Publications by authors named "Miran A Jaffa"

26 Publications

  • Page 1 of 1

Genomic and Proteomic Study of the Inflammatory Pathway in Patients With Atrial Fibrillation and Cardiometabolic Syndrome.

Front Cardiovasc Med 2020 2;7:613271. Epub 2020 Dec 2.

Department of Internal Medicine, Cardiology Division, American University of Beirut Faculty of Medicine and Medical Center, Beirut, Lebanon.

Atrial fibrillation (AF) and cardiometabolic syndrome (CMS) have been linked to inflammation and fibrosis. However, it is still unknown which inflammatory cytokines contribute to the pathogenesis of AF. Furthermore, cardiometabolic syndrome (CMS) risk factors such as obesity, hypertension, insulin resistance/glucose intolerance are also associated with inflammation and increased level of cytokines and adipokines. We hypothesized that the inflammatory immune response is exacerbated in patients with both AF and CMS compared to either AF or CMS alone. We investigated inflammatory cytokines and fibrotic markers as well as cytokine genetic profiles in patients with lone AF and CMS. CMS, lone AF patients, patients with both lone AF and CMS, and control patients were recruited. Genetic polymorphisms in inflammatory and fibrotic markers were assessed. Serum levels of connective tissue growth factor (CTGF) were tested along with other inflammatory markers including platelet-to-lymphocyte ratio (PLR), monocyte-to-HDL ratio (MHR) in three groups of AF+CMS, AF, and CMS patients. There was a trend in the CTGF levels for statistical significance between the AF and AF+CMS group ( = 0.084). Genotyping showed high percentages of patients in all groups with high secretor genotypes of Interleukin-6 (IL-6) ( = 0.037). Genotyping of IFN-γ and IL-10 at high level showed an increase in expression in the AF + CMS group compared to AF and CMS alone suggesting an imbalance between the inflammatory and anti-inflammatory cytokines which is exacerbated by AF. Serum cytokine inflammatory cytokine levels showed that IL-4, IL-5, IL-10, IL-17F, and IL-22 were significant between the AF, AF+CMS, and CMS patients. Combination of both CMS and AF may be associated with a higher degree of inflammation than what is seen in either CMS or AF alone. Thus, the identification of a biomarker capable of identifying metabolic syndrome associated with disease will help in identification of a therapeutic target in treating this devastating disease.
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http://dx.doi.org/10.3389/fcvm.2020.613271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738559PMC
December 2020

Vascular Cells Proteome Associated with Bradykinin and Leptin Inflammation and Oxidative Stress Signals.

Antioxidants (Basel) 2020 Dec 9;9(12). Epub 2020 Dec 9.

Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut 11-0236, Lebanon.

Among the primary contributors to cardiovascular diseases are inflammation and oxidative imbalance within the vessel walls as well as the fibrosis of rat aortic smooth muscle cell (RASMC). Bradykinin (BK) and leptin are inflammatory modulators that are linked to vascular injury. In this study, we employed tandem LC-MS/MS to identify protein signatures that encompass protein abundance in RASMC treated with BK or leptin followed by systems biology analyses to gain insight into the biological pathways and processes linked to vascular remodeling. In the study, 1837 proteins were identified in control untreated RASMC. BK altered the expression of 72 (4%) and 120 (6.5%) proteins, whereas leptin altered the expression of 189 (10.2%) and 127 (6.5%) proteins after 24 and 48 h, respectively, compared to control RASMC. BK increased the protein abundance of leptin receptor, transforming growth factor-β. On the other hand, leptin increased the protein abundance of plasminogen activator inhibitor 1 but decreased the protein abundance of cofilin. BK and leptin induced the expression of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) and pathway analysis revealed the activation of mitogen-activated protein kinases (MAPKs) and AKT pathways. The proteome profile in response to BK and leptin revealed mechanistic interplay of multiple processes that modulate inflammation and oxidative stress signals in the vasculature.
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http://dx.doi.org/10.3390/antiox9121251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764689PMC
December 2020

Barriers to the use of dental services by children in Lebanon and association with parental perception of oral health care.

East Mediterr Health J 2020 Nov 11;26(11):1420-1424. Epub 2020 Nov 11.

Division of Orthodontics and Dentofacial Orthopedics, Department of Otorhinolaryngology, Head and Neck Surgery, American University of Beirut Medical Center, Beirut, Lebanon.

Background: Oral health is important to general health but use of dental services varies considerably, particularly for children.

Aims: We aimed to determine factors associated with parents' use of dental services for their children in Lebanon, and their perception of dental care relative to medical care.

Methods: A convenience sample of public and private schools in Beirut was selected between January and May 2013. Parents of children in grades 2-6 (aged 7-12 years) were invited to complete a questionnaire covering socioeconomic characteristics and use of dental services. Logistic regression analysis was used to assess the relationship between use of dental services, and parents' socioeconomic characteristics and awareness and perceptions of dental services.

Results: The parents of 316 children returned the questionnaire. Most children (72.8%) had been taken to the dentist in the past year, mainly for emergency care. Most parents (78.2%) considered dental care as important as or more important than medical care, and 89.9% were willing to contribute to dental insurance. Use of dental services was significantly associated with: older age of the parent (odds ratio, OR = 1.04; 95% confidence interval, CI: 1.02-1.06); awareness of dental care centres offering affordable treatment (OR = 3.18; 95% CI: 1.52-6.68); and children being in private schools (OR = 2.00, 95% CI: 1.08-3.95). It was negatively associated with > 4 children in the family compared with 1 child (OR = 0.18; 95% CI: 0.04-0.81).

Conclusion: Barriers to dental care for children were mostly related to economic factors.
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http://dx.doi.org/10.26719/emhj.20.079DOI Listing
November 2020

Longitudinal Plasma Kallikrein Levels and Their Association With the Risk of Cardiovascular Disease Outcomes in Type 1 Diabetes in DCCT/EDIC.

Diabetes 2020 11 21;69(11):2440-2445. Epub 2020 Aug 21.

Department of Medicine, Medical University of South Carolina, Charleston, SC

We determined the relationship between plasma kallikrein and cardiovascular disease (CVD) outcomes as well as major adverse cardiovascular events (MACE) in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) cohort of type 1 diabetes (T1D). Plasma kallikrein levels were measured longitudinally in 693 subjects at DCCT baseline (1983-1989), midpoint (1988-1991), and end (1993) and at EDIC years 4-6 (1997-1999), 8-10 (2001-2003), and 11-13 (2004-2006). Cox proportional hazards regression models assessed the association between plasma kallikrein levels and the risk of CVD. In unadjusted models, higher plasma kallikrein levels were associated with higher risk of any CVD during DCCT/EDIC (hazard ratio [HR] = 1.16 per 20 nmol/L higher levels of plasma kallikrein; = 0.0177) as well as over the EDIC-only period (HR = 1.22; = 0.0024). The association between plasma kallikrein levels and the risk of any CVD remained significant during the EDIC follow-up after adjustment for age and mean HbA (HR = 1.20; = 0.0082) and in the fully adjusted model for other CVD risk factors (HR = 1.17; = 0.0330). For MACE, higher plasma kallikrein levels were associated with higher risk in the unadjusted (HR = 1.25; = 0.0145), minimally adjusted (HR = 1.23; = 0.0417, and fully adjusted (HR = 1.27; = 0.0328) models for EDIC only. These novel findings indicate that plasma kallikrein level associates with the risk of any CVD and MACE in T1D individuals.
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http://dx.doi.org/10.2337/db20-0427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576572PMC
November 2020

Thymoquinone induces apoptosis and DNA damage in 5-Fluorouracil-resistant colorectal cancer stem/progenitor cells.

Oncotarget 2020 Aug 4;11(31):2959-2972. Epub 2020 Aug 4.

Department of Biology, American University of Beirut, Lebanon.

The high recurrence rates of colorectal cancer have been associated with a small population of cancer stem cells (CSCs) that are resistant to the standard chemotherapeutic drug, 5-fluorouracil (5FU). Thymoquinone (TQ) has shown promising antitumor properties on numerous cancer systems both and ; however, its effect on colorectal CSCs is poorly established. Here, we investigated TQ's potential to target CSCs in a three-dimensional (3D) sphere-formation assay enriched for a population of colorectal cancer stem/progenitor cells. Our results showed a significant decrease in self-renewal potential of CSC populations enriched from 5FU-sensitive and resistant HCT116 cells at 10-fold lower concentrations when compared to 2D monolayers. TQ decreased the expression levels of colorectal stem cell markers CD44 and Epithelial Cell Adhesion Molecule EpCAM and proliferation marker Ki67 in colonospheres derived from both cell lines and reduced cellular migration and invasion. Further investigation revealed that TQ treatment led to increased TUNEL positivity and a dramatic increase in the amount of the DNA damage marker gamma H2AX particularly in 5FU-resistant colonospheres, suggesting that the diminished sphere forming ability in TQ-treated colonospheres is due to induction of DNA damage and apoptotic cell death. The intraperitoneal injection of TQ in mice inhibited tumor growth of spheres derived from 5FU-sensitive and 5FU-resistant HCT116 cells. Furthermore, TQ induced apoptosis and inhibited NF-κB and MEK signaling in mouse tumors. Altogether, our findings document TQ's effect on colorectal cancer stem-like cells and provide insights into its underlying mechanism of action.
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http://dx.doi.org/10.18632/oncotarget.27426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415406PMC
August 2020

Modulation of proteomic and inflammatory signals by Bradykinin in podocytes.

J Adv Res 2020 Jul 28;24:409-422. Epub 2020 May 28.

Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Lebanon.

Podocyte damage is one of the hallmarks of diabetic nephropathy leading to proteinuria and kidney damage. The underlying mechanisms of podocyte injury are not well defined. Bradykinin (BK) was shown to contribute to diabetic kidney disease. Here, we evaluated the temporal changes in proteome profile and inflammatory signals of podocytes in response to BK (10M). Protein profile was evaluated by liquid chromatography mass Spectrometry (LC-MS/MS) analysis. Proteome profile analysis of podocytes treated with BK (10M) for 3 and 6 h, revealed 61 proteins that were differentially altered compared to unstimulated control podocytes. Pathway enrichment analysis suggested inhibition of cell death pathways, engagement of cytoskeletal elements and activation of inflammatory pathways. One of the inflammatory proteins that was identified to be induced by BK treatment is Prostaglandin (PG) H Synthase-2 (Cyclooxygenase-2, COX-2). In addition, BK significantly induced the production and release of PGE and this effect was inhibited by both COX-2 and MEK Kinase inhibitors, demonstrating that the production of PGE by BK is mediated via COX-2 and MAPK-dependent mechanisms. These findings provide a global understanding of the effector modulated proteome in response to BK and also reveal BK as an important modulator of inflammation and a potential player in podocyte injury.
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http://dx.doi.org/10.1016/j.jare.2020.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270529PMC
July 2020

Knowledge and attitudes towards E-cigarette use in Lebanon and their associated factors.

BMC Public Health 2020 Feb 28;20(1):278. Epub 2020 Feb 28.

Epidemiology and Population Health Department, Faculty of Health Sciences, American University of Beirut, P.O.Box 11-0236 Riad El-Solh, Beirut, 1107 2020, Lebanon.

Background: Despite the misconceptions regarding E-cigarettes (ECs), only a few studies have been conducted in the Middle East that focused on this topic. This study assesses the knowledge of and attitudes towards ECs in Lebanon, determines how these two measures are associated, and identifies the variables that explain each of these measures.

Methods: A cross sectional study was conducted on a convenience sample of Lebanese pedestrians aged between 18 and 64 inclusive. A structured self-administered questionnaire comprising of knowledge and attitude scales, and questions on demographical, health and smoking characteristics was used.

Results: Scores for attitudes and knowledge of ECs were summed and dichotomized using a 75% cutoff, above which the participant was considered to have a positive attitude and good knowledge. Among the 352 participants (56.6% males, 43.3% females, mean age 30.3, 46.2% smokers), 63.3% exhibited a lower level of EC knowledge. More than 50% erroneously thought that ECs are not associated with lung and bladder cancer or impair lung and heart function. 65% falsely thought that it is harmless and not addictive. As for attitude, 43.3, 53.9, and 44.3% thought that it is socially acceptable, helps in smoking cessation, and is a good replacement for cigarettes and an enjoyable recreational device respectively. Our results revealed an inverse correlation between attitude and knowledge scores (Spearman's correlation = -.30, p < .001). Predictors of knowledge included health-related occupation (p = .010), regular exercise (p = .016), healthy diet (p = .026), EC use (p = .026), perception that ECs are not harmful (p = .001), and help in smoking cessation (p = .017). Predictors of attitude included EC use (p = .008), sex (p = .010), and knowledge that most ECs are addictive (p = .006), harmful (p = .014), and impair heart and lung function (p = .047).

Conclusions: Our study revealed a gap in EC knowledge, especially among participants who displayed a positive attitude towards ECs. Hence, measures should be undertaken to regulate its use by instituting more stringent laws and holding nationwide awareness campaigns.
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http://dx.doi.org/10.1186/s12889-020-8381-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049178PMC
February 2020

A Likelihood Based Approach for Joint Modeling of Longitudinal Trajectories and Informative Censoring Process.

Commun Stat Theory Methods 2019 19;48(12):2982-3004. Epub 2018 Sep 19.

Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.

We propose a joint modeling likelihood-based approach for studies with repeated measures and informative right censoring. Joint modeling of longitudinal and survival data are common approaches but could result in biased estimates if proportionality of hazards is violated. To overcome this issue, and given that the exact time of dropout is typically unknown, we modeled the censoring time as the number of follow-up visits and extended it to be dependent on selected covariates. Longitudinal trajectories for each subject were modeled to provide insight into disease progression and incorporated with the number follow-up visits in one likelihood function.
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http://dx.doi.org/10.1080/03610926.2018.1473599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768558PMC
September 2018

Awareness of Colorectal Cancer and Attitudes Towards Its Screening Guidelines in Lebanon.

Ann Glob Health 2019 05 28;85(1). Epub 2019 May 28.

Epidemiology and Population Health Department, Faculty of Health Sciences, American University of Beirut, Beirut, LB.

Background: Screening for colorectal cancer (CRC) provides an effective strategy for early detection and prevention of the disease; however, global screening rates are still low.

Purpose: This study aims at assessing the awareness of CRC risk factors, warning signs, and attitudes towards CRC guidelines and screening modalities, in order to identify the barriers to and correlates of CRC screening in the Lebanese population.

Methods: A self-administered questionnaire was distributed to 371 participants in the largest health care medical center in Lebanon. A validated 12- and 9-item Cancer Awareness Measurement questionnaire was used to assess participants' awareness of CRC risk factors and warning signs.

Results: 83% and 67% of participants were not aware of CRC risk factors and warning signs, respectively, 15% have previously undergone CRC screening, 56% were aware of the necessity for screening, and 43% were willing to undergo screening. Factors affecting awareness of the necessity for CRC screening, past screening and willingness to screen included awareness of risk factors and warning signs, undergoing regular physician check-ups, having a family physician as a primary source of knowledge of CRC, and knowing a family member or friend diagnosed with CRC. Barriers to screening were related to participants' evaluation of the screening technique and misconceptions about this disease.

Conclusion: Serious active measures should be taken by health care sectors, authoritative groups, primary care physicians, and awareness campaigns to fill the gap in awareness of this disease and to alleviate the barriers and misconceptions around it.
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http://dx.doi.org/10.5334/aogh.2437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634322PMC
May 2019

Heteromerization fingerprints between bradykinin B2 and thromboxane TP receptors in native cells.

PLoS One 2019 14;14(5):e0216908. Epub 2019 May 14.

Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.

Bradykinin (BK) and thromboxane-A2 (TX-A2) are two vasoactive mediators that modulate vascular tone and inflammation via binding to their cognate "class A" G-protein coupled receptors (GPCRs), BK-B2 receptors (B2R) and TX-prostanoid receptors (TP), respectively. Both BK and TX-A2 lead to ERK1/2-mediated vascular smooth muscle cell (VSMC) proliferation and/or hypertrophy. While each of B2R and TP could form functional dimers with various GPCRs, the likelihood that B2R-TP heteromerization could contribute to their co-regulation has never been investigated. The main objective of this study was to investigate the mode of B2R and TP interaction in VSMC, and its possible impact on downstream signaling. Our findings revealed synergistically activated ERK1/2 following co-stimulation of rat VSMC with a subthreshold dose of BK and effective doses of the TP stable agonist, IBOP, possibly involving biased agonist signaling. Single detection of each of B2R and TP in VSMC, using in-situ proximity ligation assay (PLA), provided evidence of the constitutive expression of nuclear and extranuclear B2R and TP. Moreover, inspection of B2R-TP PLA signals in VSMC revealed agonist-modulated nuclear and extranuclear proximity between B2R and TP, whose quantification varied substantially following single versus dual agonist stimulations. B2R-TP interaction was further verified by the findings of co-immunoprecipitation (co-IP) analysis of VSMC lysates. To our knowledge, this is the first study that provides evidence supporting the existence of B2R-TP heteromerization fingerprints in primary cultured VSMC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216908PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516669PMC
January 2020

Analysis of longitudinal semicontinuous data using marginalized two-part model.

J Transl Med 2018 11 6;16(1):301. Epub 2018 Nov 6.

Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.

Background: Connective tissue growth factor (CTGF), is a secreted matricellular factor that has been linked to increased risk of cardiovascular disease in diabetic subjects. Despite the biological role of CTGF in diabetes, it still remains unclear how CTGF expression is regulated. In this study, we aim to identify the clinical parameters that modulate plasma CTGF levels measured longitudinally in type 1 diabetic patients over a period of 10 years. A number of patients had negligible measured values of plasma CTGF that formed a point mass at zero, whereas others had high positive values of CTGF that were measured on a continuous scale. The observed combination of excessive zero and continuous positively distributed non-zero values in the CTGF outcome is referred to as semicontinuous data.

Methods: We propose a novel application of a marginalized two-part model (mTP) extended to accommodate longitudinal semicontinuous data in which the marginal mean is expressed in terms of the covariates and estimates of their effect on the mean responses are generated. The continuous component is assumed to follow distributions that stem from the generalized gamma family whereas the binary measure is analyzed using logistic model and both have correlated random effects. Other approaches including the one- and two-part with uncorrelated and correlated random effects models were also applied and their estimates were all compared.

Results: Our results using the mTP model identified intensive glucose control treatment and smoking as clinical factors that were associated with decreased and increased odds of observing non-zero CTGF values respectively. In addition, hemoglobin A1c, systolic blood pressure, and high density lipoprotein were all shown to be significant risk factors that contribute to increasing CTGF levels. These findings were consistently observed under the mTP model but varied with the distributions for the other models. Accuracy and precision of the mTP model was further validated using simulation studies.

Conclusion: The mTP model identified new clinical determinants that modulate the levels of CTGF in diabetic subjects. Applicability of this approach can be extended to other biomarkers measured in patient populations that display a combination of negligible zero and non-zero values.
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http://dx.doi.org/10.1186/s12967-018-1674-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219033PMC
November 2018

Plasma Connective Tissue Growth Factor (CTGF/CCN2) Levels Predict Myocardial Infarction in the Veterans Affairs Diabetes Trial (VADT) Cohort.

Diabetes Care 2018 04 30;41(4):840-846. Epub 2018 Jan 30.

Objective: Connective tissue growth factor (CTGF), also known as CCN2, is a potent chemotactic and extracellular matrix-inducing matricellular protein that has been implicated in progression of inflammatory and fibroproliferative disorders. An emerging role of CTGF/CCN2 is that of a prosclerotic factor implicated in the development of cardiac disease. Our objective was to determine the role of CTGF/CCN2 as a predictor of cardiovascular events in type 2 diabetes in the Veterans Affairs Diabetes Trial (VADT) cohort.

Research Design And Methods: Levels of CTGF/CCN2 were measured in 952 VADT patients a median of 1.9 years after entry into the study. Participants were followed for an average of 3.3 years for vascular outcomes. CTGF/CCN2 categories were defined as below the detectable limit (referent, 54.5%), lower half of detectable values (22.8%), and upper half of detectable values (22.7%). Hazard ratios (HRs) for cardiovascular end points in relation to CTGF/CCN2 categories were calculated by Cox proportional hazards models.

Results: During follow-up, 4.8% had a myocardial infarction (MI), 6.9% had an MI or cardiovascular death, and 6.9% died. After adjustments by conventional risk factors, individuals in the highest category of CTGF/CCN2 were at higher risk of MI (HR 2.43 [95% CI 1.15, 5.14]), MI or cardiovascular death (HR 2.71 [95% CI 1.44, 5.08]), and all-cause mortality (HR 2.70 [95% CI 1.43, 5.08]) relative to individuals with CTGF below the detectable limit.

Conclusions: Our study indicates that high levels of CTGF/CCN2 predict future MI and cardiovascular death in patients with type 2 diabetes.
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http://dx.doi.org/10.2337/dc17-2083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860844PMC
April 2018

Proteome profiling in the aorta and kidney of type 1 diabetic rats.

PLoS One 2017 9;12(11):e0187752. Epub 2017 Nov 9.

Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.

Diabetes is associated with a number of metabolic and cardiovascular risk factors that contribute to a high rate of microvascular and macrovascular complications. The risk factors and mechanisms that contribute to the development of micro- and macrovascular disease in diabetes are not fully explained. In this study, we employed mass spectrometric analysis using tandem LC-MS/MS to generate a proteomic profile of protein abundance and post-translational modifications (PTM) in the aorta and kidney of diabetic rats. In addition, systems biology analyses were employed to identify key protein markers that can provide insights into molecular pathways and processes that are differentially regulated in the aorta and kidney of type 1 diabetic rats. Our results indicated that 188 (111 downregulated and 77 upregulated) proteins were significantly identified in the aorta of diabetic rats compared to normal controls. A total of 223 (109 downregulated and 114 upregulated) proteins were significantly identified in the kidney of diabetic rats compared to normal controls. When the protein profiles from the kidney and aorta of diabetic and control rats were analyzed by principal component analysis, a distinct separation of the groups was observed. In addition, diabetes resulted in a significant increase in PTM (oxidation, phosphorylation, and acetylation) of proteins in the kidney and aorta and this effect was partially reversed by insulin treatment. Ingenuity pathway analysis performed on the list of differentially expressed proteins depicted mitochondrial dysfunction, oxidative phosphorylation and acute phase response signaling to be among the altered canonical pathways by diabetes in both tissues. The findings of the present study provide a global proteomics view of markers that highlight the mechanisms and putative processes that modulate renal and vascular injury in diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187752PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679573PMC
November 2017

Multivariate Generalized Linear Mixed Models With Random Intercepts To Analyze Cardiovascular Risk Markers in Type-1 Diabetic Patients.

J Appl Stat 2016 26;43(8):1447-1464. Epub 2015 Nov 26.

Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, P.O.Box 11-0236 Riad El-Solh / Beirut, Lebanon 1107 2020.

Statistical approaches tailored to analyzing longitudinal data that have multiple outcomes with different distributions are scarce. This paucity is due to the non-availability of multivariate distributions that jointly model outcomes with different distributions other than the multivariate normal. A plethora of research has been done on the specific combination of binary-Gaussian bivariate outcomes but a more general approach that allows other mixtures of distributions for multiple longitudinal outcomes has not been thoroughly demonstrated and examined. Here we study a multivariate generalized linear mixed models approach that jointly models multiple longitudinal outcomes with different combinations of distributions and incorporates the correlations between the various outcomes through separate yet correlated random intercepts. Every outcome is linked to the set of covariates through a proper link function that allows the incorporation and joint modelling of different distributions. A novel application was demonstrated on a cohort study of Type 1 diabetic patients to jointly model a mix of longitudinal cardiovascular outcomes and to explore for the first time the effect of glycemic control treatment, plasma prekallikrein biomarker, gender and age on cardiovascular risk factors collectively.
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http://dx.doi.org/10.1080/02664763.2015.1103708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098498PMC
November 2015

Joint Modeling of Covariates and Censoring Process Assuming Non-Constant Dropout Hazard.

Stat Methods Appt 2016 Jun 1;25(2):251-267. Epub 2015 Apr 1.

Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; Department of Medicine, Medical University of South Carolina, Charleston, SC. 29425, USA.

In this manuscript we propose a novel approach for the analysis of longitudinal data that have informative dropout. We jointly model the slopes of covariates of interest and the censoring process for which we assume a survival model with logistic non-constant dropout hazard in a likelihood function that is integrated over the random effects. Maximization of the marginal likelihood function results in acquiring maximum likelihood estimates for the population slopes and empirical Bayes estimates for the individual slopes that are predicted using Gaussian quadrature. Our simulation study results indicated that the performance of this model is superior in terms of accuracy and validity of the estimates compared to other models such as logistic non-constant hazard censoring model that does not include covariates, logistic constant censoring model with covariates, bootstrapping approach as well as mixed models. Sensitivity analyses for the dropout hazard and non-Gaussian errors were also undertaken to assess robustness of the proposed approach to such violations. Our model was illustrated using a cohort of renal transplant patients with estimated glomerular filtration rate as the outcome of interest.
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http://dx.doi.org/10.1007/s10260-015-0302-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010875PMC
June 2016

Plasma Prekallikrein Is Associated With Carotid Intima-Media Thickness in Type 1 Diabetes.

Diabetes 2016 Feb 24;65(2):498-502. Epub 2015 Nov 24.

Department of Medicine, Medical University of South Carolina, Charleston, SC Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon

The hypothesis that plasma prekallikrein (PK) is a risk factor for the development of vascular complications was assessed in a study using the Diabetes Control and Complications Trial (DCCT)/Epidemiology and Diabetes Interventions and Complications (EDIC) cohort of subjects with type 1 diabetes. The circulating levels of plasma PK activity were measured in the plasma of 636 subjects with type 1 diabetes (EDIC years 3-5). Common and internal carotid intima-media thickness (IMT) were measured by B-mode ultrasonography in EDIC years 1 and 6. Plasma PK levels were positively and significantly associated with BMI, hemoglobin A1c, systolic blood pressure, total cholesterol, LDL cholesterol, and triglycerides but not with age, sex, duration of diabetes, or HDL cholesterol. Univariate and multivariable statistical models after controlling for other risk factors consistently demonstrated a positive association between plasma PK and progression of internal carotid IMT. Multivariate analysis using a general linear model showed plasma PK to be significantly associated with progression of both internal and combined IMT (Wilks Λ P value of 0.005). In addition, the mean internal carotid IMT levels were higher in subjects with plasma PK levels in the highest 10th percentile compared with subjects with plasma PK levels in the lower 10th percentile (P = 0.048). These novel findings implicate plasma PK as a risk factor for vascular disease in type 1 diabetes.
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http://dx.doi.org/10.2337/db15-0930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747454PMC
February 2016

Analysis of multivariate longitudinal kidney function outcomes using generalized linear mixed models.

J Transl Med 2015 Jun 14;13:192. Epub 2015 Jun 14.

Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.

Background: Renal transplant patients are mandated to have continuous assessment of their kidney function over time to monitor disease progression determined by changes in blood urea nitrogen (BUN), serum creatinine (Cr), and estimated glomerular filtration rate (eGFR). Multivariate analysis of these outcomes that aims at identifying the differential factors that affect disease progression is of great clinical significance. Thus our study aims at demonstrating the application of different joint modeling approaches with random coefficients on a cohort of renal transplant patients and presenting a comparison of their performance through a pseudo-simulation study. The objective of this comparison is to identify the model with best performance and to determine whether accuracy compensates for complexity in the different multivariate joint models.

Methods And Results: We propose a novel application of multivariate Generalized Linear Mixed Models (mGLMM) to analyze multiple longitudinal kidney function outcomes collected over 3 years on a cohort of 110 renal transplantation patients. The correlated outcomes BUN, Cr, and eGFR and the effect of various covariates such patient's gender, age and race on these markers was determined holistically using different mGLMMs. The performance of the various mGLMMs that encompass shared random intercept (SHRI), shared random intercept and slope (SHRIS), separate random intercept (SPRI) and separate random intercept and slope (SPRIS) was assessed to identify the one that has the best fit and most accurate estimates. A bootstrap pseudo-simulation study was conducted to gauge the tradeoff between the complexity and accuracy of the models. Accuracy was determined using two measures; the mean of the differences between the estimates of the bootstrapped datasets and the true beta obtained from the application of each model on the renal dataset, and the mean of the square of these differences. The results showed that SPRI provided most accurate estimates and did not exhibit any computational or convergence problem.

Conclusion: Higher accuracy was demonstrated when the level of complexity increased from shared random coefficient models to the separate random coefficient alternatives with SPRI showing to have the best fit and most accurate estimates.
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http://dx.doi.org/10.1186/s12967-015-0557-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467678PMC
June 2015

A Joint Modeling Approach for Right Censored High Dimensional Multivariate Longitudinal Data.

J Biom Biostat 2014 Aug;5(4)

Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, P.O.Box 11-0236 Riad El-Solh / Beirut, Lebanon 1107 2020. ; Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.

Analysis of multivariate longitudinal data becomes complicated when the outcomes are of high dimension and informative right censoring is prevailing. Here, we propose a likelihood based approach for high dimensional outcomes wherein we jointly model the censoring process along with the slopes of the multivariate outcomes in the same likelihood function. We utilized pseudo likelihood function to generate parameter estimates for the population slopes and Empirical Bayes estimates for the individual slopes. The proposed approach was applied to jointly model longitudinal measures of blood urea nitrogen, plasma creatinine, and estimated glomerular filtration rate which are key markers of kidney function in a cohort of renal transplant patients followed from kidney transplant to kidney failure. Feasibility of the proposed joint model for high dimensional multivariate outcomes was successfully demonstrated and its performance was compared to that of a pairwise bivariate model. Our simulation study results suggested that there was a significant reduction in bias and mean squared errors associated with the joint model compared to the pairwise bivariate model.
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http://dx.doi.org/10.4172/2155-6180.1000203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4327878PMC
August 2014

Global renal gene expression profiling analysis in B2-kinin receptor null mice: impact of diabetes.

PLoS One 2012 18;7(9):e44714. Epub 2012 Sep 18.

Epidemiology and Population Health Department, Faculty of Health Sciences, American University of Beirut, Beirut, Lebanon.

Diabetic nephropathy (DN), the leading cause of end-stage renal failure, is clinically manifested by albuminuria and a progressive decline in glomerular filtration rate. The risk factors and mechanisms that contribute to the development and progression of DN are still incompletely defined. To address the involvement of bradykinin B(2)-receptors (B(2)R) in DN, we used a genome wide approach to study the effects of diabetes on differential renal gene expression profile in wild type and B(2)R knockout (B(2)R(-/-)) mice. Diabetes was induced with streptozotocin and plasma glucose levels and albumin excretion rate (AER) were measured at predetermined times throughout the 23 week study period. Longitudinal analysis of AER indicated that diabetic B(2)R(-/-)D null mice had a significantly decreased AER levels compared to wild type B(2)R(+/+)D mice (P = 0.0005). Results from the global microarray study comparing gene expression profiles among four groups of mice respectively: (B(2)R(+/+)C, B(2)R(+/+)D, B(2)R(-/-)C and B(2)R(-/-)D) highlighted the role of several altered pathological pathways in response to disruption of B(2)R and to the diabetic state that included: endothelial injury, oxidative stress, insulin and lipid metabolism and inflammatory process with a marked alteration in the pro-apoptotic genes. The findings of the present study provide a global genomics view of biomarkers that highlight the mechanisms and putative pathways involved in DN.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044714PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445541PMC
March 2013

Slope Estimation of Covariates that Influence Renal Outcome following Renal Transplant Adjusting for Informative Right Censoring.

J Appl Stat 2012;39(3):631-642

Harvard Medical School, Boston, Massachusetts, 02120, USA.

A new statistical model is proposed to estimate population and individual slopes that are adjusted for covariates and informative right censoring. Individual slopes are assumed to have a mean that depends on the population slope for the covariates. The number of observations for each individual is modeled as a truncated discrete distribution with mean dependent on the individual subjects' slopes. Our simulation study results indicated that the associated bias and mean squared errors for the proposed model were comparable to those associated with the model that only adjusts for informative right censoring. The proposed model was illustrated using renal transplant dataset to estimate population slopes for covariates that could impact the outcome of renal function following renal transplantation.
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http://dx.doi.org/10.1080/02664763.2011.610441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343305PMC
January 2012

Slope estimation for informatively right censored longitudinal data modelling the number of observations using geometric and Poisson distributions: application to renal transplant cohort.

Stat Methods Med Res 2015 Dec 4;24(6):819-35. Epub 2011 Dec 4.

Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA. Center for Health Services Research in Primary Care, Durham VAMC, Durham, NC, USA. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA.

Analysis of longitudinal data is often complicated by the presence of informative right censoring. This type of censoring should be accounted for in the analysis so that valid slope estimates are attained. In this study, we developed a new likelihood-based approach wherein the likelihood function is integrated over random effects to obtain a marginal likelihood function. Maximum likelihood estimates for the population slope were acquired by direct maximisation of the marginal likelihood function and empirical Bayes estimates for the individual slopes were generated using Gaussian quadrature. The performance of the model was assessed using the geometric and Poisson distributions to model the number of observations for every individual subject. Our model generated valid estimates for the slopes under both distributions with minimal bias and mean squared errors. Our sensitivity analysis confirmed the robustness of the model to assumptions pertaining to the underlying distribution and demonstrated its insensitivity to normality assumptions. Moreover, superiority of the model in terms of accuracy of slope estimates was consistently shown across the different levels of censoring in comparison to the naïve and bootstrap approaches. This model was illustrated using the cohort of renal transplant patients and estimates of the slopes that are adjusted for informative right censoring were acquired.
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http://dx.doi.org/10.1177/0962280211430681DOI Listing
December 2015

Slope Estimation for Bivariate Longitudinal Outcomes Adjusting for Informative Right Censoring Using Discrete Survival Model: Application to the Renal Transplant Cohort.

J R Stat Soc Ser A Stat Soc 2011 04;174(2):387-402

Department of Medicine, Division of Biostatistics and Epidemiology Medical University of South Carolina, Charleston, SC. 29425.

Patients undergoing renal transplantation are prone to graft failure which causes lost of follow-up measures on their blood urea nitrogen and serum creatinine levels. These two outcomes are measured repeatedly over time to assess renal function following transplantation. Loss of follow-up on these bivariate measures results in informative right censoring, a common problem in longitudinal data that should be adjusted for so that valid estimates are obtained. In this study, we propose a bivariate model that jointly models these two longitudinal correlated outcomes and generates population and individual slopes adjusting for informative right censoring using a discrete survival approach. The proposed approach is applied to the clinical dataset of patients who had undergone renal transplantation. A simulation study validates the effectiveness of the approach.
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http://dx.doi.org/10.1111/j.1467-985X.2010.00671.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082945PMC
April 2011

Analyses of renal outcome following transplantation adjusting for informative right censoring and demographic factors: A longitudinal study.

Ren Fail 2010 Jul;32(6):691-8

Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.

Demographic factors such as race, vital status, gender, and age could affect the final renal outcome of patients who undergo renal transplantation. These demographic factors could be assessed at the recipient and donor levels. Repeated measures for blood urea nitrogen (BUN) are typically recorded for each patient following renal transplantation, as a biomarker to assess renal progress. However, once a patient develops renal failure due to graft rejection, no measurement of BUN can be registered and the patient goes back to dialysis. This causes loss of follow-up and incomplete data on BUN measurements, a problem referred to as informative right censoring. If this problem is ignored, inaccurate, and biased estimates will be generated. In this study, unbiased estimates for the rate of change of BUN levels over time adjusted for informative right censoring and demographic factors were acquired using a sophisticated model of analysis. Our results demonstrated that BUN levels for Caucasians were decreasing at a greater rate than African Americans (p < 0.0001). When donors are deceased, African American recipients showed an increase instead of a decrease in their BUN levels following transplantation. Moreover, African Americans showed a decrease in their BUN levels when the donors were African Americans compared with when donors were Caucasians (p = 0.03). Our results also showed that BUN levels were decreasing at a greater rate when donors and recipients were of different gender than when they were of the same gender (p = 0.009). These results suggest that the success of renal transplantation is impacted by the donor/recipient demographic factors.
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http://dx.doi.org/10.3109/0886022X.2010.486495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093108PMC
July 2010

Genetic variant in the promoter of connective tissue growth factor gene confers susceptibility to nephropathy in type 1 diabetes.

J Med Genet 2010 Jun;47(6):391-7

Department of Medicine, Medical University of South Carolina, 114 Doughty Street, P.O. Box 250776 Charleston, SC 29425, USA.

BACKGROUND The evidence for genetic susceptibility in the pathogenesis of diabetic nephropathy is well recognised, but the genes involved remain to be identified. It is hypothesised that mutations within the gene encoding connective tissue growth factor (CTGF/CCN2) will increase the propensity of diabetic subjects to develop nephropathy. METHODS AND RESULTS Genomic screening was performed for single nucleotide polymorphisms (SNPs) within the CTGF gene in 862 subjects from the DCCT/EDIC cohort of type 1 diabetes. A novel SNP was identified in the promoter region that changes a C-G at the position -20. The frequency of GG genotype in microalbuminuric patients (albumin excretion rate (AER) >40 mg/24 h) is significantly greater than diabetics with AER <40 mg/24 h, p<0.0001. The relative risk (RR) to develop microalbuminuria in diabetic subjects with the polymorphism is 3X higher than diabetic subjects without the polymorphism (RR 3.142, 95% CI 1.9238 to 5.1249; p<0.05). Kaplan-Meier survival curves demonstrated that the GG genotype group developed microalbuminuria and macroalbuminuria at a more rapid rate than the GC or CC genotypes. Functional studies demonstrated that the basal activity of the substituted allele/promoter (-20 GG allele) was significantly greater than that of the wild type promoter (-20 CC genotype). This higher level of basal activity of substituted allele CTGF/CCN2 promoter was abrogated upon suppression of Smad1 levels, indicating that SNP region in the CTGF/CCN2 promoter plays a vital role in the gene expression. CONCLUSIONS These findings provide the first evidence that variants within the promoter region of the CTGF/CCN2 gene predisposes diabetic subjects to develop albuminuria and demonstrate that Smad1 [corrected] controls the expression of CTGF/CCN2 promoter through this region.
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http://dx.doi.org/10.1136/jmg.2009.073098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828650PMC
June 2010

Evidence for prostacyclin and cAMP upregulation by bradykinin and insulin-like growth factor 1 in vascular smooth muscle cells.

J Recept Signal Transduct Res 2010 Apr;30(2):61-71

Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC 29425, USA.

Although bradykinin (BK) and insulin like growth factor-1 (IGF-1) have been shown to modulate the functional and structural integrity of the arterial wall, the cellular mechanisms through which this regulation occurs is still undefined. The present study examined the role of second messenger molecules generated by BK and IGF-1 that could ultimately result in proliferative or antiproliferative signals in vascular smooth muscle cells (VSMC). Activation of BK or IGF-1 receptors stimulated the synthesis and release of prostacyclin (PGI(2)) leading to increased production of cAMP in VSMC. Inhibition of p42/p44(mapk) or src kinases prevented the increase in PGI(2) and cAMP observed in response to BK or IGF-1, indicating a role for these kinases in the regulation of cPLA(2) activity in the VSMC. Inhibition of PKC failed to alter production of PGI(2) in response to BK, but further increased both p42/p44(mapk) activation and the synthesis of PGI(2) produced in response to IGF-1. In addition, both BK and IGF-1 significantly induced the expression of c-fos mRNA levels in VSMC, and this effect of BK was accentuated in the presence a cPLA(2) inhibitor. Finally, inhibition of cPLA(2) activity and/or cyclooxygenase activity enhanced the expression of collagen I mRNA levels in response to BK and IGF-1 stimulation. These findings indicate that the effect of BK or IGF-1 to stimulate VSMC growth is an integrated response to the activation of multiple signaling pathways. Thus, the excessive cell growth that occurs in certain forms of vascular disease could reflect dysfunction in one or more of these pathways.
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http://dx.doi.org/10.3109/10799890903563768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4327880PMC
April 2010

Connective tissue growth factor and susceptibility to renal and vascular disease risk in type 1 diabetes.

J Clin Endocrinol Metab 2008 May 4;93(5):1893-900. Epub 2008 Mar 4.

Department of Medicine, Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, 114 Doughty Street, Charleston, SC 29425, USA.

Objective: We explored the relevance and significance of connective tissue growth factor (CTGF) as a determinant of renal and vascular complications among type 1 diabetic patients.

Methods And Results: We measured the circulating and urinary levels of CTGF and CTGF N fragment in 1050 subjects with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study cohort. We found that hypertensive diabetic subjects have significantly higher levels of plasma log CTGF N fragment relative to normotensive subjects (P = 0.0005). Multiple regression analysis showed a positive and independent association between CTGF N fragment levels and log albumin excretion rate (P < 0.0001). In categorical analysis, patients with macroalbuminuria had higher levels of CTGF N fragment than diabetic subjects with or without microalbuminuria (P < 0.0001). Univariate and multiple regression analyses demonstrated an independent and significant association of log CTGF N fragment with the common and internal carotid intima-media thickness. The relative risk for increased carotid intima-media thickness was higher in patients with concomitantly elevated plasma CTGF N fragment and macroalbuminuria relative to patients with normal plasma CTGF N fragment and normal albuminuria (relative risk = 4.76; 95% confidence interval, 2.21-10.25; P < 0.0001).

Conclusion: These findings demonstrate that plasma CTGF is a risk marker of diabetic renal and vascular disease.
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http://dx.doi.org/10.1210/jc.2007-2544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386274PMC
May 2008