Effect of Ascertainment Bias on Estimates of Patient Mortality in Inherited Cardiac Diseases

Eline A. Nannenberg, Ingrid A.W. van Rijsingen, Paul A. van der Zwaag, Maarten P. van den Berg, J. Peter van Tintelen, Michael W.T. Tanck, Michael John Ackerman, Arthur A.M. Wilde, Imke Christiaans

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

BACKGROUND: Accurate estimates of survival are indispensable for cardiologists, clinical geneticists, and genetic counselors dealing with families with an inherited cardiac disease. However, a bias towards a more severe disease with a worse outcome in the first publications may not accurately represent the actual survival forecast. We, therefore, evaluated the effect of ascertainment bias on survival in 3 different inherited cardiac diseases (idiopathic ventricular fibrillation, SCN5A overlap syndrome, and arrhythmogenic cardiomyopathy) caused by a founder mutation.

METHODS: We collected mortality data from mutation-positive subjects with either DPP6-associated idiopathic ventricular fibrillation, SCN5A overlap syndrome, and PLN-R14del-mediated arrhythmogenic cardiomyopathy >2 to 10 years of ongoing clinical/cascade genetic screening.

RESULTS: The median age of survival in DPP6 mutation-positive subjects increased from 44.6 years in the original cohort from 2008 (n=60; 95% CI, 36.8-52.4 years) to 68.2 years in the extended cohort from 2012 (n=235; 95% CI, 64.6-71.7 years; P<0.001). In the SCN5A overlap syndrome, survival increased from 56.1 years in 1999 (n=86; 95% CI, 48.0-64.2 years) to 69.7 years in 2009 (n=197; 95% CI, 61.3-78.2 years; P=0.049). In PLN-R14del positive patients, the median age of survival increased from 63.5 years in 2010 (n=89; 95% CI, 59.1-68.0 years) to 65.2 years in 2012 (n=370; 95% CI, 62.0-68.3 years; P=0.046).

CONCLUSIONS: The median age of survival in 3 different inherited cardiac diseases with an established pathogenic substrate significantly increased once genetic testing and cascade screening extended, after the first publication that elucidated the discovery of the disease-susceptibility gene/mutation. This underscores the direct and negative influence of ascertainment bias on survival forecasts and the importance of ongoing clinical/genetic follow-up to establish the most accurate disease prognosis for genetically mediated heart diseases.

Original languageEnglish (US)
Pages (from-to)e001797
JournalCirculation. Genomic and precision medicine
Volume11
Issue number10
DOIs
StatePublished - Oct 1 2018

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Heart Diseases
Survival
Mortality
Mutation
Genetic Testing
Cardiomyopathies
Publications
Disease Susceptibility
Genes

Keywords

  • arrhythmias, cardiac
  • bias
  • cardiomyopathies
  • genes
  • mortality
  • ventricular fibrillation

Cite this

Nannenberg, E. A., van Rijsingen, I. A. W., van der Zwaag, P. A., van den Berg, M. P., van Tintelen, J. P., Tanck, M. W. T., ... Christiaans, I. (2018). Effect of Ascertainment Bias on Estimates of Patient Mortality in Inherited Cardiac Diseases. Circulation. Genomic and precision medicine, 11(10), e001797. https://doi.org/10.1161/CIRCGEN.117.001797

Effect of Ascertainment Bias on Estimates of Patient Mortality in Inherited Cardiac Diseases. / Nannenberg, Eline A.; van Rijsingen, Ingrid A.W.; van der Zwaag, Paul A.; van den Berg, Maarten P.; van Tintelen, J. Peter; Tanck, Michael W.T.; Ackerman, Michael John; Wilde, Arthur A.M.; Christiaans, Imke.

In: Circulation. Genomic and precision medicine, Vol. 11, No. 10, 01.10.2018, p. e001797.

Research output: Contribution to journalArticle

Nannenberg, EA, van Rijsingen, IAW, van der Zwaag, PA, van den Berg, MP, van Tintelen, JP, Tanck, MWT, Ackerman, MJ, Wilde, AAM & Christiaans, I 2018, 'Effect of Ascertainment Bias on Estimates of Patient Mortality in Inherited Cardiac Diseases', Circulation. Genomic and precision medicine, vol. 11, no. 10, pp. e001797. https://doi.org/10.1161/CIRCGEN.117.001797
Nannenberg EA, van Rijsingen IAW, van der Zwaag PA, van den Berg MP, van Tintelen JP, Tanck MWT et al. Effect of Ascertainment Bias on Estimates of Patient Mortality in Inherited Cardiac Diseases. Circulation. Genomic and precision medicine. 2018 Oct 1;11(10):e001797. https://doi.org/10.1161/CIRCGEN.117.001797
Nannenberg, Eline A. ; van Rijsingen, Ingrid A.W. ; van der Zwaag, Paul A. ; van den Berg, Maarten P. ; van Tintelen, J. Peter ; Tanck, Michael W.T. ; Ackerman, Michael John ; Wilde, Arthur A.M. ; Christiaans, Imke. / Effect of Ascertainment Bias on Estimates of Patient Mortality in Inherited Cardiac Diseases. In: Circulation. Genomic and precision medicine. 2018 ; Vol. 11, No. 10. pp. e001797.
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AU - Nannenberg, Eline A.

AU - van Rijsingen, Ingrid A.W.

AU - van der Zwaag, Paul A.

AU - van den Berg, Maarten P.

AU - van Tintelen, J. Peter

AU - Tanck, Michael W.T.

AU - Ackerman, Michael John

AU - Wilde, Arthur A.M.

AU - Christiaans, Imke

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N2 - BACKGROUND: Accurate estimates of survival are indispensable for cardiologists, clinical geneticists, and genetic counselors dealing with families with an inherited cardiac disease. However, a bias towards a more severe disease with a worse outcome in the first publications may not accurately represent the actual survival forecast. We, therefore, evaluated the effect of ascertainment bias on survival in 3 different inherited cardiac diseases (idiopathic ventricular fibrillation, SCN5A overlap syndrome, and arrhythmogenic cardiomyopathy) caused by a founder mutation.METHODS: We collected mortality data from mutation-positive subjects with either DPP6-associated idiopathic ventricular fibrillation, SCN5A overlap syndrome, and PLN-R14del-mediated arrhythmogenic cardiomyopathy >2 to 10 years of ongoing clinical/cascade genetic screening.RESULTS: The median age of survival in DPP6 mutation-positive subjects increased from 44.6 years in the original cohort from 2008 (n=60; 95% CI, 36.8-52.4 years) to 68.2 years in the extended cohort from 2012 (n=235; 95% CI, 64.6-71.7 years; P<0.001). In the SCN5A overlap syndrome, survival increased from 56.1 years in 1999 (n=86; 95% CI, 48.0-64.2 years) to 69.7 years in 2009 (n=197; 95% CI, 61.3-78.2 years; P=0.049). In PLN-R14del positive patients, the median age of survival increased from 63.5 years in 2010 (n=89; 95% CI, 59.1-68.0 years) to 65.2 years in 2012 (n=370; 95% CI, 62.0-68.3 years; P=0.046).CONCLUSIONS: The median age of survival in 3 different inherited cardiac diseases with an established pathogenic substrate significantly increased once genetic testing and cascade screening extended, after the first publication that elucidated the discovery of the disease-susceptibility gene/mutation. This underscores the direct and negative influence of ascertainment bias on survival forecasts and the importance of ongoing clinical/genetic follow-up to establish the most accurate disease prognosis for genetically mediated heart diseases.

AB - BACKGROUND: Accurate estimates of survival are indispensable for cardiologists, clinical geneticists, and genetic counselors dealing with families with an inherited cardiac disease. However, a bias towards a more severe disease with a worse outcome in the first publications may not accurately represent the actual survival forecast. We, therefore, evaluated the effect of ascertainment bias on survival in 3 different inherited cardiac diseases (idiopathic ventricular fibrillation, SCN5A overlap syndrome, and arrhythmogenic cardiomyopathy) caused by a founder mutation.METHODS: We collected mortality data from mutation-positive subjects with either DPP6-associated idiopathic ventricular fibrillation, SCN5A overlap syndrome, and PLN-R14del-mediated arrhythmogenic cardiomyopathy >2 to 10 years of ongoing clinical/cascade genetic screening.RESULTS: The median age of survival in DPP6 mutation-positive subjects increased from 44.6 years in the original cohort from 2008 (n=60; 95% CI, 36.8-52.4 years) to 68.2 years in the extended cohort from 2012 (n=235; 95% CI, 64.6-71.7 years; P<0.001). In the SCN5A overlap syndrome, survival increased from 56.1 years in 1999 (n=86; 95% CI, 48.0-64.2 years) to 69.7 years in 2009 (n=197; 95% CI, 61.3-78.2 years; P=0.049). In PLN-R14del positive patients, the median age of survival increased from 63.5 years in 2010 (n=89; 95% CI, 59.1-68.0 years) to 65.2 years in 2012 (n=370; 95% CI, 62.0-68.3 years; P=0.046).CONCLUSIONS: The median age of survival in 3 different inherited cardiac diseases with an established pathogenic substrate significantly increased once genetic testing and cascade screening extended, after the first publication that elucidated the discovery of the disease-susceptibility gene/mutation. This underscores the direct and negative influence of ascertainment bias on survival forecasts and the importance of ongoing clinical/genetic follow-up to establish the most accurate disease prognosis for genetically mediated heart diseases.

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KW - bias

KW - cardiomyopathies

KW - genes

KW - mortality

KW - ventricular fibrillation

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