James P. Corsetti, M.D., Ph.D.
Brown University Bio/Med Sciences
Department of Pathology and Laboratory Medicine
The Corsetti Laboratory is involved in studies of cardiovascular disease risk in human populations using non-traditional statistical approaches, in particular, exploratory data analysis techniques for multivariable assessment of novel blood and genetic biomarkers of risk. Our approach is based upon the notion that current limitations on the implementation of personalized medicine can be broached by identification of patient subgroups with common underlying pathophysiologic features. Such subgroups, we believe, would manifest particular combinations of biomarkers of risk that, in general, will be different dependent on different underlying pathophysiologies. As such, we have developed a 3-dimensional graphical exploratory data analysis tool ("outcome event mapping") that allows identification of high-risk patient subgroups. The technique is not constrained by traditional rectilinear approaches to subgroup identification and it allows subgroup identification in unexpected regions of risk parameter spaces. Recently, we adapted the approach for the handling of differential risk associations with single-nucleotide polymorphisms (SNP).
As an example, we have demonstrated for both incident as well as recurrent coronary events a completely unexpected high-risk subgroup of individuals characterized by high levels of HDL cholesterol ("the good cholesterol") and high levels of C-reactive protein (CRP), a marker of systemic inflammation. The high CRP underscores the important role of inflammation in the transformation of HDL, normally anti-atherogenic, to a pro-atherogenic form. This is a significant finding in that intensive efforts are currently underway to decrease the residual cardiovascular disease risk characteristic of statin use by using agents to raise HDL. Future collaborative efforts will be oriented towards elucidation of mechanisms involved in elevated HDL risk including proteomic analysis of HDL particle constituents to fully characterize the physico-chemical nature of risk-associated HDL and, in addition, to elucidate the role of aberrant HDL in a potentially important aspect of the atherogenic process, namely, endothelial dysfunction induced by disturbed vascular blood flow.
In addition, we are continuing our efforts to utilize advanced exploratory data analysis approaches for biomarker assessment. Most recently, collaborative efforts are underway to develop and utilize the technique of Bayesian network analysis (BNA) to approach large databases of blood and genetic biomarkers to provide novel mechanistic insights on disease-associated pathways.
Corsetti JP, Salzman P, Ryan D, Moss AJ, Zareba W, Sparks CE. "Data in support of a central role of plasminogen activator inhibitor-2 polymorphism in recurrent cardiovascular disease risk in the setting of high HDL cholesterol and C-reactive protein using Bayesian network modeling." Data in brief.. 2016 Sep 0; 8:98-104. Epub 2016 May 21.
Corsetti JP, Salzman P, Ryan D, Moss AJ, Zareba W, Sparks CE. "Influences on plasminogen activator inhibitor-2 polymorphism-associated recurrent cardiovascular disease risk in patients with high HDL cholesterol and inflammation." Atherosclerosis.. 2016 Jul 0; 250:1-8. Epub 2016 Apr 21.
Corsetti JP, Gansevoort RT, Bakker SJ, Dullaart RP. "Apolipoprotein E levels and apolipoprotein E genotypes in incident cardiovascular disease risk in subjects of the Prevention of Renal and Vascular End-stage disease study." Journal of clinical lipidology.. 2016 10(4):842-50. Epub 2016 Mar 12.
Corsetti JP, Gansevoort RT, Bakker SJ, Sparks CE, Vart P, Dullaart RP. "Apolipoprotein B attenuates albuminuria-associated cardiovascular disease in prevention of renal and vascular endstage disease (PREVEND) participants." Journal of the American Society of Nephrology : JASN.. 2014 Dec 0; 25(12):2906-15. Epub 2014 May 22.
Sparks CE, Corsetti JP, Sparks JD. "High-density lipoproteins: taking the good with the bad." Current opinion in lipidology.. 2014 Jun 0; 25(3):230-2.
Corsetti JP, Gansevoort RT, Bakker SJL, Navis GJ, Sparks CE, and Dullaart RPF. Apolipoprotein E Predicts Incident Cardiovascular Disease Risk in Women but not in Men with Concurrently High Levels of High-Density Lipoprotein Cholesterol and C-Reactive Protein. Metabolism Clinical and Experimental. In Press (2012).
Corsetti JP, Gansevoort RT, Navis GJ, Sparks CE, Dullaart RPF. LPL Polymorphism (D9N) Predicts Cardiovascular Disease Risk Directly and Through Interaction with CETP Polymorphism (TaqIB) in Women with High HDL Cholesterol and CRP. Atherosclerosis. 2011;214:373-376.
Corsetti JP, Ryan D, Moss AJ, McCarthy JJ, Goldenberg I, Zareba W, Sparks CE. Thrombospondin-4 Polymorphism (A387P) Predicts Risk in Postinfarction Patients with High HDL Cholesterol and CRP Levels. Thrombosis and Haemostasis. 2011;106:1170-1178.
Ryan D, Rainwater DL, Moss AJ, Zareba W, and Sparks CE. Decreased CETP Activity Associates with Recurrent Risk in Postinfarction Patients with High HDL Cholesterol and High CRP. Atherosclerosis, Thrombosis, and Vascular Biology. 2010;30:1657-1664.