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PREBIC Publications

Preterm Birth Genome Project (PGP) Validation of resources for preterm birth genome-wide studies.

Pennell CE, Vadillo-Ortega F, Olson DM, Ha EH, Williams S, Frayling TM, Dolan S, Katz M, Merialdi M; Preterm Birth Genome Project(PGP) Consortium, Menon R.

J Perinat Med. 2013 Jan;41(1):45-9.


We determined a series of quality control (QC) analyses to assess the usability of DNA collected and processed from different countries utilizing different DNA extraction techniques prior to genome-wide association studies (GWAS). The quality of DNA collected utilizing four different DNA extraction techniques and the impact of shipping DNA at different temperatures on array performance were evaluated. Fifteen maternal-fetal pairs were used from four countries. DNA was extracted using four approaches: whole blood, blood spots with whole genome amplification (WGA), saliva and buccal swab. Samples were sent to a genotyping facility, either on dry ice or at room temperature and genotyped using Affymetrix SNP array 6.0. QC measured included extraction techniques, effect of shipping temperatures, accuracy and Mendelian concordance. Significantly fewer (50 % ) single nucleotide polymorphisms (SNPs) passed QC metrics for buccal swab DNA (P < 0.0001) due to missing genotype data (P < 0.0001). Whole blood or saliva DNA had the highest call rates (99.2 0.4 % and 99.3 0.2 % , respectively) and Mendelian concordance. Shipment temperature had no effect. DNA from blood or saliva had the highest call rate accuracy, and buccal swabs had the lowest. DNA extracted from blood, saliva and blood spots were found suitable for GWAS in our study.

An integrated systems biology approach to the study of preterm birth using "-omic" technology- a guideline for research.

Gracie S, Pennell C, Ekman-Ordeberg G, Lye S, McManaman J, Williams S, Palmer L, Kelley M, Menon R, Gravett M; PREBIC "-Omics" Research Group.

BMC Pregnancy Childbirth. 20121 Oct; 11(71)


Preterm birth is the leading cause of neonatal mortality and perinatal morbidity. The etiology of preterm is multi-factorial and still unclear. As evidence increases for a genetic contribution to PTB, so does the need to explore genomics, transcriptomics, proteomics and metabolomics in its study. This review suggests research guidelines for the conduct of high throughput systems biology investigations into preterm birth with the expectation that this will facilitate the sharing of samples and data internationally through consortia, generating the power needed to study preterm birth using integrated "-omics" technologies. The issues to be addressed include: (1) integrated "-omics" approaches, (2) phenotyping, (3) sample collection, (4) data management-integrative databases, (5) international consortia and (6) translational feasibility. This manuscript is the product of discussions initiated by the "-Omics" Working Group at the Preterm Birth International Collaborative Meeting held at the World Health Organization, Geneva, Switzerland in April 2009.

A standardized template for clinical studies in preterm birth.

Myatt L, Eschenbach DA, Lye SJ, Mesiano S, Murtha AP, Williams SM, Pennell CE; International Preterm Birth Collaborative Pathways and Systems Biology Working Groups. Gravett M, Jacobsson B, Sengpiel V, Uldbjerg N, Ang W, Ekman-Ordeberg G, Olson D, Helmig RB, Becher N, Chudzik A, Drobek CO.

Reprod Sci. 2012 May;19(5):474-82.  


 Preterm birth is a major societal and economic problem accounting for 80 to 90% of neonatal morbidity and mortality worldwide. It is recognized as a complex multifactorial condition comprising several distinct clinical phenotypes with different underlying etiologies. As animal models are expensive and fail to mimic the biology of spontaneous preterm birth in humans, understanding the pathophysiology requires detailed clinical studies. Meta-analyses and clinical translation of data, however, are limited by heterogeneity of study design and size, publication and reporting biases, definition of patient groups, and a lack of standard universal definitions. This article provides a harmonized open-source template for designing clinical studies addressing preterm birth.

METHODS: Recommendations are made for clinical definitions, choice and assignment to preterm birth phenotypes, selection of enriched populations and control pregnancies, and potential confounding factors. In addition, recommendations are made for study design, sample size and power calculations, the minimal data sets needed for any study of preterm birth, and the optimal data set of an ideal study.

RESULTS: Recommended patient phenotypes are infection, uterine overdistension, hemorrhage, stress (either maternal or fetal), and idiopathic. Confounding factors include medical conditions, obesity, antenatal glucocorticoids, multifetal pregnancies, and fetal sex. Guidelines regarding study design, sample size, and clinical data acquisition are provided to serve as a universal template for preterm birth studies.

CONCLUSIONS: Adoption of a harmonized template will allow generation of protocols and studies with a basic degree of compatibility and will allow data to be compared, and samples and data sets to be combined for meaningful meta-analyses. 

Genetic epidemiologic studies of preterm birth: guidelines for research.

Pennell CE, Jacobsson B, Williams SM, Buus RM, Muglia LJ, Dolan SM, Morken NH, Ozcelik H, Lye SJ; PREBIC Genetics Working Group, Relton C.

Am J Obstet Gynecol. 2007 Feb;196(2):107-18.


Over the last decade, it has become increasingly apparent that the cause of preterm birth is multifactorial, involving both genetic and environmental factors. With the development of new technologies capable of probing the genome, exciting possibilities now present themselves to gain new insight into the mechanisms leading to preterm birth. This review aims to develop research guidelines for the conduct of genetic epidemiology studies of preterm birth with the expectation that this will ultimately facilitate the comparison of data sets between study cohorts, both nationally and internationally. Specifically, the 4 areas addressed in this review includes: (1) phenotypic criteria, (2) study design, (3) considerations in the selection of control populations, and (4) candidate gene selection. This article is the product of discussions initiated by the authors at the 3rd International Workshop on Biomarkers and Preterm Birth held at the University of California, Los Angeles, Los Angeles, CA, in March 2005.

Biomarkers of spontaneous preterm birth: an overview of the literature in the last four decades.

Menon R, Torloni MR, Voltolini C, Torricelli M, Merialdi M, Betrán AP, Widmer M, Allen T, Davydova I, Khodjaeva Z, Thorsen P, Kacerovsky M, Tambor V, Massinen T, Nace J, Arora C.

Reprod Sci. 2011 Nov; (18)11:1046-70


Understanding spontaneous preterm birth (PTB < 37 weeks) is difficult due to heterogeneities associated with multitudes of risk factors and pathophysiological pathways. Several biomarkers are routinely used clinically for predicting preterm labor; however, these factors are either nonspecific or detected too late.

OBJECTIVE: Systematic review of literature on PTB biomarkers in the last 40 years to map out the existing knowledge and gaps in understanding PTB biomarkers. Search strategies: Five electronic databases were searched for human studies on PTB biomarkers published in any language between 1965 and 2008. Selection criteria: The phenotype of interest for final data extraction was exclusively spontaneous PTB with no rupture of membranes. Data extraction included (a) general characteristics of the study (clinical setting, period, and study design), (b) study/participant characteristics (inclusion and exclusion criteria, race/ethnicity, number of participants, gestational age at sampling, (c) characteristics of the biomarker (type, rationale for its selection, type of biological sample, and assay used, and (d) concentration of biomarkers in cases and controls. Data collection and analysis: The search yielded 7255 citations and data were extracted from 217 articles which met our inclusion and exclusion criteria.

MAIN RESULTS: A total of 116 different biomarkers were reported and these were assayed 578 times in the 217 included studies. Over two thirds of the 217 studies were performed on North American or European populations. No reliable biomarkers emerged as a risk predictor of PTB.

CONCLUSIONS: Identifying similar studies on biomarkers for the prediction of PTB was a very challenging task due heterogeneities in study design, sampling issues (types, timing and processing), assay methods, and analyses. Major areas of concern identified in this review include poor phenotype definition, nonideal study designs and poor rationale for biomarker selection and assays and population stratification issues.

Maternal BMI and preterm birth: a systematic review of the literature with meta-analysis.

Torloni MR, Betrán AP, Daher S, Widmer M, Dolan SM, Menon R, Bergel E, Allen T, Merialdi M.

 J Matern Fetal Neonatal Med. 2009 Nov;22(11):957-70.  


To examine the association between high prepregnancy maternal body mass index (BMI) and the risk of preterm birth (PTB).

METHODS: A systematic review of the literature. We included cohorts and case-control studies published since 1968 that examined the association between BMI and PTB of all types, spontaneous (s), elective and with ruptured membranes (PPROM) in three gestational age categories: general ( 40) have an even higher risk for very PTB (AOR = 2.27, 95%CI: 1.76-2.94). High BMI does not modify the risk for PPROM and increases the risk for elective PTB.

CONCLUSIONS: High maternal BMI may have different effects on different types of PTB. 

The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity.

Bull World Health Organ. 2010 Jan;88(1):31-8.


To analyse preterm birth rates worldwide to assess the incidence of this public health problem, map the regional distribution of preterm births and gain insight into existing assessment strategies.

METHODS: Data on preterm birth rates worldwide were extracted during a previous systematic review of published and unpublished data on maternal mortality and morbidity reported between 1997 and 2002. Those data were supplemented through a complementary search covering the period 2003-2007. Region-specific multiple regression models were used to estimate the preterm birth rates for countries with no data.

FINDINGS: We estimated that in 2005, 12.9 million births, or 9.6% of all births worldwide, were preterm. Approximately 11 million (85%) of these preterm births were concentrated in Africa and Asia, while about 0.5 million occurred in each of Europe and North America (excluding Mexico) and 0.9 million in Latin America and the Caribbean. The highest rates of preterm birth were in Africa and North America (11.9% and 10.6% of all births, respectively), and the lowest were in Europe (6.2%).

CONCLUSION: Preterm birth is an important perinatal health problem across the globe. Developing countries, especially those in Africa and southern Asia, incur the highest burden in terms of absolute numbers, although a high rate is also observed in North America. A better understanding of the causes of preterm birth and improved estimates of the incidence of preterm birth at the country level are needed to improve access to effective obstetric and neonatal care. 

Synopsis of preterm birth genetic association studies: the preterm birth genetics knowledge base (PTBGene).

Dolan SM, Hollegaard MV, Merialdi M, Betran AP, Allen T, Abelow C, Nace J, Lin BK, Khoury MJ, Ioannidis JP, Bagade S, Zheng X, Dubin RA, Bertram L, Velez Edwards DR, Menon R.

Public Health Genomics. 2010;13(7-8):514-23.


Our goal wasto produce a field synopsis of genetic associations with preterm birth and to set up a publicly available online database summarizing the data.

METHODS: We performed a systematic review and meta-analyses to identify genetic associations with preterm birth. We have set up a publicly available online database of genetic association data on preterm birth called PTBGene and report on a structured synopsis there of as of December 1, 2008.

RESULTS: Data on 189 polymorphisms in 84 genes have been included and 36 meta-analyses have been performed. Five gene variants (4 in maternal DNA, one in newborn DNA) have shown nominally significant associations, but all have weak epidemiological credibility.

CONCLUSION: After publishing this field synopsis, the PTBGene database will be regularly updated to keep track of the evolving evidence base of genetic factors in preterm birth with the goal of promoting knowledge sharing and multicenter collaboration among preterm birth research groups. 

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