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1.  PARAMO: A Parallel Predictive Modeling Platform for Healthcare Analytic Research using Electronic Health Records 
Objective
Healthcare analytics research increasingly involves the construction of predictive models for disease targets across varying patient cohorts using electronic health records (EHRs). To facilitate this process, it is critical to support a pipeline of tasks: 1) cohort construction, 2) feature construction, 3) cross-validation, 4) feature selection, and 5) classification. To develop an appropriate model, it is necessary to compare and refine models derived from a diversity of cohorts, patient-specific features, and statistical frameworks. The goal of this work is to develop and evaluate a predictive modeling platform that can be used to simplify and expedite this process for health data.
Methods
To support this goal, we developed a PARAllel predictive MOdeling (PARAMO) platform which 1) constructs a dependency graph of tasks from specifications of predictive modeling pipelines, 2) schedules the tasks in a topological ordering of the graph, and 3) executes those tasks in parallel. We implemented this platform using Map-Reduce to enable independent tasks to run in parallel in a cluster computing environment. Different task scheduling preferences are also supported.
Results
We assess the performance of PARAMO on various workloads using three datasets derived from the EHR systems in place at Geisinger Health System and Vanderbilt University Medical Center and an anonymous longitudinal claims database. We demonstrate significant gains in computational efficiency against a standard approach. In particular, PARAMO can build 800 different models on a 300,000 patient data set in 3 hours in parallel compared to 9 days if running sequentially.
Conclusion
This work demonstrates that an efficient parallel predictive modeling platform can be developed for EHR data. This platform can facilitate large-scale modeling endeavors and speed-up the research workflow and reuse of health information. This platform is only a first step and provides the foundation for our ultimate goal of building analytic pipelines that are specialized for health data researchers.
doi:10.1016/j.jbi.2013.12.012
PMCID: PMC4075460  PMID: 24370496
predictive modeling; electronic health records; scientific workflows; parallel computing; map reduce
2.  Pharmacodynamic interplay of the P2Y1, P2Y12, and TxA2 pathways in platelets: the potential of triple antiplatelet therapy with P2Y1 receptor antagonism 
Thrombosis research  2012;131(2):e64-e70.
Introduction
Previous work suggests that the extent of platelet inhibition by P2Y1 receptor antagonism may be underappreciated, particularly in the context of dual antiplatelet therapy with aspirin and clopidogrel.
Materials and Methods
Using P2Y1, P2Y12, and TxA2 receptor antagonists individually and in combination, we assessed the incremental changes from baseline platelet reactivity in blood collected from healthy volunteers.
Results
The P2Y1 receptor antagonist further inhibited platelet activation and aggregation in several assay conditions ex vivo when combined with P2Y12 and/or TxA2 receptor blockers. Collagen and TRAP-induced platelet aggregation measured by light transmittance aggregometry was inhibited to a greater extent with the triple combination relative to each of the antagonists alone. The triple combination of P2Y1, P2Y12, and TxA2 receptor antagonists also significantly shifted adenosine diphosphate (ADP)-stimulated platelet glycoprotein IIb/IIIa receptor and P-selectin expression compared to individual or dual antagonists.
Conclusions
These results substantiate that additional platelet inhibition occurs with the triple combination of P2Y1, P2Y12, and TxA2 receptor antagonists and support further testing of P2Y1 receptor antagonists as an option for alternative, synergistic, or triple antiplatelet therapy.
doi:10.1016/j.thromres.2012.11.019
PMCID: PMC3545076  PMID: 23245937
MRS2179; P2Y1 receptor; ADP receptors; platelet pharmacology; platelet function test
3.  Salivary Biomarkers Associated with Myocardial Necrosis: Results from an Alcohol Septal Ablation Model 
Objective
To determine if salivary biomarkers demonstrate utility for identifying aspects of myocardial necrosis.
Methods
Twenty-one patients undergoing alcohol septal ablation (ASA) for treatment of hypertrophic cardiomyopathy provided serum and unstimulated whole saliva at baseline and incremental time points post-ASA. Samples were analyzed for seven biomarkers related to myocardial damage, inflammation and tissue remodeling using immunosorbent assays. Levels were compared to baseline and levels observed in 97 healthy controls.
Results
Biomarkers of myocardial damage and inflammation (i.e., troponin I, creatine kinase-MB, myoglobin, C-reactive protein) rose in serum 2 to 812-fold after ASA (p<0.01). Significant elevations of 2 to 3.5-fold were observed with C-reactive protein and troponin I in saliva (p<0.02). Significant correlations between levels in serum and saliva were observed for C-reactive protein, matrix metalloproteinase-9, and myeloperoxidase (p < 0.001).
Conclusions
Select salivary biomarkers reflect changes that occur during, and subsequent to, myocardial necrosis caused by ASA.
doi:10.1016/j.oooo.2012.05.024
PMCID: PMC3736120  PMID: 23021916
Alcohol Septal Ablation; Biomarkers; Cardiac Biomarkers; Cardiovascular Disease; Coronary; Myocardial Ischemia; Myocardial Necrosis; Saliva
4.  Oral Fluids that Detect Cardiovascular Disease Biomarkers 
Objective
To determine the utility of oral fluids for assessment of coronary and cardiovascular (CVD) health.
Study Design
Twenty-nine patients with pre-existing CVD disease underwent an invasive cardiac procedure (alcohol septal ablation or percutaneous coronary intervention) and provided unstimulated whole saliva (UWS), sublingual swabs (LS), gingival swabs (GS) and serum at 0, 8, 16, 24, 48 hr. Concentrations of 13 relevant biomarkers were determined and correlated with levels in serum and the oral fluids.
Results
Concentrations of the majority of biomarkers were higher in UWS than LS and GS. Coronary and CVD disease biomarkers in UWS correlated better with serum than LS and GS based on group status and measures of time effect. Seven biomarkers demonstrated time effect changes consistent with serum biomarkers, including C-reactive protein and troponin I.
Conclusions
Changes in serum biomarker profiles are reflected in oral fluids suggesting that oral fluid biomarkers could aid in the assessment of cardiac ischemia/necrosis.
doi:10.1016/j.oooo.2012.03.003
PMCID: PMC3548400  PMID: 22769406
Alcohol Septal Ablation; Cardiac Biomarkers; Cardiovascular Disease; Myocardial Ischemia; Myocardial Necrosis; Saliva; Oral; Mouth
6.  Impact of Proton Pump Inhibitor Therapy on the Efficacy of Clopidogrel in the CAPRIE and CREDO Trials 
Background
Proton pump inhibitors (PPIs) may interfere with the metabolic activation of clopidogrel via inhibition of cytochrome P450 2C19, but the clinical implications remain unclear.
Methods and Results
The impact of PPI use on the 1‐year primary end point (ischemic stroke, myocardial infarction [MI], or vascular death) in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial and the 28‐day (all‐cause death, MI, or urgent target vessel revascularization) and 1‐year (all‐cause death, MI, or stroke) primary end points in the Clopidogrel for Reduction of Events During Observation (CREDO) trial were examined. Clopidogrel appeared to elevate risk for the primary end point in CAPRIE among PPI users (estimated hazard ratio [EHR] 2.66, 95% CI 0.94 to 7.50) while lowering it for non‐PPI users (EHR 0.90, 95% CI 0.83 to 0.99, interaction P=0.047). Moreover, PPI use was associated with worse outcomes in patients receiving clopidogrel (EHR 2.39, 95% CI 1.74 to 3.28) but not aspirin (EHR 1.04, 95% CI 0.70 to 1.57, interaction P=0.001). Clopidogrel did not significantly alter risk for the 1‐year primary end point in CREDO among PPI users (EHR 0.82, 95% CI 0.48 to 1.40) while lowering it for non‐PPI users (EHR 0.71, 95% CI 0.52 to 0.98, interaction P=0.682). Also, PPI use was associated with worse outcomes in both patients receiving clopidogrel (EHR 1.67, 95% CI 1.06 to 2.64) and those receiving placebo (EHR 1.56, 95% CI 1.06 to 2.30, interaction P=0.811).
Conclusions
In CREDO, the efficacy of clopidogrel was not significantly affected by PPI use. However, in CAPRIE, clopidogrel was beneficial to non‐PPI users while apparently harmful to PPI users. Whether this negative interaction is clinically important for patients receiving clopidogrel without aspirin needs further study.
doi:10.1161/JAHA.112.004564
PMCID: PMC3603228  PMID: 23525436
CAPRIE; clopidogrel; CREDO; drug–drug interaction; proton pump inhibitors
7.  Smoking, Clopidogrel, and Mortality in Patients with Established Cardiovascular Disease 
Circulation  2009;120(23):2337.
Background
Smoking increases platelet aggregability, and the degree of platelet inhibition by clopidogrel on ex vivo platelet function tests. Whether smoking status affects the relationship between clopidogrel and clinical outcomes is unknown.
Methods and Results
We evaluated the relationship between smoking status (current smoker (CS), former smoker (FS), and never smoker (NS)) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12,152 participants from the CHARISMA trial with established cardiovascular disease. Current smoking was associated with an increase in all-cause (adjusted hazard ratio [HR] 2.58, [1.85–3.60]), cardiovascular (HR 2.26, [1.48–3.45]), and cancer mortality (HR 4.16, [2.46–7.03]) compared to NS. The impact of clopidogrel and mortality differed by smoking status (P for interaction = 0.018 for current smokers). Among CS, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, [0.49–0.94]); clopidogrel did not reduce all cause mortality among FS (HR 0.95, [0.75–1.19]) or NS (HR 1.14, [0.83–1.58]). A similar pattern was noted for cardiovascular mortality. As expected, no relationship was observed between clopidogrel and cancer mortality by smoking status. The risk of bleeding seemed to differ according to smoking status; randomized clopidogrel was associated with a significantly increased hazard of severe or moderate bleeding (HR 1.62, P=0.04) among CS, but a smaller and nonsignificant increase among NS (HR 1.31, P=0.15).
Conclusion
Clopidogrel therapy may be more effective, but with a greater bleeding risk in CS than in patients who are not smokers. Further studies are needed to investigate this possibility.
doi:10.1161/CIRCULATIONAHA.109.866533
PMCID: PMC2814172  PMID: 19933933
Smoking; Clopidogrel; Mortality; Cardiovascular disease
8.  Impact of genetic polymorphisms on clinical response to antithrombotics 
Antithrombotic therapy, including anticoagulants as well as antiplatelet drugs, is an important component in the treatment of cardiovascular disease. Variability in response to such medications, of which pharmacogenetic response is a major source, can decrease or enhance the benefits expected. This review is a comprehensive assessment of the literature published to date on the effects of genetic polymorphisms on the actions of a variety of antithrombotic medications, including warfarin, clopidogrel, prasugrel, and aspirin. Literature evaluating surrogate markers in addition to the impact of pharmacogenetics on clinical outcomes has been reviewed. The results of the studies are conflicting as to what degree pharmacogenetics will affect medication management in cardiovascular disease. Additional research is necessary to discover, characterize, and prospectively evaluate genetic and non-genetic factors that impact antithrombotic treatment in order to maximize the effectiveness and limit the harmful effects of these valuable agents.
PMCID: PMC3513211  PMID: 23226045
aspirin; warfarin; clopidogrel; prasugrel; pharmacogenetic; antithrombotic; antiplatelet
9.  Considerable Variability in Platelet Activity among Patients with Coronary Artery Disease in Response to an Increased Maintenance Dose of Clopidogrel 
Coronary artery disease  2009;20(3):207-213.
Background
Variable platelet response to clopidogrel has been widely observed. Studies have shown that the mean aggregation response to clopidogrel can be changed by a higher maintenance dose. However, these studies have not focused on individual changes.
Objectives
This study examined the platelet function effects of increasing the maintenance clopidogrel dose from 75 mg/day to 150 mg/day with a focus on inter-individual response.
Patients/Methods
Twenty patients with known coronary artery disease receiving 75 mg/day clopidogrel were recruited and given 150 mg/day of clopidogrel for 30 days, then returned to 75 mg/day for an additional 30 days. Platelet function was assessed via light-transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay at baseline, 30 days, and 60 days.
Results
Mean platelet inhibition was significantly improved with the increased maintenance dose when measured by the VerifyNow P2Y12 assay (PRU: 191 ± 15 vs. 158 ± 17, p = 0.013), but not when measured by LTA (LTA-ADP5: 40 ± 3 vs. 36 ± 3, p = 0.11; LTA-ADP20: 50 ± 3 vs. 47 ± 3, p = 0.23). However, only 50% of individual patients experienced improved platelet inhibition, as measured by the VerifyNow P2Y12 assay, when treated with the increased maintenance dose. Furthermore, poor baseline platelet response did not predict improved responsiveness at the increased dose.
Conclusions
Despite changing the population's mean antiplatelet response, an increased maintenance dose of clopidogrel did not improve antiplatelet response in a substantial number of patients; nor did baseline platelet function predict response to a higher maintenance dose.
doi:10.1097/MCA.0b013e328329924b
PMCID: PMC2801158  PMID: 19318928
clopidogrel; coronary artery disease; blood platelets; platelet aggregation; adenosine diphosphate; purinoceptor P2Y12
11.  Antithrombotic therapy with intracoronary stenting 
Heart  1997;78(Suppl 2):21-23.
PMCID: PMC484826  PMID: 9422970

Results 1-11 (11)