Cost-effectiveness of whole-exome sequencing in progressive neurological disorders of children

Objectives: To clarify the diagnostic utility and the cost-effectiveness of whole-exome sequencing (WES) as a routine early-diagnostic tool in children with progressive neurological disorders. Methods: Patients with infantile-onset severe neurological diseases or childhood-onset progressive neurological disorders were prospectively recruited to this WES study, in the pediatric neurology clinic at Helsinki University Hospital during 2016-2018. A total of 48 patients underwent a singleton WES. A control group of 49 children underwent traditional diagnostic examinations and were retrospectively collected from the hospital records. Their use of health care services, related to the diagnostic process, was gathered. Incremental cost-effectiveness ratio (ICER) per additional diagnosis was calculated from the health care provider perspective. Bootstrapping methods were used to estimate the uncertainty of cost-effectiveness outcomes. Results: WES provided a better diagnostic yield (38%) than diagnostic pathway that did not prioritize WES in early diagnosis (25%). WES outperformed other diagnostic paths especially when made early, within one year of first admission (44%). Cost-effectiveness in our results are conservative, affected by WES costs during 2016-18. Conclusions: WES is an efficient and cost-effective diagnostic tool that should be prioritized in early diagnostic path of children with progressive neurological disorders. The progressively decreasing price of the test improves cost-effectiveness further. (C) 2021 The Authors. Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.Peer reviewe

Effectiveness of clinical exome sequencing in adult patients with difficult-to-diagnose neurological disorders

Objectives Clinical diagnostics in adults with hereditary neurological diseases is complicated by clinical and genetic heterogeneity, as well as lifestyle effects. Here, we evaluate the effectiveness of exome sequencing and clinical costs in our difficult-to-diagnose adult patient cohort. Additionally, we expand the phenotypic and genetic spectrum of hereditary neurological disorders in Finland. Methods We performed clinical exome sequencing (CES) to 100 adult patients from Finland with neurological symptoms of suspected genetic cause. The patients were classified as myopathy (n = 57), peripheral neuropathy (n = 16), ataxia (n = 15), spastic paraplegia (n = 4), Parkinsonism (n = 3), and mixed (n = 5). In addition, we gathered the costs of prior diagnostic work-up to retrospectively assess the cost-effectiveness of CES as a first-line diagnostic tool. Results The overall diagnostic yield of CES was 27%. Pathogenic variants were found for 14 patients (in genes ANO5, CHCHD10, CLCN1, DES, DOK7, FKBP14, POLG, PYROXD1, SCN4A, TUBB3, and TTN) and likely pathogenic previously undescribed variants for 13 patients (in genes ABCD1, AFG3L2, ATL1, CACNA1A, COL6A1, DYSF, IRF2BPL, KCNA1, MT-ATP6, SAMD9L, SGCB, and TPM2). Age of onset below 40 years increased the probability of finding a genetic cause. Our cost evaluation of prior diagnostic work-up suggested that early CES would be cost-effective in this patient group, in which diagnostic costs increase linearly with prolonged investigations. Conclusions Based on our results, CES is a cost-effective, powerful first-line diagnostic tool in establishing the molecular diagnosis in adult neurological patients with variable symptoms. Importantly, CES can markedly shorten the diagnostic odysseys of about one third of patients.Peer reviewe

Attitudes towards genetic testing and information : does parenthood shape the views?

This study examines how parents of pediatric patients might differ in their views and attitudes towards genetic technology and information when compared to adult patients. There is surprisingly little evidence on how parents compare to other parts of population in their attitudes. Previous empirical studies often relate health-related preferences and attitudes to factors such as age, education, and income instead of parental status, thus evading comparison of parents to others as health-related decision makers. Findings related to the parental status can be useful when implementing genetic technology in clinical practice. We conducted a survey of views on genetic technology and information for groups of adult neurology patients (n = 68) and parents of pediatric neurology patients (n = 31) to shed some light on this issue. In addition to our own survey instrument, we conducted other surveys to gain insight on psychosocial factors that might affect these attitudes. The results suggest that parents are more concerned about their children's genetic risk factors when compared to the attitudes of adult patients about their own risk. For both groups, negative emotional state was associated with more concerns towards genetic information. Our study provides insights on how parental views might affect the acceptance of genetic technology and information.Peer reviewe

Cost-effectiveness of whole-exome sequencing in progressive neurological disorders of children

ObjectivesTo clarify the diagnostic utility and the cost-effectiveness of whole-exome sequencing (WES) as a routine early-diagnostic tool in children with progressive neurological disorders.MethodsPatients with infantile-onset severe neurological diseases or childhood-onset progressive neurological disorders were prospectively recruited to this WES study, in the pediatric neurology clinic at Helsinki University Hospital during 2016–2018. A total of 48 patients underwent a singleton WES. A control group of 49 children underwent traditional diagnostic examinations and were retrospectively collected from the hospital records. Their use of health care services, related to the diagnostic process, was gathered. Incremental cost-effectiveness ratio (ICER) per additional diagnosis was calculated from the health care provider perspective. Bootstrapping methods were used to estimate the uncertainty of cost-effectiveness outcomes.ResultsWES provided a better diagnostic yield (38%) than diagnostic pathway that did not prioritize WES in early diagnosis (25%). WES outperformed other diagnostic paths especially when made early, within one year of first admission (44%). Cost-effectiveness in our results are conservative, affected by WES costs during 2016–18.ConclusionsWES is an efficient and cost-effective diagnostic tool that should be prioritized in early diagnostic path of children with progressive neurological disorders. The progressively decreasing price of the test improves cost-effectiveness further.</div

Effectiveness of clinical exome sequencing in adult patients with difficult-to-diagnose neurological disorders

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Attitudes towards genetic testing and information: does parenthood shape the views?

This study examines how parents of pediatric patients might differ in their views and attitudes towards genetic technology and information when compared to adult patients. There is surprisingly little evidence on how parents compare to other parts of population in their attitudes. Previous empirical studies often relate health-related preferences and attitudes to factors such as age, education, and income instead of parental status, thus evading comparison of parents to others as health-related decision makers. Findings related to the parental status can be useful when implementing genetic technology in clinical practice. We conducted a survey of views on genetic technology and information for groups of adult neurology patients (n = 68) and parents of pediatric neurology patients (n = 31) to shed some light on this issue. In addition to our own survey instrument, we conducted other surveys to gain insight on psychosocial factors that might affect these attitudes. The results suggest that parents are more concerned about their children's genetic risk factors when compared to the attitudes of adult patients about their own risk. For both groups, negative emotional state was associated with more concerns towards genetic information. Our study provides insights on how parental views might affect the acceptance of genetic technology and information

Eksomisekvensointi lasten perinnöllisten aivosairauksien diagnostiikassa

Tausta: DNA:n sekvensointitekniikoiden kehitys mahdollistaa yhä useammin harvinaista perinnöllistä sairautta sairastavan potilaan molekyyligeneettisen diagnoosin löytämisen. Uuden sukupolven sekvensointitekniikoista etenkin koko geenistön analyysiä eli eksomisekvensointia on alettu käyttää yleisesti suurien potilaskohorttien taudinaiheuttajamutaatioiden löytämiseen. Suomessa perinnöllisten sairauksien diagnostiikka keskittyy edelleen erilaisten geenitestien ja –paneelien käyttämiseen kliinisen epäilyn perusteella. Eksomisekvensoinnilla voidaan arvioida yhdellä kertaa potilaan kaikkia proteiinia koodaavia geenin alueita mutaation löytämiseksi. Tavoitteet ja menetelmät: Tutkiaksemme eksomidiagnostiikan merkitystä perinnöllisten sairauksien diagnostiikassa, teimme prospektiivisesti eksomisekvensoinnin 48:lle vaikeaa aivosairautta sairastavalle lapselle, ja vertailimme retrospektiivisesti 48:n kontrollipotilaan sairauskertomustietoja selvittääksemme, onko alkuvaiheen eksomisekvensointi parempi vaihtoehto harvinaisten aivosairauksien diagnostiikassa lapsilla. Tulokset: Eksomikohortista 18/48 (37,5%) potilaista sai diagnoosin eksomisekvensoinnilla, kontrollikohortissa muulla kuin eksomisekvensoinnilla diagnoosin sai 10/48 (20,8%). Kontrollikohortista 10 potilasta päätyi myöhäisessä vaiheessa eksomisekvensointiin, jolloin 5/48 (10,4%) sai diagnoosin. Ero eksomisekvensoinnilla ja muulla kuin eksomisekvensoinnilla saatujen diagnoosien (37,5%, 20,8%) välillä ei ollut tilastollisesti merkitsevä (p=0,072). Diagnoosiin kuluvassa ajassa eksomikohortissa diagnoosi saatiin keskimäärin 2,8 vuodessa, kontrollikohortissa 4,0 vuodessa (n=18, n=15). Ero ajassa diagnoosiin ei ollut tilastollisesti merkitsevä (p=0,401). Eksomikohortin potilaista 3 geenidiagnoosia mahdollisti hoitokokeilun aloittamisen. Pohdinta: Tutkimuksellamme saimme eron diagnostiikassa kohorttien välille, vaikka ero ei ollutkaan tilastollisesti merkitsevä. Tuloksessa on pidettävä mielessä, että monet eksomisekvensoinnilla saaduista geenidiagnooseista eivät olisi olleet sairaaladiagnostiikassa käytettävillä geenitesteillä mahdollisia. Tutkimuksemme jatkuu eksomidiagnostiikan kustannustehokkuuden tutkimisella, jolloin selvitämme kohorttien välisiä kustannuksia diagnostisissa selvittelyissä

Genetic etiology of progressive pediatric neurological disorders

BackgroundThe aim of the study was to characterize molecular diagnoses in patients with childhood-onset progressive neurological disorders of suspected genetic etiology.MethodsWe studied 48 probands (age range from newborn to 17 years old) with progressive neurological disorders of unknown etiology from the largest pediatric neurology clinic in Finland. Phenotypes included encephalopathy (54%), neuromuscular disorders (33%), movement disorders (11%), and one patient (2%) with hemiplegic migraine. All patients underwent whole-exome sequencing and disease-causing genes were analyzed.ResultsWe found 20 (42%) of the patients to have variants in genes previously associated with disease. Of these, 12 were previously reported disease-causing variants, whereas eight patients had a novel variant on a disease-causing gene: ATP7A, CHD2, PURA, PYCR2, SLC1A4, SPAST, TRIT1, and UPF3B. Genetics also enabled us to define atypical clinical presentations of Rett syndrome (MECP2) and Menkes disease (ATP7A). Except for one deletion, all findings were single-nucleotide variants (missense 72%, truncating 22%, splice-site 6%). Nearly half of the variants were de novo.ConclusionsThe most common cause of childhood encephalopathies are de novo variants. Whole-exome sequencing, even singleton, proved to be an efficient tool to gain specific diagnoses and in finding de novo variants in a clinically heterogeneous group of childhood encephalopathies.ImpactWhole-exome sequencing is useful in heterogeneous pediatric neurology cohorts.Our article provides further evidence for and novel variants in several genes.De novo variants are an important cause of childhood encephalopathies.Peer reviewe