597: Metabolomic prediction of trisomy 18 first trimester pregnancies
1
597 Metabolomic prediction of trisomy 18 first trimester pregnancies Ray Bahado-Singh 1 , Ranjit Akolekar 2 , Rupsari Mandal 3 , Anushka Chelliah 1 , Edison Dong 4 , Jianguo Xia 3 , Mike Kruger 1 , David Wishart 3 , Kypros NIcolaides 5 1 Wayne State University - School of Medicine, Obstetrics and Gynecology, Detroit, MI, 2 Medway NHS Foundation Trust, Fetal Medicine Unit, Gillingham, United Kingdom, 3 University of Alberta, Biological Sciences, Edmonton, AB, Canada, 4 University of Alberta, Computing Sciences, Edmonton, AB, Canada, 5 The Fetal Medicine Foundation, Fetal Medicine, London, United Kingdom OBJECTIVE: Metabolomics is a rapidly developing field of omics sci- ence that employs a high throughput quantitative approach to char- acterize small molecule metabolites and their metabolism at the sys- tem-wide level.. Our purpose was to determine whether the metabolomic profile is altered in Trisomy 18 (T18) pregnancies and whether these biomarkers can predict T18. STUDY DESIGN: This was a case control study. NMR based metabolo- mic analyses of maternal serum prospectively collected between 110 and 136 weeks were performed. Metabolite concentrations in 30 T18 and 114 euploid controls were compared. Statistical analyses in- cluding logistic regression and genetic programming (GP) [www.Thegmax.com] were performed. Predictive algorithms for T18 detection consisting of metabolites by themselves or in combination with maternal age and delta nuchal translucency (NT) measure- ments were evaluated. RESULTS: Of a total of 40 metabolites analyzed, 29 had significant dif- ferences in serum concentrations between the groups. Several models for T18 prediction were developed. A logistic model-based on 2-hy- droxybytrate, formate and maternal age had 56.7% sensitivity and 95.6 % specificity for T18 detection, AUC (95% CI); 0.91 (0.86, 0.96), p 0.001. For 2-hydroxybutyrate plus delta nuchal translucency (NT) these values were 96.7% and 99.1%; AUC (95% CI): 0.99 (0.97Using GP analysis, a metabolite only model had 66.7% sensitivity and 99.1% specificity. The addition of NT further improved these values to 93.3% and 98.3 % respectively., 1.000), p 0.001 respec- tively. CONCLUSION: Conclusion: An extensive group difference in metabo- lomic profile was observed. Metabolomics appears to be a novel tool for aneuploidy prediction. When combined with NT measurements, preliminary data suggest that high diagnostic accuracy is achievable. 598 The association of 2 adrenoceptor genotype with short-cervix mediated preterm birth Russell Miller 1 , Richard Smiley 1 1 Maternal-Fetal Medicine Units Network, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD OBJECTIVE: 2 adrenoceptor (2AR) genotype has been linked to obstet- rical phenotypes. Polymorphic variation encoding for Arg16 homozy- gosity (Arg16Arg) in the transcribed protein is associated with decreased risk of preterm labor and preterm delivery (PTD), altered -agonist re- sponsiveness, and slower rate of active labor. This study was designed to determine if 2AR genotype is associated with short cervix occurrence or PTD risk following identification of a short cervix. STUDY DESIGN: Nulliparous women with short cervices (length 30mm upon screening sonogram performed between 16-22 weeks) recruited into a multi-center trial were approached to participate. Race-matched women with cervical lengths 40mm were recruited as controls (2:1 case:control ratio). Subjects provided blood for DNA isolation. 2AR genotype was determined using primers for polymor- phisms at positions encoding for amino acid residues 16 and 27. Base- line data were collected for all subjects, as well as outcomes data for short cervix cases. Genotype distributions were compared between case and control groups. Within the short cervix group, baseline char- acteristics and outcomes were compared among genotype groups. The primary outcome was PTD 37 weeks. Data were compared using chi-squared or Fisher’s exact tests. RESULTS: 444 subjects participated, including 315 cases. Genotype data were available at position 16 for 433 subjects (2.5% failure), and position 27 for 437 subjects (1.6% failure). Expected Hardy-Weinberg equilibrium existed at both positions. There was no difference in frequency of Arg16Arg (22.4% vs 25.0%, p0.56) or Gln27 homozygosity (Gln27Gln, 8.0% vs 7.3%, p0.82) between cases and controls. Among cases, Arg16Arg had no effect on PTD nor spontaneous PTD (table). Gln27Gln had no effect on PTD, although sample size for this analysis was limited. CONCLUSION: 2AR genotype is not associated with short cervix oc- currence or PTD after a short cervix diagnosis. Putative protection from PTD associated with Arg16Arg does not involve short cervix pathways. Scatter plot showing maternal serum PAPP-A MoM versus HbA1c values First-trimester screening marker differences in IDDM compared to NDC 1 P value less than 0.05 is considered to be significant. 2AR genotype and preterm delivery in subjects with short cervix 1. PTD, preterm delivery. www.AJOG.org Academic Issues, Antepartum Fetal, Clinical Ob, Fetus, Genetics, Hypertension, Med-Surg-Diseases, Operative Ob, U/S Poster Session IV Supplement to JANUARY 2013 American Journal of Obstetrics & Gynecology S255
Transcript of 597: Metabolomic prediction of trisomy 18 first trimester pregnancies
597 Metabolomic prediction of trisomy 18first trimester pregnanciesRay Bahado-Singh1, Ranjit Akolekar2, Rupsari Mandal3, AnushkaChelliah1, Edison Dong4, Jianguo Xia3, Mike Kruger1, DavidWishart3, Kypros NIcolaides5
1Wayne State University - School of Medicine, Obstetrics and Gynecology,Detroit, MI, 2Medway NHS Foundation Trust, Fetal Medicine Unit,Gillingham, United Kingdom, 3University of Alberta, Biological Sciences,Edmonton, AB, Canada, 4University of Alberta, Computing Sciences,Edmonton, AB, Canada, 5The Fetal Medicine Foundation, Fetal Medicine,London, United KingdomOBJECTIVE: Metabolomics is a rapidly developing field of omics sci-ence that employs a high throughput quantitative approach to char-acterize small molecule metabolites and their metabolism at the sys-tem-wide level.. Our purpose was to determine whether themetabolomic profile is altered in Trisomy 18 (T18) pregnancies andwhether these biomarkers can predict T18.STUDY DESIGN: This was a case control study. NMR based metabolo-mic analyses of maternal serum prospectively collected between 11�0and 13�6 weeks were performed. Metabolite concentrations in 30T18 and 114 euploid controls were compared. Statistical analyses in-cluding logistic regression and genetic programming (GP)[www.Thegmax.com] were performed. Predictive algorithms for T18detection consisting of metabolites by themselves or in combinationwith maternal age and delta nuchal translucency (NT) measure-ments were evaluated.RESULTS: Of a total of 40 metabolites analyzed, 29 had significant dif-ferences in serum concentrations between the groups. Several modelsfor T18 prediction were developed. A logistic model-based on 2-hy-
droxybytrate, formate and maternal age had 56.7% sensitivity and95.6 % specificity for T18 detection, AUC (95% CI); 0.91 (0.86, 0.96),p � 0.001. For 2-hydroxybutyrate plus delta nuchal translucency(NT) these values were 96.7% and 99.1%; AUC (95% CI): 0.99(0.97Using GP analysis, a metabolite only model had 66.7% sensitivityand 99.1% specificity. The addition of NT further improved thesevalues to 93.3% and 98.3 % respectively., 1.000), p � 0.001 respec-tively.CONCLUSION: Conclusion: An extensive group difference in metabo-lomic profile was observed. Metabolomics appears to be a novel toolfor aneuploidy prediction. When combined with NT measurements,preliminary data suggest that high diagnostic accuracy is achievable.
598 The association of �2 adrenoceptor genotype withshort-cervix mediated preterm birthRussell Miller1, Richard Smiley1
1Maternal-Fetal Medicine Units Network, for the Eunice Kennedy ShriverNational Institute of Child Health and Human Development, Bethesda, MDOBJECTIVE: �2 adrenoceptor (�2AR) genotype has been linked to obstet-rical phenotypes. Polymorphic variation encoding for Arg16 homozy-gosity (Arg16Arg) in the transcribed protein is associated with decreasedrisk of preterm labor and preterm delivery (PTD), altered �-agonist re-sponsiveness, and slower rate of active labor. This study was designed todetermine if �2AR genotype is associated with short cervix occurrence orPTD risk following identification of a short cervix.STUDY DESIGN: Nulliparous women with short cervices (length�30mm upon screening sonogram performed between 16-22 weeks)recruited into a multi-center trial were approached to participate.Race-matched women with cervical lengths �40mm were recruited ascontrols (2:1 case:control ratio). Subjects provided blood for DNAisolation. �2AR genotype was determined using primers for polymor-phisms at positions encoding for amino acid residues 16 and 27. Base-line data were collected for all subjects, as well as outcomes data forshort cervix cases. Genotype distributions were compared betweencase and control groups. Within the short cervix group, baseline char-acteristics and outcomes were compared among genotype groups.The primary outcome was PTD �37 weeks. Data were comparedusing chi-squared or Fisher’s exact tests.RESULTS: 444subjectsparticipated, including315cases.Genotypedatawereavailableatposition16for433subjects(2.5%failure),andposition27for437subjects (1.6% failure). Expected Hardy-Weinberg equilibrium existed atboth positions. There was no difference in frequency of Arg16Arg (22.4% vs25.0%, p�0.56) or Gln27 homozygosity (Gln27Gln, 8.0% vs 7.3%, p�0.82)between cases and controls. Among cases, Arg16Arg had no effect on PTDnor spontaneous PTD (table). Gln27Gln had no effect on PTD, althoughsample size for this analysis was limited.CONCLUSION: �2AR genotype is not associated with short cervix oc-currence or PTD after a short cervix diagnosis. Putative protectionfrom PTD associated with Arg16Arg does not involve short cervixpathways.
Scatter plot showing maternal serumPAPP-A MoM versus HbA1c values
First-trimester screening markerdifferences in IDDM compared to NDC
1 P value less than 0.05 is considered to be significant.
�2AR genotype and preterm delivery insubjects with short cervix
1. PTD, preterm delivery.
www.AJOG.org Academic Issues, Antepartum Fetal, Clinical Ob, Fetus, Genetics, Hypertension, Med-Surg-Diseases, Operative Ob, U/S Poster Session IV
Supplement to JANUARY 2013 American Journal of Obstetrics & Gynecology S255
