title: Effectiveness of alternative strategies to define index case phenotypes to aid genetic diagnosis of familial hypercholesterolaemia.
abstract: OBJECTIVE
  To determine the utility of secondary stratification measures to improve the ascertainment of index cases of familial hypercholesterolaemia (FH).
  
  
  METHODS
  A retrospective study of genotyped index patients with Simon Broome (SB) FH.
  
  
  METHODS
  University teaching hospital.
  
  
  METHODS
  204 patients aged 55±14 years; 36% had tendon xanthoma (TX), 21% had coronary heart disease (CHD), low-density lipoprotein cholesterol (LDL-C) was 6.20±2.24 mmol/l and 55% had genetic FH.
  
  
  METHODS
  The effects of different staging systems (SB vs Dutch criteria), presence of TX, use of LDL-C level, personal history of CHD and imaging evidence of atheroma by carotid intima-media thickness or coronary artery calcium score to identify genetic FH was explored.
  
  
  METHODS
  Changes in C-statistic and net reclassification index (NRI).
  
  
  RESULTS
  SB criteria gave a C-statistic of 0.64 comprising C=0.65 in TX(+) and C=0.5 in TX(-) patients. Genetic FH was present in 75% of TX(+) compared with 44% in TX(-) patients. The Dutch criteria gave C=0.72. Addition of imaging criteria to prior CHD raised C=0.64 to C=0.65 in all patients with a NRI of 19% (p=0.06). In TX(-) patients imaging raised C=0.50 to C=0.65 with a NRI of 0.38 (p=0.001) and a weighted comparison index of 0.28, implying the detection of 14 more FH cases per thousand.
  
  
  CONCLUSIONS
  Patients with tendon xanthoma (definite FH) should be genotyped. In patients with possible FH, the presence of a personal history of CHD or imaging evidence of increased atheroma offers the best method of identifying index patients likely to have monogenic FH.
authors.affiliation: Department of Chemical Pathology, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.
authors.forename: Rosemary E J
authors.initials: RE
authors.lastname: Clarke
authors.forename: Soundrie T
authors.initials: ST
authors.lastname: Padayachee
authors.forename: Rebecca
authors.initials: R
authors.lastname: Preston
authors.forename: Zofia
authors.initials: Z
authors.lastname: McMahon
authors.forename: Mitchell
authors.initials: M
authors.lastname: Gordon
authors.forename: Colin
authors.initials: C
authors.lastname: Graham
authors.forename: Martin A
authors.initials: MA
authors.lastname: Crook
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Wierzbicki
mesh_terms: D008078:Cholesterol, LDL / Q000097:blood; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics; D003937:Diagnosis, Differential; D003952:Diagnostic Imaging / Q000379:methods / Q000592:standards*; D005260:Female; D005500:Follow-Up Studies; D005820:Genetic Testing / Q000379:methods* / Q000592:standards*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D017410:Practice Guidelines as Topic; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D008078:Cholesterol, LDL