ArticleAmerican journal of human genetics2014
Ascertainment bias causes false signal of anticipation in genetic prion disease.
Article in American journal of human genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
18 citing papers in PubMed, 46 citations in OpenAlex.
- Mortality of Individuals WithNeurology. Genetics · 2026Article
- Pedigree analysis and genetic inheritance of fatal familial insomnia (FFI) in a Portuguese multigenerational family.Journal of neurology · 2025Article
- Mortality of individuals with antemortem genetic testing formedRxiv : the preprint server for health sciences · 2025Article
- Theoretical Framework for the Study of Genetic Diseases Caused by Dominant Alleles.Life (Basel, Switzerland) · 2023Article
- Diagnostic accuracy of cerebrospinal fluid biomarkers in genetic prion diseases.Brain : a journal of neurology · 2022Article
- Genetic aspects of human prion diseases.Frontiers in neurology · 2022Review
- Penetrance of Breast Cancer Susceptibility Genes From the eMERGE III Network.JNCI cancer spectrum · 2021Article
- Estimating the Posttest Probability of Long QT Syndrome Diagnosis for RareCirculation. Genomic and precision medicine · 2021Article
- Data-driven phenotype discovery ofScience advances · 2019Article
- Article
- Epilepsy in families: Age at onset is a familial trait, independent of syndrome.Annals of neurology · 2019Article
- Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.American journal of human genetics · 2019Article
- The Medical Genome Reference Bank: a whole-genome data resource of 4000 healthy elderly individuals. Rationale and cohort design.European journal of human genetics : EJHG · 2019Article
- Genetic PrP Prion Diseases.Cold Spring Harbor perspectives in biology · 2018Review
- Simulating pedigrees ascertained for multiple disease-affected relatives.Source code for biology and medicine · 2018Article
- Genetic Prion Disease Caused by PRNP Q160X Mutation Presenting with an Orbitofrontal Syndrome, Cyclic Diarrhea, and Peripheral Neuropathy.Journal of Alzheimer's disease : JAD · 2017Article
- Genetic prion disease: Experience of a rapidly progressive dementia center in the United States and a review of the literature.American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics · 2017Review
- Quantifying prion disease penetrance using large population control cohorts.Science translational medicine · 2016Article
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Authors and funding
14 authors at 9 institutions in 4 countries.
Funding
Abstract
Anticipation is the phenomenon whereby age of onset in genetic disease decreases in successive generations. Three independent reports have claimed anticipation in Creutzfeldt-Jakob disease (CJD) caused by the c.598G > A mutation in PRNP encoding a p.Glu200Lys (E200K) substitution in the prion protein. If confirmed, this finding would carry clear implications for genetic counseling. We analyzed pedigrees with this mutation from four prion centers worldwide (n = 217 individuals with the mutation) to analyze age of onset and death in affected and censored individuals. We show through simulation that selective ascertainment of individuals whose onset falls within the historical window since the mutation's 1989 discovery is sufficient to create robust false signals both of anticipation and of heritability of age of onset. In our data set, the number of years of anticipation observed depends upon how strictly the data are limited by the ascertainment window. Among individuals whose disease was directly observed at a study center, a 28-year difference between parent and child age of onset is observed (p = 0.002), but including individuals ascertained retrospectively through family history reduces this figure to 7 years (p = 0.005). Applying survival analysis to the most thoroughly ascertained subset of data eliminates the signal of anticipation. Moreover, even non-CJD deaths exhibit 16 years anticipation (p = 0.002), indicating that ascertainment bias can entirely explain observed anticipation. We suggest that reports of anticipation in genetic prion disease are driven entirely by ascertainment bias. Guidelines for future studies claiming statistical evidence for anticipation are suggested.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.