

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). 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. 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. 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.

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