ProSanos Corporation Confidential and Proprietary Modeling and clustering disease progression for correlation with genetic and demographic factors Robert Kingan

ProSanos Corporation Confidential and Proprietary What is SSIFT?  “To address […] common diseases, which include schizophrenia, depression, and breast cancer, it is essential to incorporate observations of the clinical progression of the disease to refine the definition of phenotype.” – Michael N. Liebman, U. Penn.  Yes, but what is SSIFT? –SSIFT = Stratification and Synchronization Inference Technology

ProSanos Corporation Confidential and Proprietary What is SSIFT?  Stratification: Dividing a patient population into groups which are meaningful for diagnosis, prognosis, treatment selection, or genotype- phenotype correlation.  Synchronization: Recognizing a pattern of disease progression, regardless of disease stage for a particular patient.

ProSanos Corporation Confidential and Proprietary SSIFT overview  Assumptions—what is SSIFT-able  Other constraints on data selection  Outline of technique –Identifying variables –Modeling disease progression –Parameterizing different models –Clustering patients by progression patterns –Interpreting the results

ProSanos Corporation Confidential and Proprietary Pattern of disease progression Time Disease marker initial value final value period of change

ProSanos Corporation Confidential and Proprietary SSIFT workflow Survey the data Select useful variables Fit disease progression models Construct feature vectors Assign feature weights Cluster weighted feature vectors Evaluate the clustering results Complete? No Yes

ProSanos Corporation Confidential and Proprietary SSIFT workflow SSIFT

ProSanos Corporation Confidential and Proprietary SSIFT curve types

ProSanos Corporation Confidential and Proprietary Converting parameters Logistic Constant Linear Early stable Late stable y* = population mean, t 1 =first time point, t n =last time point

ProSanos Corporation Confidential and Proprietary Modified Mahalanobis distance

ProSanos Corporation Confidential and Proprietary SSIFT workflow Survey the data Select useful variables Fit disease progression models Construct feature vectors Assign feature weights Cluster weighted feature vectors Evaluate the clustering results Complete? No Yes

ProSanos Corporation Confidential and Proprietary SSIFT workflow Survey the data Select useful variables Fit disease progression models Construct feature vectors Assign feature weights Cluster weighted feature vectors Evaluate the clustering results Complete? No Yes Correlate results with: demographic data genetic data

ProSanos Corporation Confidential and Proprietary Application of SSIFT to NIDDK  About NIDDK  SSIFT and transplant data  Variable selection  Modeling  Results

ProSanos Corporation Confidential and Proprietary Candidate variables   -Fetoprotein  Albumin  Alkaline phosphatase (AP)  Bicarbonate  Blood urea nitrogen (BUN)  Calcium  Creatinine clearance  Cholesterol  Chlorine  Corrected PT control  Creatinine  Direct bilirubin  FK506 level  Glomerular filtration rate  Gamma GTP  Glucose  Hematocrit (HCT)  Hemoglobin  CSA HPLC level  Potassium  CSA monoclonal level  Sodium  Platelet count  Prothrombin time  Part. thromboplastin CT  Part. thromboplastin PT  CSA RIA level  SGOT (AST)  SGPT (ALT)  Total bilirubin  CSA TDX level  Total protein  White blood cells (WBC)  Weight in KG

ProSanos Corporation Confidential and Proprietary Selected variables VariableLog? ŜuŜu Weights ŜwŜw abm  ASTYes APYes HemoglobinNo Total bilirubinYes PotassiumNo HematocritNo WBCYes BUNYes CreatinineYes SodiumNo

ProSanos Corporation Confidential and Proprietary Evaluating Kaplan-Meier curves ŜŜ

ProSanos Corporation Confidential and Proprietary Final selected variables  Best pair: AST + AP,  Ŝ=0.34  Best triple: AST + AP + hematocrit,  Ŝ=0.42  No set of four variables exceeded  Ŝ=0.42

ProSanos Corporation Confidential and Proprietary Survival by clustered SSIFT AST, AP and HCT parameters  Ŝ = 0.42

ProSanos Corporation Confidential and Proprietary Cluster mean curves Best cluster Worst cluster

ProSanos Corporation Confidential and Proprietary SSIFT in Gene Discovery: Simulation Time Markers SSIFT™ Disease Genes Disease Progression Pattern Determine Analyze Discover

ProSanos Corporation Confidential and Proprietary Simulated data Marker Value (relative scale) Time (years)

ProSanos Corporation Confidential and Proprietary Clustering Results

ProSanos Corporation Confidential and Proprietary Nearest-Neighbor Analysis GeneGenotype for Nearest Neighbors, based on SSIFT Pattern C D J A J W C2353 L P R K K D S S B B S T C2353 is related to SSIFT pattern of disease progression (p< ).

ProSanos Corporation Confidential and Proprietary SSIFT: Stratification and Synchronization Inference Technology Discussion