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Papers by Gaurav Bhatti

Journal of Perinatal Medicine

Objectives The heterogeneous nature of preeclampsia is a major obstacle to early screening and pr... more Objectives The heterogeneous nature of preeclampsia is a major obstacle to early screening and prevention, and a molecular taxonomy of disease is needed. We have previously identified four subclasses of preeclampsia based on first-trimester plasma proteomic profiles. Herein, we expanded this approach by using a more comprehensive panel of proteins profiled in longitudinal samples. Methods Proteomic data collected longitudinally from plasma samples of women who developed preeclampsia (n=109) and of controls (n=90) were available from our previous report on 1,125 proteins. Consensus clustering was performed to identify subgroups of patients with preeclampsia based on data from five gestational-age intervals by using select interval-specific features. Demographic, clinical, and proteomic differences among clusters were determined. Differentially abundant proteins were used to identify cluster-specific perturbed KEGG pathways. Results Four molecular clusters with different clinical phen...

Additional file 9: Table S3. Biological processes from DFLAT database associated with gestational... more Additional file 9: Table S3. Biological processes from DFLAT database associated with gestational age differential expression from midtrimester to term. Count: number of differentially expressed genes associated with the ontology. Size: total number of genes associated with the ontology that were tested; odds ratio of enrichment based on a Fisher's exact test; q: adjusted p-value

Additional file 8: Table S2. Genes differentially expressed with gestational age during midtrimes... more Additional file 8: Table S2. Genes differentially expressed with gestational age during midtrimester. Columns are the same as in Table S1, except that the comparison is between late (21.1–24.0 weeks) versus early (16.4–21.0 weeks) midtrimester gestation

Additional file 6: Figure S6. Correlation of expression changes with maternal obesity between stu... more Additional file 6: Figure S6. Correlation of expression changes with maternal obesity between studies. Each dot represents a unique annotated gene. The y axis represents the log2 fold change (obese/lean) obtained in the current study. The x-axis represents the log2 expression of 182 genes detected as present in the current study among those reported as differentially expressed with obesity by Edlow et al. [99]. R: Spearman's correlation coefficient

Additional file 3: Figure S3. Changes in the expression of RNA Seq single-cell signatures with ge... more Additional file 3: Figure S3. Changes in the expression of RNA Seq single-cell signatures with gestational age. For each single-cell signature, the expression the all specific genes (based on Tsang et al. [105]) was transformed into a Z-score and averaged in each AF sample (dots). A Robust Locally Weighted Regression and Smoothing Scatterplots (LOESS) model fit through the Z-scores as a function of gestational age is shown using lines. AF, amniotic fluid

Additional file 15: Table S9. MSigDB database canonical pathways associated with gestational-age ... more Additional file 15: Table S9. MSigDB database canonical pathways associated with gestational-age differential splicing but not with differential expression from midtrimester to term. Columns are as shown in the Table S3 legend

Additional file 13: Table S7. Genes differentially spliced with gestational age (term versus midt... more Additional file 13: Table S7. Genes differentially spliced with gestational age (term versus midtrimester). The table includes results for the single most-significant exon or exon junction based on splicing index analysis. The columns include the Affymetrix transcript cluster identifier (ID), gene symbol, gene name, probeset identifier, exon splicing index, corresponding p-value, adjusted p-value, name of the alternative splicing event type, and adjusted p-value based on the diffSplice algorithm

Description This is a collection of 24 data sets for which the phenotype is a disease with a corr... more Description This is a collection of 24 data sets for which the phenotype is a disease with a corresponding pathway in the KEGG database.This collection of datasets were used as gold standard in comparing gene set analysis methods by the PADOG package.

Journal of Perinatal Medicine, 2020

Background Normal development of the human placenta, referred to as villous tree maturation, enta... more Background Normal development of the human placenta, referred to as villous tree maturation, entails formation of the vasculosyncytial membranes. These structures develop by the approximation of syncytiotrophoblasts with the villous capillary endothelium and constitute the most efficient sites of gaseous exchange in the placenta. Defective maturation of the villous tree can lead to deficient vasculosyncytial membranes, implicated in the high incidence of hypoxic complications. Hypoxia, in turn, can stimulate production of erythropoietin, whereby increased fetal plasma or amniotic fluid concentrations of this hormone reflect fetal hypoxemia. The current study was undertaken to determine whether delayed villous maturation is associated with changes in amniotic fluid erythropoietin concentrations. Methods Placental histologic examination was performed using hematoxylin and eosin. Subsequent to histologic assessment of delayed villous maturation, the diagnosis was confirmed with CD-15 i...

American Journal of Obstetrics and Gynecology, 2021

BACKGROUND: The current approach to predict preeclampsia combines maternal risk factors and evide... more BACKGROUND: The current approach to predict preeclampsia combines maternal risk factors and evidence from biophysical markers (mean arterial pressure, Doppler velocimetry of the uterine arteries) and maternal blood proteins (placental growth factor, soluble vascular endothelial growth factor receptor-1, pregnancy-associated plasma protein A). Such models require the transformation of biomarker data into multiples of the mean values by using population-and site-specific models. Previous studies have focused on a narrow window in gestation and have not included the maternal blood concentration of soluble endoglin, an important antiangiogenic factor up-regulated in preeclampsia. OBJECTIVE: This study aimed (1) to develop models for the calculation of multiples of the mean values for mean arterial pressure and biochemical markers; (2) to build and assess the predictive models for preeclampsia based on maternal risk factors, the biophysical (mean arterial pressure) and biochemical (placental growth factor, soluble vascular endothelial growth factor receptor-1, and soluble endoglin) markers collected throughout pregnancy; and (3) to evaluate how prediction accuracy is affected by the presence of chronic hypertension and gestational age. STUDY DESIGN: This longitudinal case-cohort study included 1150 pregnant women: women without preeclampsia with (n¼49) and without chronic hypertension (n¼871) and those who developed preeclampsia (n¼166) or superimposed preeclampsia (n¼64). Mean arterial pressure and immunoassay-based maternal plasma placental growth factor, soluble vascular endothelial growth factor receptor-1, and soluble endoglin concentrations were available throughout pregnancy (median of 5 observations per patient). A prior-risk model for preeclampsia was established by using Poisson regression based on maternal characteristics and obstetrical history. Next, multiple regression was used to fit biophysical and biochemical marker data as a function of maternal characteristics by using data collected at 8 to 15 þ6 , 16 to 19 þ6 , 20 to 23 þ6 , 24 to 27 þ6 , 28 to 31 þ6 , and 32 to 36 þ6 week intervals, and observed values were converted into multiples of the mean values. Then, multivariable prediction models for preeclampsia were fit based on the biomarker multiples of the mean data and prior-risk estimates. Separate models were derived for overall, preterm, and term preeclampsia, which were evaluated by receiver operating characteristic curves and sensitivity at fixed false-positive rates. RESULTS: (1) The inclusion of soluble endoglin in prediction models for all preeclampsia, together with the prior-risk estimates, mean arterial pressure, placental growth factor, and soluble vascular endothelial growth factor receptor-1, increased the sensitivity (at a fixed false-positive rate of 10%) for early prediction of superimposed preeclampsia, with the largest increase (from 44% to 54%) noted at 20 to 23 þ6 weeks (McNemar test, P<.05); (2) combined evidence from prior-risk estimates and biomarkers predicted preterm preeclampsia with a sensitivity (false-positive rate, 10%) of 55%, 48%, 62%, 72%, and 84% at 8 to 15 þ6 , 16 to 19 þ6 , 20 to 23 þ6 , 24 to 27 þ6 , and 28 to 31 þ6 week intervals, respectively; (3) the sensitivity for term preeclampsia (false-positive rate, 10%) was 36%, 36%, 41%, 43%, 39%, and 51% at 8 to 15 þ6 , 16 to 19 þ6 , 20 to 23 þ6 , 24 to 27 þ6 , 28 to 31 þ6 , and 32 to 36 þ6 week intervals, respectively; (4) the detection rate for superimposed preeclampsia among women with chronic hypertension was similar to that in women without chronic hypertension, especially earlier in pregnancy, reaching at most 54% at 20 to 23 þ6 weeks (false-positive rate, 10%); and (5) prediction models performed comparably to the Fetal Medicine Foundation calculators when the same maternal risk factors and biomarkers (mean arterial pressure, placental growth factor, and soluble vascular endothelial growth factor receptor-1 multiples of the mean values) were used as input. CONCLUSION: We introduced prediction models for preeclampsia throughout pregnancy. These models can be useful to identify women at risk during the first trimester who could benefit from aspirin treatment or later in pregnancy to inform patient management. Relative to prediction performance at 8 to 15 þ6 weeks, there was a substantial improvement in the detection rate for preterm and term preeclampsia by using data collected after 20 and 32 weeks' gestation, respectively. The inclusion of plasma soluble endoglin improves the early prediction of superimposed preeclampsia, which may be valuable when Doppler velocimetry of the uterine arteries is not available.

Journal of Perinatal Medicine, 2020

ObjectiveThe aims of this study were to ascertain the frequency of disorders of villous maturatio... more ObjectiveThe aims of this study were to ascertain the frequency of disorders of villous maturation in fetal death and to also delineate other placental histopathologic lesions in fetal death.MethodsThis was a retrospective observational cohort study of fetal deaths occurring among women between January 2004 and January 2016 at Hutzel Women’s Hospital, Detroit, MI, USA. Cases comprised fetuses with death beyond 20 weeks’ gestation. Fetal deaths with congenital anomalies and multiple gestations were excluded. Controls included pregnant women without medical/obstetrical complications and delivered singleton, term (37–42 weeks) neonate with 5-min Apgar score ≥7 and birthweight between the 10thand 90thpercentiles.ResultsNinety-two percent (132/143) of placentas with fetal death showed placental histologic lesions. Fetal deaths were associated with (1) higher frequency of disorders of villous maturation [44.0% (64/143) vs. 1.0% (4/405), P < 0.0001, prevalence ratio, 44.6; delayed villo...

American Journal of Obstetrics and Gynecology, 2019

2 weeks of presentation and gestational age (GA) at delivery. Continuous variables were compared ... more 2 weeks of presentation and gestational age (GA) at delivery. Continuous variables were compared using the Kruskal-Wallis test, while categorical variables were compared using Chi-squared or Fisher's exact test as appropriate. The Wilcoxon test for difference in survival time was used to compare GA at delivery among the 4 CL groups with data stratified based on GA at presentation. RESULTS: 126 pregnancies met inclusion criteria. Baseline characteristics were similar among all four groups. Primary and secondary outcomes are reported in Table 1. The probability of delivery as a function of Dt is presented in Figure 1. There was a direct correlation between shorter CL and shorter Dt (p ¼ 0.003). Regardless of the CL at presentation, delivery within 2 weeks was uncommon (1 patient; 0.8%). CONCLUSION: As expected, the risk for sPTB in asymptomatic women with short cervix increases as the CL shortens, with CL 10mm associated with the highest risk. Nevertheless, regardless of the CL, delivery within 2 weeks is highly unlikely. Therefore, we suggest that the timing of administration of ACS in this population should be delayed until additional indications are present.

Journal of perinatal medicine, Jan 19, 2018

Objectives To investigate mechanisms of in utero death in normally formed fetuses by measuring am... more Objectives To investigate mechanisms of in utero death in normally formed fetuses by measuring amniotic fluid (AF) biomarkers for hypoxia (erythropoietin [EPO]), myocardial damage (cardiac troponin I [cTnI]) and brain injury (glial fibrillary acidic protein [GFAP]), correlated with risk factors for fetal death and placental histopathology. Methods This retrospective, observational cohort study included intrauterine deaths with transabdominal amniocentesis prior to induction of labor. Women with a normal pregnancy and an indicated amniocentesis at term were randomly selected as controls. AF was assayed for EPO, cTnI and GFAP using commercial immunoassays. Placental histopathology was reviewed, and CD15-immunohistochemistry was used. Analyte concentrations >90th centile for controls were considered "raised". Raised AF EPO, AF cTnI and AF GFAP concentrations were considered evidence of hypoxia, myocardial and brain injury, respectively. Results There were 60 cases and 60 c...

Frontiers in immunology, 2018

Preeclampsia is a disease of the mother, fetus, and placenta, and the gaps in our understanding o... more Preeclampsia is a disease of the mother, fetus, and placenta, and the gaps in our understanding of the complex interactions among their respective disease pathways preclude successful treatment and prevention. The placenta has a key role in the pathogenesis of the terminal pathway characterized by exaggerated maternal systemic inflammation, generalized endothelial damage, hypertension, and proteinuria. This of preeclampsia may be triggered by distinct underlying mechanisms that occur at early stages of pregnancy and induce different phenotypes. To gain insights into these molecular pathways, we employed a systems biology approach and integrated different "omics," clinical, placental, and functional data from patients with distinct phenotypes of preeclampsia. First trimester maternal blood proteomics uncovered an altered abundance of proteins of the renin-angiotensin and immune systems, complement, and coagulation cascades in patients with term or preterm preeclampsia. More...

Journal of perinatal medicine, Jan 26, 2018

To determine whether a soft cervix identified by shear-wave elastography between 18 and 24 weeks ... more To determine whether a soft cervix identified by shear-wave elastography between 18 and 24 weeks of gestation is associated with increased frequency of spontaneous preterm delivery (sPTD). This prospective cohort study included 628 consecutive women with a singleton pregnancy. Cervical length (mm) and softness [shear-wave speed: (SWS) meters per second (m/s)] of the internal cervical os were measured at 18-24 weeks of gestation. Frequency of sPTD <37 (sPTD<37) and <34 (sPTD<34) weeks of gestation was compared among women with and without a short (≤25 mm) and/or a soft cervix (SWS <25th percentile). There were 31/628 (4.9%) sPTD<37 and 12/628 (1.9%) sPTD<34 deliveries. The combination of a soft and a short cervix increased the risk of sPTD<37 by 18-fold [relative risk (RR) 18.0 (95% confidence interval [CI], 7.7-43.9); P<0.0001] and the risk of sPTD<34 by 120-fold [RR 120.0 (95% CI 12.3-1009.9); P<0.0001] compared to women with normal cervical length....

Journal of perinatal medicine, Jan 25, 2018

Objective To determine the frequency and type of histopathologic lesions in placentas delivered b... more Objective To determine the frequency and type of histopathologic lesions in placentas delivered by women with a normal pregnancy outcome. Methods This retrospective cohort study included placental samples from 944 women with a singleton gestation who delivered at term without obstetrical complications. Placental lesions were classified into the following four categories as defined by the Society for Pediatric Pathology and by our unit: (1) acute placental inflammation, (2) chronic placental inflammation, (3) maternal vascular malperfusion and (4) fetal vascular malperfusion. Results (1) Seventy-eight percent of the placentas had lesions consistent with inflammatory or vascular lesions; (2) acute inflammatory lesions were the most prevalent, observed in 42.3% of the placentas, but only 1.0% of the lesions were severe; (3) acute inflammatory lesions were more common in the placentas of women with labor than in those without labor; (4) chronic inflammatory lesions of the placenta were ...

The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians, 2018

The objective of this study was to determine the profiles of maternal plasma soluble adhesion mol... more The objective of this study was to determine the profiles of maternal plasma soluble adhesion molecules in patients with preeclampsia, small-for-gestational-age (SGA) fetuses, acute pyelonephritis, preterm labor with intact membranes (PTL), preterm prelabor rupture of the membranes (preterm PROM), and fetal death. A cross-sectional study was conducted to determine maternal plasma concentrations of sE-selectin, sL-selectin, and sP-selectin as well as sICAM-1, sVCAM-1, and sPECAM-1 in patients with (1) an uncomplicated pregnancy (control, n = 100); (2) preeclampsia (n = 94); (3) SGA fetuses (in women without preeclampsia/hypertension, n = 45); (4) acute pyelonephritis (n = 25); (5) PTL (n = 53); (6) preterm PROM (n = 24); and (7) fetal death (n = 34). Concentrations of soluble adhesion molecules and inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-8) were determined with sensitive and specific enzyme-linked immunoassays. In comparison to women with a normal p...

Among patients presenting with preterm labor and intact membranes, those with intra-amniotic infl... more Among patients presenting with preterm labor and intact membranes, those with intra-amniotic inflammation have worse obstetrical and neonatal outcomes. The diagnosis of intra-amniotic inflammation can be easily made by detecting an elevated concentration of the cytokine interleukin (IL)-6 or the enzyme neutrophil collagenase, also known as matrix metalloproteinase (MMP)-8. The diagnostic performances of MMP-8 and IL-6 enzyme-linked immunosorbent assay (ELISA) tests are similar. Recently, a rapid test has become available for point-of-care determination of either MMP-8 or IL-6. The objectives of this study were to compare the diagnostic indices and predictive values between the rapid MMP-8 and IL-6 tests for the identification of intra-amniotic inflammation. We performed a retrospective cohort study including 124 women with singleton pregnancies who presented with symptoms of preterm labor and underwent transabdominal amniocentesis for the evaluation of MIAC. MIAC was defined accordi...

Journal of Perinatal Medicine, 2015

Recent studies indicate that clinical chorioamnionitis is a heterogeneous condition and only appr... more Recent studies indicate that clinical chorioamnionitis is a heterogeneous condition and only approximately one-half of the patients have bacteria in the amniotic cavity, which is often associated with intra-amniotic inflammation. The objective of this study is to characterize the nature of the inflammatory response within the amniotic cavity in patients with clinical chorioamnionitis at term according to the presence or absence of 1) bacteria in the amniotic cavity and 2) intra-amniotic inflammation.A retrospective cross-sectional case-control study was conducted to examine cytokine and chemokine concentrations in the amniotic fluid (AF). Cases consisted of women with clinical chorioamnionitis at term (n=45). Controls were women with uncomplicated pregnancies at term who did not have intra-amniotic inflammation and were in labor (n=24). Women with clinical chorioamnionitis were classified according to the results of AF cultures, broad-range polymerase chain reaction coupled with ele...

PLOS ONE, 2015

Background Neurocognitive impairment among children born preterm may arise from complex interacti... more Background Neurocognitive impairment among children born preterm may arise from complex interactions between genes and the intra-uterine environment. Objectives (1) To characterize the transcriptomic profiles of chorioamniotic membranes in preterm neonates with and without neurocognitive impairment via microarrays and (2) to determine if neonates with neurocognitive impairment can be identified at birth. Materials/Methods A retrospective case-control study was conducted to examine the chorioamniotic transcriptome of gestational-age matched very preterm neonates with and without neurocognitive impairment at 18-24 months' corrected-age defined by a Bayley-III Cognitive Composite Score <80 (n = 14 each). Pathway analysis with down-weighting of overlapping genes (PADOG) was performed to identify KEGG pathways relevant to the phenotype. Select differentially expressed genes were profiled using qRT-PCR and a multi-gene disease prediction model was developed using linear discriminant analysis. The model's predictive performance was tested on a new set of cases and controls (n = 19 each).

Journal of Perinatal Medicine

Journal of Perinatal Medicine, 2020

American Journal of Obstetrics and Gynecology, 2021

Journal of Perinatal Medicine, 2020

American Journal of Obstetrics and Gynecology, 2019

Journal of perinatal medicine, Jan 19, 2018

Frontiers in immunology, 2018

Journal of perinatal medicine, Jan 26, 2018

Journal of perinatal medicine, Jan 25, 2018

Journal of Perinatal Medicine, 2015

PLOS ONE, 2015