Integrated Proteomics Pipeline Yields Novel Biomarkers for Predicting Preeclampsia

Abstract

P reeclampsia continues to be a major cause of maternal mortality, resulting in >50 000 maternal deaths worldwide each year, and is the leading cause of iatrogenic preterm birth. 1To prevent preeclampsia, women at high risk of the condition need to be identified early in pregnancy. Although there is significant interest in the prediction of preeclampsia using combinations of clinical risk factors, biophysical measurements, and biochemical tests, to date no screening test has achieved the requisite sensitivity and specificity to be useful and costeffective in a clinical setting. 2-5Prediction of preeclampsia in healthy nulliparous women is particularly challenging, despite the greatest proportion of cases occurring in this population. The best known combination of markers tested in a low-risk nulliparous population had a sensitivity of 46% for a specificity of 80%, equating to a PPV of around 15.5%. 4 Other reports of better prediction have studied general obstetric populations that include high-risk women 3 or have used a nested case-control design with controls comprising uncomplicated pregnancies with the consequent overestimation of predictive performance. 6A screening test is likely to require multiple biomarkers that reflect different aspects of the complex pathological processes that culminate in preeclampsia.7 Several proteins indicative of abnormal placentation, such as placental growth factor (PlGF) and pregnancy-associated plasma protein A, have been demonstrated to be predictive of preeclampsia, especially preterm disease.8 Novel plasma biomarkers, representative of placentation or the maternal vascular and inflammatory response in preeclampsia, may be discovered using an unbiased proteomic approach. Unfortunately, to date, most proteomic research, which has aimed to discover biomarkers, has failed to incorporate adequate biomarker validation studies in independent sample sets. These are necessary steps in the translation of potential biomarkers into Abstract-Preeclampsia, a hypertensive pregnancy complication, is largely unpredictable in healthy nulliparous pregnant women. Accurate preeclampsia prediction in this population would transform antenatal care. To identify novel protein markers relevant to the prediction of preeclampsia, a 3-step mass spectrometric work flow was applied. On selection of candidate biomarkers, mostly from an unbiased discovery experiment (19 women), targeted quantitation was used to verify and validate candidate biomarkers in 2 independent cohorts from the SCOPE (SCreening fOr Pregnancy Endpoints) study. Candidate proteins were measured in plasma specimens collected at 19 to 21 weeks' gestation from 100 women who later developed preeclampsia and 200 women without preeclampsia recruited from Australia and New Zealand. Protein levels (n=25), age, and blood pressure were then analyzed using logistic regression to identify multimarker models (maximum 6 markers) that met predefined criteria: sensitivity ≥50% at 20% positive predictive value. These 44 algorithms were then tested i...

Transformative Impact of Proteomics on Cardiovascular Health and Disease

“…With traditional biomarkers not generally fulfilling clinical needs, the condition has been the subject of a number of proteomic studies, the results of which are inconsistent and only marginally overlapping. [121][122][123] These shortcomings, however, are not attributable to proteomic techniques but to the suboptimal design of studies, limited sample size, substandard sample collection, and lack of replication in independent cohorts. Thus, to fully realize the potential of proteomic approaches to improve patient care, unmet expectations can be overcome by adhering to rigorous standards that apply to other types of biomarker studies.…”

Towards biomarker-based tests that can facilitate decisions about prevention and management of preeclampsia in low-resource settings

“…Another 10 blood experimental biomarkers (AT-1AA [31], calcyclin, copeptin [34], galectin-1 [36], Gas6 [37], HIF-1aOH [38], IGFALS [41], mammalian HtrA3 [45], NT-proBNP [47], and PTX3 [49]), and four urine ones (C5b-9 [33], nephrin [46], iodine [42], and prolactin [52]) had limited clinical evaluation information, which impeded the evaluation of their performance for the diagnosis of PE. No clinical data were found for the remaining nine blood markers, which consisted of adipsin, α enolase, ADMA, Ba, 2,3-BPGM, Fetal DNA, marinobufagenin, plasma UA [51], and soluble CD117.…”

“…Such a study would ultimately result in consensus regarding a screening and diagnostic algorithm. At the end of 2012, IMPROvED (Improved Pregnancy Outcomes via Early Detection), a consortium comprising of European enterprises and academic institutions launched a Phase 2a prognostic multicenter hospital-based clinical study [69] using biomarkers previously identified through metabolomic and proteomic platforms for PE prediction [41,70]. This ongoing study will allow assessment of the predictive performance of the proteomic and metabolomics tests throughout pregnancy, and offers mothers accurate risk assessment for PE, thus impacting the provision of ANC care in high-resource countries.…”

Utilizing proteomics to understand and define hypertension: where are we and where do we go?

“…Of these the study by Myers et al [84] who employed an integrated approach of unbiased screening, targeted quantitation and supplementation of models with known pathogenetic factors to describe novel biomarkers for prediction of preeclampsia. The most promising models centered on insulin-like growth factor acid labile subunit.…”