A population‐based cost‐effectiveness study of early genetic testing in severe epilepsies of infancy
Open accessAbstract
Summary: Objective: The severe epilepsies of infancy ( SEI ) are a devastating group of disorders that pose a major care and economic burden on society; early diagnosis is critical for optimal management. This study sought to determine the incidence and etiologies of SEI , and model the yield and cost‐effectiveness of early genetic testing. Methods: A population‐based study was undertaken of the incidence, etiologies, and cost‐effectiveness of a whole exome sequencing–based gene panel (targeted WES ) in infants with SEI born during 2011‐2013, identified through electroencephalography ( EEG ) and neonatal databases. SEI was defined as seizure onset before age 18 months, frequent seizures, epileptiform EEG , and failure of ≥2 antiepileptic drugs. Medical records, investigations, MRIs, and EEG s were analyzed, and genetic testing was performed if no etiology was identified. Economic modeling was performed to determine yield and cost‐effectiveness of investigation of infants with unknown etiology at epilepsy onset, incorporating targeted WES at different stages of the diagnostic pathway. Results: Of 114 infants with SEI (incidence = 54/100 000 live births/y), the etiology was determined in 76 (67%): acquired brain injuries (n = 14), focal cortical dysplasias (n = 14), other brain malformations (n = 17), channelopathies (n = 11), chromosomal (n = 9), metabolic (n = 6), and other genetic (n = 5) disorders. Modeling showed that incorporating targeted WES increased diagnostic yield compared to investigation without targeted WES (48/86 vs 39/86). Early targeted WES had lower total cost ($677 081 U.S. dollars [ USD ] vs $738 136 USD ) than late targeted WES . A pathway with early targeted WES and limited metabolic testing yielded 7 additional diagnoses compared to investigation without targeted WES (46/86 vs 39/86), with lower total cost ($455 597 USD vs $661 103 USD ), lower cost per diagnosis ($9904 USD vs $16 951 USD ), and a dominant cost‐effectiveness ratio. Significance: Severe epilepsies occur in 1 in 2000 infants, with the etiology identified in two‐thirds, most commonly malformative. Early use of targeted WES yields more diagnoses at lower cost. Early genetic diagnosis will enable timely administration of precision medicines, once developed, with the potential to improve long‐term outcome.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Acquired causes, such as ischaemic injury, infection, and hypoglycaemia, are a small but important group of DEE causes.
“Acquired causes, such as ischaemic injury, infection, and hypoglycaemia, are a small but important group 166 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [166]
The Results (Etiology; page unavailable) report acquired brain injury in 14 of 114 infants with severe epilepsies of infancy, and the Discussion identifies hypoxic-ischemic encephalopathy as an example. This supports acquired causes as a small group, but the copy does not identify infection or hypoglycaemia as examples, or establish the proportion for DEE more broadly. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNext generation sequencing has transformed our understanding of the aetiologies of the DEEs, enabling identification of their cause in 50% of patients.
“Next generation sequencing has transformed our understanding of the aetiologies of the DEEs, enabling identification of their cause in 50% of patients 166,167 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [166]
The Introduction describes next-generation sequencing as a way to investigate many genes, and the Results (Economic modelling) show that adding targeted whole-exome sequencing increased diagnostic yield in infants with severe epilepsy. But the model’s 56% figure is the yield of an entire diagnostic pathway, not the proportion diagnosed by sequencing; the Results (Etiology) report a 32% yield for non-chromosomal genetic testing among infants investigated after epilepsy onset. The paper therefore supports sequencing’s diagnostic value, but not the claim that it identifies the cause in 50% of patients with DEEs. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOverall, relatively few patients with DEEs are candidates for epilepsy surgery but, if a unifocal resectable lesion is identified, such as a FCD, successful surgery can be transformational.
“Overall, relatively few patients with DEEs are candidates for epilepsy surgery but, if a unifocal resectable lesion is identified, such as a FCD, successful surgery can be transformational 166,171 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [166]
The Discussion reports that FCD occurred in 12% of infants with severe epilepsies of infancy and that surgery may control seizures, potentially enabling developmental acceleration. It does not establish how many patients with DEEs are surgical candidates or report surgical outcomes; its population is also narrower than DEEs generally. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn an epidemiological study of severe epilepsies beginning before age 18 months, which excluded patients with Dravet syndrome for methodological reasons, the aetiology was determined in 67% (76/114) of patients.
“In an epidemiological study of severe epilepsies beginning before age 18 months, which excluded patients with Dravet syndrome for methodological reasons, the aetiology was determined in 67% (76/114) of patients.”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [166]
The Methods (Inclusion/exclusion criteria and Assessment) describe a population-based cohort of 114 infants meeting severe-epilepsy criteria before 18 months. The Results (Etiology) report that etiology was identified in 76 (67%). Our copy does not state that patients with Dravet syndrome were excluded or give a methodological reason for excluding them. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn that epidemiological study, a genetic or presumed genetic basis was identified in 62 (54%) patients: 14 with FCD, 17 had other brain malformations, 6 had a metabolic disorder, 9 with chromosomal disorders and 16 had a single gene disorder, and 14 with acquired brain lesions.
“Specifically, a genetic or presumed genetic basis was identified in 62 (54%) patients: 14 with FCD, 17 had other brain malformations, 6 had a metabolic disorder, 9 with chromosomal disorders and 16 had a single gene disorder, and 14 with acquired brain lesions 8, 166 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [166]
The Results > Etiology section reports 62 infants (54%) with genetic or presumed genetic etiologies and gives the stated counts for FCD, other brain malformations, metabolic disorders, chromosomal abnormalities, and single-gene disorders. It separately classifies 14 infants as having acquired brain injury; they are not part of the 62 with genetic or presumed genetic etiologies. (LLM, conf=0.92)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Methods for the Economic Evaluation of Health Care Programmes
Drummond, M. E., Sculpher, M. J., Torrance, G. W., O’Brien, B. J., & Stoddart, G. L. (2005) · doi:10.1093/oso/9780198529446.001.0001 · Cited by 13,648 · see citing works
Berg, A. T., Berkovic, S. F., Brodie, M. J., Buchhalter, J., Cross, J. H., Van Emde Boas, W., Engel, J., French, J., Glauser, T. A., Mathern, G. W., et al. (2010) · Epilepsia · doi:10.1111/j.1528-1167.2010.02522.x · Cited by 4,363 · see citing works
Self-citationFeigin, V. L., Lawes, C. M., Bennett, D. A., & Anderson, C. S. (2003) · The Lancet Neurology · doi:10.1016/s1474-4422(03)00266-7 · Cited by 1,932 · cited 1× · see citing works
“au, NEMESIS stroke study).(11) The study began in 2013; ascertainment was retrospective for infants presenting during 2011-2012 and prospective for 2013-2015.”
BackgroundDe novo mutations in epileptic encephalopathies
Epi4K Consortium, & Epilepsy Phenome/Genome Project (2013) · Nature · doi:10.1038/nature12439 · Cited by 1,514 · see citing works
Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders
O’Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., et al. (2012) · Science · doi:10.1126/science.1227764 · Cited by 1,240 · see citing works
Self-citationEvans, D. G., Howard, E., Giblin, C., Clancy, T., Spencer, H., Huson, S., & Lalloo, F. I. (2010) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.33139 · Cited by 990 · see citing works
Evidence-based path to newborn screening for Duchenne muscular dystrophy
Mendell, J. R., Shilling, C., Leslie, N. D., Flanigan, K. M., al‐Dahhak, R., Gastier‐Foster, J., Kneile, K., Dunn, D. M., Duval, B., Aoyagi, A., et al. (2012) · Annals of Neurology · doi:10.1002/ana.23528 · Cited by 813 · see citing works
Neurological Disorders. Public Health Challenges
Vardi, G., & Merrick, J. (2007) · Journal of Policy and Practice in Intellectual Disabilities · doi:10.1111/j.1741-1130.2007.00122.x · Cited by 766 · see citing works
The genetic landscape of the epileptic encephalopathies of infancy and childhood
McTague, A., Howell, K. B., Cross, J. H., Kurian, M. A., & Scheffer, I. E. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)00250-1 · Cited by 605 · see citing works
Self-citationSoden, S. E., Saunders, C., Willig, L. K., Farrow, E., Smith, L. D., Petrikin, J. E., LePichon, J.-B., Miller, N., Thiffault, I., Dinwiddie, D. L., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3010076 · Cited by 525 · see citing works
Schwarze, K., Buchanan, J., Taylor, J. C., & Wordsworth, S. (2018) · Genetics in Medicine · doi:10.1038/gim.2017.247 · Cited by 516 · see citing works
Wilmshurst, J. M., Gaillard, W. D., Vinayan, K. P., Tsuchida, T. N., Plouin, P., Van Bogaert, P., Carrizosa, J., Elia, M., Craiu, D., Jovic, N. J., et al. (2015) · Epilepsia · doi:10.1111/epi.13057 · Cited by 418 · see citing works
Targeted next generation sequencing as a diagnostic tool in epileptic disorders
Lemke, J. R., Riesch, E., Scheurenbrand, T., Schubach, M., Wilhelm, C., Steiner, I., Hansen, J., Courage, C., Gallati, S., Bürki, S. E., et al. (2012) · Epilepsia · doi:10.1111/j.1528-1167.2012.03516.x · Cited by 332 · see citing works
Developmental Outcome After Epilepsy Surgery in Infancy
Loddenkemper, T., Holland, K. D., Stanford, L. D., Kotagal, P., Bingaman, W. E., & Wyllie, E. (2007) · PEDIATRICS · doi:10.1542/peds.2006-2530 · Cited by 263 · see citing works
Diagnostic yield of genetic testing in epileptic encephalopathy in childhood
Mercimek‐Andrews, S., Patel, J., Cordeiro, D., Hewson, S., Callen, D. F., Donner, E. J., Hahn, C. D., Kannus, P., Kobayashi, J., Minassian, B. A., et al. (2015) · Epilepsia · doi:10.1111/epi.12954 · Cited by 259 · see citing works
<i>SCN2A</i> encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures
Howell, K. B., McMahon, J. M., Carvill, G. L., Tambunan, D., Mackay, M. T., Rodriguez-Casero, V., Webster, R., Clark, D., Freeman, J. L., Calvert, S., et al. (2015) · Neurology · doi:10.1212/wnl.0000000000001926 · Cited by 255 · see citing works
Self-citationStark, Z., SCHOFIELD, D. J., Alam, K., Wilson, W., Mupfeki, N., Macciocca, I., Shrestha, R. N., White, S. M., & Gaff, C. (2017) · Genetics in Medicine · doi:10.1038/gim.2016.221 · Cited by 238 · see citing works
The Epidemiology and Natural History of Infantile Spasms
Cowan, L. D., & Hudson, L. S. (1991) · Journal of Child Neurology · doi:10.1177/088307389100600412 · Cited by 202 · see citing works
Berry, J. G., Poduri, A., Bonkowsky, J. L., Zhou, J., Graham, D. A., Welch, C., Putney, H., & Srivastava, R. (2012) · PLoS Medicine · doi:10.1371/journal.pmed.1001158 · Cited by 200 · see citing works
Monroe, G. R., Frederix, G., Savelberg, S. M. C., de Vries, T. I., Duran, K. J., van der Smagt, J. J., Terhal, P. A., van Hasselt, P. M., Kroes, H. Y., Verhoeven‐Duif, N. M., et al. (2016) · Genetics in Medicine · doi:10.1038/gim.2015.200 · Cited by 188 · see citing works
Wirrell, E. C., Shellhaas, R. A., Joshi, C., Keator, C. G., Kumar, S., & Mitchell, W. G. (2015) · Epilepsia · doi:10.1111/epi.12951 · Cited by 187 · see citing works
Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion
Allen, N. M., Conroy, J., Shahwan, A., Lynch, B., Correa, R. G., Pena, S. D. J., McCreary, D., Magalhães, T. R., Ennis, S., Lynch, S. A., et al. (2015) · Epilepsia · doi:10.1111/epi.13250 · Cited by 181 · see citing works
Whole exome sequencing in patients with white matter abnormalities
Vanderver, A., Simons, C., Helman, G., Crawford, J., Wolf, N. I., Bernard, G., Pizzino, A., Schmidt, J. L., Takanohashi, A., Miller, D., et al. (2016) · Annals of Neurology · doi:10.1002/ana.24650 · Cited by 145 · see citing works
Self-citationRiechmann, J., Strzelczyk, A., Reese, J. P., et al. (2015) · Epilepsia · doi:10.1111/epi.13089 · Cited by 112 · see citing works
Cpipe: a shared variant detection pipeline designed for diagnostic settings
Sadedin, S., Dashnow, H., James, P. A., Bahlo, M., Bauer, D. C., Lonie, A. J., Lunke, S., Macciocca, I., Ross, J. P., Siemering, K. R., et al. (2015) · Genome Medicine · doi:10.1186/s13073-015-0191-x · Cited by 106 · see citing works
Berg, A. T., Loddenkemper, T., & Baca, C. B. (2013) · Epilepsia · doi:10.1111/epi.12479 · Cited by 106 · see citing works
Dyment, D. A., Tétreault, M., Beaulieu, C. L., Hartley, T., Ferreira, P. C., Warman‐Chardon, J., Marcadier, J., Sawyer, S. L., Mosca, S. J., Innes, A. M., et al. (2014) · Clinical Genetics · doi:10.1111/cge.12464 · Cited by 90 · see citing works
Might, M., & Wilsey, M. (2014) · Genetics in Medicine · doi:10.1038/gim.2014.23 · Cited by 84 · see citing works
Diagnostic and cost utility of whole exome sequencing in peripheral neuropathy
Walsh, M., Bell, K. M., Chong, B., Creed, E., Brett, G. R., Pope, K., Thorne, N., Sadedin, S., Georgeson, P., Phelan, D., et al. (2017) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.409 · Cited by 46 · see citing works
Metabolic and monogenic causes of seizures in neonates and young infants
Hove, J. L. K. V., & Lohr, N. J. (2011) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2011.04.020 · Cited by 32 · see citing works
Schwarze, K., Buchanan, J., Taylor, J., et al. (2018) · Value in Health · doi:10.1016/j.jval.2018.04.677 · Cited by 31 · see citing works
Double Inversion Recovery Magnetic Resonance Imaging in Identifying Focal Cortical Dysplasia
Wong‐Kisiel, L. C., Britton, J. W., Witte, R. J., Kelly-Williams, K. M., Kotsenas, A. L., Krecke, K. N., Watson, R. E., Patton, A. C., Hanson, D. P., & Mandrekar, J. N. (2016) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2016.04.013 · Cited by 25 · see citing works
Gulati, S., Jain, P., Kannan, L., Sehgal, R., & Chakrabarty, B. (2015) · Journal of Child Neurology · doi:10.1177/0883073815569304 · Cited by 22 · see citing works
Chromosomal microarray in unexplained severe early onset epilepsy – A single centre cohort
Allen, N. M., Conroy, J., Shahwan, A., et al. (2015) · European Journal of Paediatric Neurology · doi:10.1016/j.ejpn.2015.03.010 · Cited by 17 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [4]Bureau M Thomas P Genton P Epileptic syndromes in infancy, childhood and adolescence Fifth edition with video sequences. ed:1 online resource 682
Cited by
Sorted by citations
Symonds, J. D., Zuberi, S. M., Stewart, K., McLellan, A., O‘Regan, M., MacLeod, S., Jollands, A., Joss, S., Kirkpatrick, M., Brunklaus, A., et al. (2019) · Brain · doi:10.1093/brain/awz195 · Cited by 459 · see citing works
The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures
Burgess, R., Wang, S., McTague, A., Boysen, K. E., Yang, X., Zeng, Q., Myers, K. A., Rochtus, A., Trivisano, M., Gill, D., et al. (2019) · Annals of Neurology · doi:10.1002/ana.25619 · Cited by 141 · see citing works
Self-citationDevelopmental and epileptic encephalopathies
Scheffer, I. E., Zuberi, S., Mefford, H. C., Guerrini, R., & McTague, A. (2024) · Nature Reviews Disease Primers · doi:10.1038/s41572-024-00546-6 · Cited by 128 · see citing works
Self-citationD'Gama, A. M., Mulhern, S., Sheidley, B. R., Boodhoo, F., Buts, S., Chandler, N. J., Cobb, J., Curtis, M., Higginbotham, E. J., Holland, J., et al. (2023) · The Lancet Neurology · doi:10.1016/s1474-4422(23)00246-6 · Cited by 80 · see citing works
Self-citationThe severe epilepsy syndromes of infancy: A population‐based study
Howell, K. B., Freeman, J. L., Mackay, M. T., Fahey, M. C., Archer, J., Berkovic, S. F., Chan, E., Dabscheck, G., Eggers, S., Hayman, M., et al. (2021) · Epilepsia · doi:10.1111/epi.16810 · Cited by 72 · see citing works
Self-citationNEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns
Stamberger, H., Hammer, T. B., Gardella, E., Vlaskamp, D. R. M., Bertelsen, B., Mandelstam, S., de Lange, I., Zhang, J., Myers, C. T., Fenger, C., et al. (2021) · Genetics in Medicine · doi:10.1038/s41436-020-00988-9 · Cited by 57 · see citing works
Self-citationPalmer, E. E., Howell, K., & Scheffer, I. E. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01133-3 · Cited by 53 · see citing works
Self-citation
- Authors
- Howell, K. B., Eggers, S., Dalziel, K., Riseley, J., Mandelstam, S., Myers, C. T., McMahon, J. M., Schneider, A., Carvill, G. L., Mefford, H. C., the Victorian Severe Epilepsy of Infancy Study Group, Scheffer, I. E., & Harvey, A. S.
- Affiliations
- Royal Children's Hospital (AU)
- Murdoch Children's Research Institute (AU)
- The University of Melbourne (AU)
- University of Washington (US)
- Northwestern University (US)
- Corresponding author
- Howell, Katherine B.
- ORCID
- Venue
- Epilepsia
- Publisher
- Wiley
- Published
- 2018-05-11
- Volume
- 59
- Issue
- 6
- Pages
- 1177-1187
- ISSN
- 0013-9580 (ISSN-L)
- 1528-1167
- PMC
- PMC5990455
- OpenAlex
- W2800239415
- Cited by
- 114
- References
- 34
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 18 · 2023: 12 · 2022: 14 · 2021: 15 · 2020: 10 · 2019: 15 · 2018: 5
- FWCI
- 8.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Epilepsia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- National Health and Medical Research Council
- National Institute of Neurological Disorders and Stroke (R01NS069605)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- cost-effectiveness, diagnostic yield, epilepsy etiology, incidence, metabolic testing, diagnostic pathway, acquired brain injury, focal cortical dysplasia, channelopathies, chromosomal abnormalities, infants, epileptiform EEG
- MeSH terms
- Australia, Cost-Benefit Analysis, Electroencephalography, Epilepsy, Female, Genetic Testing, Humans, Infant, Male, Incidence, Community Health Planning, Models, Economic
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
