title: Selection of individuals for genetic testing for familial hypercholesterolaemia: development and external validation of a prediction model for the presence of a mutation causing familial hypercholesterolaemia.
abstract: OBJECTIVE
  Familial hypercholesterolaemia (FH) is an autosomal dominant disease that warrants early diagnosis to prevent premature cardiovascular disease (CVD). However, genetic testing to make a definite diagnosis is costly, and careful selection of eligible subjects is important. Unfortunately, accuracy of current diagnostic criteria is poor, especially in young individuals. We therefore developed and validated a model to predict the presence of an FH causing mutation in persons referred by general practitioners.
  
  
  RESULTS
  All participants in the Dutch FH screening programme from 1994 to 2014 were included in the development cohort. The validation cohort consisted of consecutive patients, suspected for FH, attending the outpatient lipid clinic in Saguenay (Quebec) from 1993 to 2014. Cross-sectional data were available on medical history, lipid profile, and DNA analysis. Multivariable logistic regression analysis was used for model development. The primary outcome was the presence of a deleterious FH mutation. The development cohort comprised 26 167 FH patients and 37 939 unaffected relatives. Our final model included age; sex; levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides; history and age of CVD; use of statins; smoking; alcohol; and presence of hypertension. The area under the receiver operating characteristic curve (AUC) was 85.4% (95% CI: 85.0-85.9). The calibration slope was 1.02 (where 1.00 is optimal). In the validation cohort (1436 FH patients and 1767 unaffected persons), the AUC was 95.4% (95% CI: 94.7-96.1%) and the calibration slope 1.06.
  
  
  CONCLUSIONS
  Our model showed good discrimination and calibration. We specifically expect our model to be of added value for young persons set against current diagnostic criteria, since LDL-C and age are now used as continuous predictors. The equation will be available as an online calculator to estimate the probability of the presence of an FH mutation in individual patients. This tool might aid physicians in the decision for referral of patients for molecular testing.
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Meibergdreef 9, Room F4-136, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Besseling
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Johannes B
authors.initials: JB
authors.lastname: Reitsma
authors.affiliation: Department of Medicine, Université de Montréal, Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, Quebec, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
authors.affiliation: Department of Medicine, Université de Montréal, Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, Quebec, Canada.
authors.forename: Diane
authors.initials: D
authors.lastname: Brisson
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Meibergdreef 9, Room F4-136, 1105 AZ Amsterdam, The Netherlands.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Meibergdreef 9, Room F4-136, 1105 AZ Amsterdam, The Netherlands.
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Hutten
mesh_terms: D000328:Adult; D017668:Age of Onset; D002318:Cardiovascular Diseases / Q000235:genetics; D003430:Cross-Sectional Studies; D005260:Female; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy / Q000235:genetics*; D008075:Lipoproteins, HDL / Q000235:genetics; D008077:Lipoproteins, LDL / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D018579:Patient Selection; D011379:Prognosis; D012042:Registries
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL
keywords: Development; External validation; Familial hypercholesterolaemia; Prediction model; Presence of mutation