PMID- 27321816
OWN - NLM
STAT- MEDLINE
DCOM- 20170502
LR  - 20211204
IS  - 1098-2272 (Electronic)
IS  - 0741-0395 (Print)
IS  - 0741-0395 (Linking)
VI  - 40
IP  - 6
DP  - 2016 Sep
TI  - A Clustered Multiclass Likelihood-Ratio Ensemble Method for Family-Based 
      Association Analysis Accounting for Phenotypic Heterogeneity.
PG  - 512-9
LID - 10.1002/gepi.21987 [doi]
AB  - Although compelling evidence suggests that the genetic etiology of complex 
      diseases could be heterogeneous in subphenotype groups, little attention has been 
      paid to phenotypic heterogeneity in genetic association analysis of complex 
      diseases. Simply ignoring phenotypic heterogeneity in association analysis could 
      result in attenuated estimates of genetic effects and low power of association 
      tests if subphenotypes with similar clinical manifestations have heterogeneous 
      underlying genetic etiologies. To facilitate the family-based association 
      analysis allowing for phenotypic heterogeneity, we propose a clustered multiclass 
      likelihood-ratio ensemble (CMLRE) method. The proposed method provides an 
      alternative way to model the complex relationship between disease outcomes and 
      genetic variants. It allows for heterogeneous genetic causes of disease 
      subphenotypes and can be applied to various pedigree structures. Through 
      simulations, we found CMLRE outperformed the commonly adopted strategies in a 
      variety of underlying disease scenarios. We further applied CMLRE to a 
      family-based dataset from the International Consortium to Identify Genes and 
      Interactions Controlling Oral Clefts (ICOC) to investigate the genetic variants 
      and interactions predisposing to subphenotypes of oral clefts. The analysis 
      suggested that two subphenotypes, nonsyndromic cleft lip without palate (CL) and 
      cleft lip with palate (CLP), shared similar genetic etiologies, while cleft 
      palate only (CP) had its own genetic mechanism. The analysis further revealed 
      that rs10863790 (IRF6), rs7017252 (8q24), and rs7078160 (VAX1) were jointly 
      associated with CL/CLP, while rs7969932 (TBK1), rs227731 (17q22), and rs2141765 
      (TBK1) jointly contributed to CP.
CI  - (c) 2016 WILEY PERIODICALS, INC.
FAU - Wen, Yalu
AU  - Wen Y
AD  - Department of Statistics, University of Auckland, Auckland, New Zealand.
FAU - Lu, Qing
AU  - Lu Q
AD  - Department of Epidemiology and Biostatics, Michigan State University, East 
      Lansing, Michigan, United States of America.
LA  - eng
GR  - K01 DA033346/DA/NIDA NIH HHS/United States
GR  - R03 DE022379/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20160619
PL  - United States
TA  - Genet Epidemiol
JT  - Genetic epidemiology
JID - 8411723
RN  - 0 (IRF6 protein, human)
RN  - 0 (Interferon Regulatory Factors)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TBK1 protein, human)
SB  - IM
MH  - Cleft Lip/*genetics/pathology
MH  - Cleft Palate/*genetics/pathology
MH  - Genetic Loci
MH  - Genetic Variation
MH  - Humans
MH  - Interferon Regulatory Factors/genetics
MH  - Linkage Disequilibrium
MH  - Models, Genetic
MH  - Phenotype
MH  - Protein Serine-Threonine Kinases/genetics
PMC - PMC5289649
MID - NIHMS841651
OTO - NOTNLM
OT  - family-based study
OT  - nonparametric method
OT  - oral clefts
OT  - subphenotypes
EDAT- 2016/06/21 06:00
MHDA- 2017/05/04 06:00
PMCR- 2017/02/02
CRDT- 2016/06/21 06:00
PHST- 2015/12/03 00:00 [received]
PHST- 2016/05/04 00:00 [revised]
PHST- 2016/05/08 00:00 [accepted]
PHST- 2016/06/21 06:00 [entrez]
PHST- 2016/06/21 06:00 [pubmed]
PHST- 2017/05/04 06:00 [medline]
PHST- 2017/02/02 00:00 [pmc-release]
AID - 10.1002/gepi.21987 [doi]
PST - ppublish
SO  - Genet Epidemiol. 2016 Sep;40(6):512-9. doi: 10.1002/gepi.21987. Epub 2016 Jun 19.