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Academia and the Profession |

Methodologic Pitfalls in the Determination of Genetic Anticipation: The Case of Crohn Disease

Michael F. Picco, MD, PhD; Steven Goodman, MD, PhD; James Reed, PhD; and Theodore M. Bayless, MD
[+] Article and Author Information

From Mayo Clinic Jacksonville, Jacksonville, Florida; Johns Hopkins University School of Medicine, Baltimore, Maryland; and Research Institute, St. Luke's Hospital, Bethlehem, Pennsylvania.


Acknowledgment: The authors thank Gloria M. Petersen, PhD, for critical review of the manuscript.

Grant Support: By the National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Dr. Picco); Harvey M. and Lyn Pancoe Meyerhoff Center for Inflammatory Bowel Diseases; Glaxo Institute for Digestive Health (Dr. Picco); and the Allan Guerreri Family Fund (Dr. Picco). Dr. Bayless receives support from the Meyerhoff Center for Inflammatory Bowel Diseases, the Peter and Cynthia Rosenwald Fund, and the Steven A. Mullaney Fund.

Requests for Single Reprints: Michael F. Picco, MD, PhD, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224.

Current Author Addresses: Dr. Picco: Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224.

Dr. Goodman: Johns Hopkins University Department of Medicine, 550 Building, 600 North Wolfe Street, Baltimore, MD 21287.

Dr. Reed: Research Institute, St. Luke's Hospital, 801 Ostrum Street, Bethlehem, PA 18105.

Dr. Bayless: Johns Hopkins University Department of Medicine, Blalock 461, 600 North Wolfe Street, Baltimore, MD 21287.


Ann Intern Med. 2001;134(12):1124-1129. doi:10.7326/0003-4819-134-12-200106190-00013
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Background: The term genetic anticipation is used when genetically transmitted disease manifests at increasingly younger ages with each succeeding generation: that is, if the offspring of patients develop the disease, they will tend to do so at an earlier age than their parents. In some monogenetic disorders, genetic anticipation has a biological basis in expanded genetic triplet repeats; however, some have claimed that it occurs in polygenic disorders, such as Crohn disease, in which its mechanism cannot be explained.

Objective: To show how apparent changes in age at diagnosis of Crohn disease between generations, which could suggest genetic anticipation, can be an artifact of inadequate analysis based on age at diagnosis in cohorts that have not been followed for a sufficiently long time.

Design: Comparison of ages at diagnosis of Crohn disease among different birth cohorts, before and after adjustment for observation time.

Setting: Meyerhoff Center for Inflammatory Bowel Disease, Johns Hopkins Hospital, Baltimore, Maryland.

Patients: 928 consecutive outpatients with Crohn disease.

Measurements: Trends in age at diagnosis of Crohn disease among birth cohorts were determined by calculating Pearson correlation coefficients and performing Kaplan–Meyer analysis before and after adjustment for observation time. Adjustment for observation time was performed by ensuring that the time during which all included patients were at risk for Crohn disease was equal and that all patients had developed disease by the end of the risk period.

Results: Mean age at diagnosis decreased by approximately 5 years with each subsequent 10-year birth cohort on the basis of crude cross-sectional data that could suggest genetic anticipation between generations. However, after adjustment for observation time, the age at diagnosis decreased minimally, if at all, with each successive generation.

Conclusions: Apparent genetic anticipation can be explained by observational biases without invoking any additional genetic influences. Claims for genetic anticipation must be based on methods that properly account for the duration of observation in all persons being studied.

Figures

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Figure 1.
Evidence of genetic anticipation in Crohn disease from different centers based on differences in age at diagnosis between parents (white bars) and children (gray bars).P

*  < 0.001 for comparison of mean age at diagnosis between parents and children at all centers. Baltimore = Johns Hopkins University, Baltimore, Maryland; Belgium = Service d'Hepato-Gastroenterologie, Liège, Belgium, and Hôpital Huriez, Lille, France; CCFA = Crohn's and Colitis Foundation of America, New York, New York; Oxford = Radcliffe Infirmary, Oxford University, Oxford, United Kingdom.

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Figure 2.
Age at study entry (white bars) and mean age at diagnosis (gray bars) in six birth cohorts of patients with Crohn disease.PrPrP

Both ages decrease with each successive birth cohort (  < 0.01, trend test), and age at diagnosis is significantly correlated with birth cohort ( = −0.71;  < 0.001) and attained age ( = −0.958;  < 0.001). Whisker bars represent 1 SD.

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Figure 3.
Kaplan–Meier estimates of the proportion of patients with undiagnosed Crohn disease in successive 10-year birth cohorts according to age, before adjustment for period of risk.P[18]

An apparent 5-year decrease in median age at diagnosis in each successive birth cohort was observed (  < 0.001, log-rank test for equality of survivor functions ).

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Figure 4.
Kaplan–Meier estimates of the proportion of patients with undiagnosed Crohn disease in successive 10-year birth cohorts according to age, after adjustment for period of risk.

Adjustment was made by restricting the analysis to patients in whom disease was diagnosed before 41 years of age and who had lived for at least 40 years. The birth cohorts overlap and are indistinguishable.

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