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      Genetic Testing among Children in a Complex Care Program


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          Little is known about the pattern of genetic testing and frequency of genetic diagnoses among children enrolled in structured complex care programs (CCPs). Such information may inform the suitability of emerging genome diagnostics for this population. The objectives were to describe the proportion of children with undiagnosed genetic conditions despite genetic testing and measure the testing period, types and costs of genetic tests used. A retrospective analysis of 420 children enrolled in Toronto’s Hospital for Sick Children’s CCP from January 2010 until June 2014 was conducted. Among those who underwent genetic testing ( n = 319; 76%), a random sample of 20% ( n = 63) was further analyzed. A genetic diagnosis was confirmed in 48% of those who underwent testing. Those with no genetic diagnosis underwent significantly more genetic tests than those with a confirmed genetic diagnosis [median interquartile range (IQR): six tests (4–9) vs. three tests (2–4), p = 0.002], more sequence-level tests and a longer, more expensive testing period than those with a genetic diagnosis [median (IQR): length of testing period: 4.12 years (1.73–8.42) vs. 0.35 years (0.12–3.04), p < 0.001; genetic testing costs C$8496 ($4399–$12,480) vs. C$2614 ($1605–$4080), p < 0.001]. A genetic diagnosis was not established for 52% of children. Integrating genome-wide sequencing into clinical care may improve diagnostic efficiency and yield in this population.

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          Children with medical complexity: an emerging population for clinical and research initiatives.

          Children with medical complexity (CMC) have medical fragility and intensive care needs that are not easily met by existing health care models. CMC may have a congenital or acquired multisystem disease, a severe neurologic condition with marked functional impairment, and/or technology dependence for activities of daily living. Although these children are at risk of poor health and family outcomes, there are few well-characterized clinical initiatives and research efforts devoted to improving their care. In this article, we present a definitional framework of CMC that consists of substantial family-identified service needs, characteristic chronic and severe conditions, functional limitations, and high health care use. We explore the diversity of existing care models and apply the principles of the chronic care model to address the clinical needs of CMC. Finally, we suggest a research agenda that uses a uniform definition to accurately describe the population and to evaluate outcomes from the perspectives of the child, the family, and the broader health care system.
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            Whole-genome sequencing expands diagnostic utility and improves clinical management in paediatric medicine

            The standard of care for first-tier clinical investigation of the aetiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy-number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion–deletions (indels) and single-nucleotide variant (SNV) mutations. Whole-genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilised WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a fourfold increase in diagnostic rate over CMA (8%; P value=1.42E−05) alone and more than twofold increase in CMA plus targeted gene sequencing (13%; P value=0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harbouring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.
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              Increasing prevalence of medically complex children in US hospitals.

              In this study we used national data to determine changes in the prevalence of hospital admissions for medically complex children over a 15-year period. Data from the Nationwide Inpatient Sample, a component of the Healthcare Cost and Utilization Project, was analyzed in 3-year increments from 1991 to 2005 to determine national trends in rates of hospitalization of children aged 8 days to 4 years with chronic conditions. Discharge diagnoses from the Nationwide Inpatient Sample were grouped into 9 categories of complex chronic conditions (CCCs). Hospitalization rates for each of the 9 CCC categories were studied both individually and in combination. Trends of children hospitalized with 2 specific disorders, cerebral palsy (CP) and bronchopulmonary dysplasia, with additional diagnoses in more than 1 CCC category were also examined. Hospitalization rates of children with diagnoses in more than 1 CCC category increased from 83.7 per 100,000 (1991-1993) to 166 per 100 000 (2003-2005) (P[r]<.001). The hospitalization rate of children with CP plus more than 1 CCC diagnosis increased from 7.1 to 10.4 per 100 000 (P=.002), whereas the hospitalization rates of children with bronchopulmonary dysplasia plus more than 1 CCC diagnosis increased from 9.8 to 23.9 per 100,000 (P<.001). Consistent increases in hospitalization rates were noted among children with diagnoses in multiple CCC categories, whereas hospitalization rates of children with CP alone have remained stable. The relative medical complexity of hospitalized pediatric patients has increased over the past 15 years.

                Author and article information

                Role: Academic Editor
                Children (Basel)
                Children (Basel)
                22 May 2017
                May 2017
                : 4
                : 5
                : 42
                [1 ]Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; krista.oei@ 123456mail.utoronto.ca
                [2 ]Division of Paediatric Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
                [3 ]Child Health Evaluative Studies, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; robin.hayeems@ 123456sickkids.ca (R.Z.H.); wendy.ungar@ 123456sickkids.ca (W.J.U.)
                [4 ]Institute of Health Policy and Management and Evaluation, University of Toronto, Toronto, ON M5T 3M6, Canada
                [5 ]Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada; ronald.cohn@ 123456sickkids.ca
                [6 ]Program in Genetics and Genomic Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
                Author notes
                [* ]Correspondence: eyal.cohen@ 123456sickkids.ca ; Tel.: +1-416-813-5795
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                : 28 February 2017
                : 16 May 2017

                children with medical complexity,complex care,genetic testing,health care utilization


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