DOES THE ALCOHOL T SCORE (ATS) PREDICT MORTALITY IN THE PLCO POPULATION? - EXCESSIVE ALCOHOL CONSUMPTION IS THOUGHT TO BE THE THIRD LEADING PREVENTABLE CAUSE OF DEATH IN THE UNITED STATES. BUT THESE ESTIMATES OF THE DELETERIOUS EFFECT OF ALCOHOL ARE LARGELY BASED OFF SELF-REPORTS OF ALCOHOL CONSUMPTION. CONCERNINGLY, BECAUSE WE AND OTHERS HAVE SHOWN THAT CLINICAL SELF-REPORTS ARE UNRELIABLE, WHILE OTHERS HAVE SHOWN THAT THE ESTIMATES OF DAILY ALCOHOL CONSUMPTION BY CDC ARE OFF BY AT LEAST THREE-FOLD, THE TRUE COST OF EXCESSIVE DRINKING MAY BE MUCH HIGHER. IN FACT, IT IS POSSIBLE THAT EXCESSIVE ALCOHOL CONSUMPTION IS THE LEADING PREVENTABLE CAUSE OF DEATH. WE HAVE DEVELOPED A METHYLATION SENSITIVE DIGITAL PCR (MSDPCR) TEST CALLED THE ALCOHOL T SCORE (ATS) THAT QUANTIFIES CHRONIC ALCOHOL CONSUMPTION. IN SEVERAL PEER REVIEWED STUDIES, WE HAVE SHOWN THAT THE ATS SIGNIFICANTLY OUTPERFORMS THE CARBOHYDRATE DEFICIENT TRANSFERRIN (CDT) TEST, THE CURRENT INDUSTRY GOLD STANDARD, IN PREDICTING CHRONIC HEAVY ALCOHOL CONSUMPTION (HAC; 6 DRINKS/DAY FOR 8 WEEKS) AND STRONGLY PREDICTS DEATH IN THOSE WITH SEVERE CORONARY HEART DISEASE. WE RECENTLY EXAMINED AN EPIDEMIOLOGICALLY SOUND SAMPLE OF DNA AND DATA FROM 4910 SUBJECTS (3:1 MIX OF LUNG CANCER CASES AND CONTROLS) WHO PARTICIPATED IN THE PROSTATE, LUNG, COLORECTAL AND OVARIAN (PLCO) CANCER SCREENING TRIAL WITH THE ATS. WE FOUND THAT THE ATS WAS A POWERFUL PREDICTOR OF MORTALITY IN SMOKERS WITH (N=92) AND WITHOUT LUNG CANCER (N=402). IN FACT, IN BOTH GROUPS, THE EFFECTS OF ALCOHOL CONSUMPTION ON MORTALITY GREATLY OUTWEIGHED THOSE OF SMOKING. TAKEN TOGETHER WITH OUR PRIOR FINDINGS, THESE NEW FINDINGS STRONGLY SUGGEST THAT HEAVY DRINKING, NOT SMOKING IS THE LARGEST PREVENTABLE CAUSE OF MORTALITY IN THE UNITED STATES. UNFORTUNATELY, THIS SAMPLE WAS LARGELY WHITE AND NONSMOKING, WHICH LIMITS GENERALIZABILITY OF THE RESULTS. THEREFORE, IN THIS HIGH-RISK R43 STUDY, WE PROPOSE TO EXTEND OUR ATS DETERMINATIONS TO ALL NON-SMOKING SUBJECTS IN THIS GROUP (N=612) AND ALL OF THOSE OF NON-WHITE ANCESTRY (N=985) FROM OUR EXISTING COHORT OF 5000 SUBJECTS FROM THE PLCO COHORT. WE HYPOTHESIZE THAT THE ATS WILL PREDICT MORTALITY BROADLY ACROSS BOTH SEXES, AND IN ALL ANCESTRIES WHETHER OR NOT THEY SMOKE. THIS PROJECT IS INNOVATIVE BECAUSE HEAVY ALCOHOL CONSUMPTION (HAC) IS OFTEN MISSED BY CLINICIANS. IT IS HIGH IMPACT BECAUSE HAC MAY BE A SIGNIFICANT, IF NOT THE LARGEST PREVENTABLE CAUSE OF DEATH IN THE UNITED STATES. THE TEAM IS WELL PREPARED TO CONDUCT THE RESEARCH INCLUDING STATISTICIANS AND A LEADING EXPERT ON DNA METHYLATION. IT IS HIGHLY FEASIBLE BECAUSE THE ASSAY ALREADY EXISTS AND WE HAVE BOTH THE DNA AND THE DATA. AS A DIRECT RESULT OF THIS RESEARCH, WE WILL DETERMINE THE FREQUENCY AND EFFECT OF HAC ON A BROAD EPIDEMIOLOGICALLY SOUND, CROSS SECTION OF THE AMERICAN PUBLIC. AS AN INDIRECT OUTCOME, WE WILL DEMONSTRATE THE POTENTIAL USE CASE FOR CONDUCTING THIS RAPID, EASY TO PERFORM MSDPCR TEST AS PART OF MEDICAL ASSESSMENTS OF THOSE PRESENTING FOR LUNG OR PERHAPS ANY OTHER CANCER SCREENING WHILE GATHERING NEEDED DATA FOR EVENTUAL APPROVAL OF THE ATS BY THE FDA AS A TEST FOR HAC.