Biomarkers and undiagnosed disease Soham Al Snih, MD, Ph.D The University of Texas Medical Branch, Galveston, TX May 29, 2015 Mexico City, Mexico
Biomarkers Broad subcategory of medical signs Objective indications of medical state observed from outside the patient Can be measured accurately and reproducibly
Biomarkers Many terms are used to describe measurements of disease and treatment: Biological markers Biomarkers Surrogate markers Surrogate endpoints Intermediate endpoints Involvement of a variety of disciplines - clinical trialists, statisticians, regulators, and therapeutic developers
Biomarkers Biomarkers Definition Working Group, convened by the National Institutes of Health Director's Initiative on Biomarkers and Surrogate Endpoints - 1998 Biological marker (biomarker) A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention
Biomarkers Applications in disease detection and monitoring of health status Use as a diagnostic tool for the identification of those patients with a disease or abnormal condition - Elevated blood glucose concentration for the diagnosis of diabetes mellitus Use as a tool for staging of disease - Measurements of carcinoembryonic antigen- 125 for various cancers - Classification of the extent of disease (prostatespecific antigen concentration in blood used to reflect extent of tumor growth and metastasis)
Biomarkers Applications in disease detection and monitoring of health status Use as an indicator of disease prognosis - Anatomic measurement of tumor shrinkage of certain cancers Use for prediction and monitoring of clinical response to an intervention - Blood cholesterol concentrations for determination of the risk of heart disease
Biomarkers Clinical endpoint A characteristic or variable that reflects how a patient feels, functions, or survives - Quality of life - Physical and cognitive function - Disability
Biomarkers Surrogate endpoint A biomarker that is intended to substitute for a clinical endpoint Is expected to predict clinical benefit (or harm or lack of benefit) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence
Biomarkers Characteristics of an ideal biomarker Safe and easy to measure Cost efficient to follow up Modifiable with treatment Consistent across gender and race/ethnic groups
Biomarkers Biomarkers of aging Predict a person s physiological, cognitive, and physical function independent of chronological age Testable and not harmful to the test subjects (blood tests or imaging technique) Work in laboratory animals as well as humans
Biomarkers Advantages and Disadvantages Advantages Objective assessment Precision of measurement Reliable; validity can be established Less biased than questionnaires Disease mechanisms often studied Homogeneity of risk or disease Disadvantages Timing is critical Expensive (costs for analyses) Storage (longevity of samples) Laboratory errors Normal range difficult to establish Ethical responsibility
Biomarkers Biomarkers of aging under investigation in laboratory and epidemiologic research Biomarker Measured aspect of aging Associated disease if high Interleukin 6 C-reactive protein Inflammation, infection, oxidation Inflammation, infection, oxidation, liver function CVD, cancer, diabetes, sarcopenia, frailty, cognitive decline CVD, cancer, diabetes, sarcopenia, frailty, cognitive decline Aortic calcification Arteriosclerosis Arteriosclerosis Pulse wave velocity Arterial stiffness Hypertension Associated disease if low Liver disease Brain volume Cognitive reserve Dementia Gait speed Muscle function, peripheral and central nervous system function, cardio-pulmonary fitness
Biomarkers NIA Biomarkers of disease progression Launch research programs to develop and validate sensitive neuropsychological assessment measures to detect and track the earliest clinical manifestations of Alzheimer s disease
Biomarkers Latin America Mexican Health and Aging Study (MHAS) Cost a Rican Longevity and Health Aging Study Health, Well-Being and Aging in Latin America and the Caribbean (SABE) Study SABE Brazil SABE Colombia United States Health and Retirement Study Baltimore Longitudinal Study on Aging Europe English Longitudinal Study of Ageing (ELSA) Survey of Health, Aging and Retirement in Europe (SHARE) The Irish Longitudinal Study on Ageing (TILDA) Asia Korean Longitudinal Study on Ageing Japanese Study of Aging and Retirement (JSTAR) The China Health Aging and Retirement Longitudinal Study
Undiagnosed disease Undiagnosed diabetes: Findings from the Mexican Health and Aging Study Use as a diagnostic tool for the identification of those patients with a disease or abnormal condition
Undiagnosed disease Global diabetes prevalence International Diabetes Federation, 6 th Edition, 2014
Undiagnosed disease NORTH AMERICA AND CARIBBEAN at a glance 38.8 million people have diabetes - 1 in 9 adults Highest prevalence across regions 11.5% Lowest undiagnosed rate 27.1% USD 310 billion expenditure more than all other regions combined International Diabetes Federation, 6 th Edition, 2014
Undiagnosed disease SOUTH AND CENTRAL AMERICA at a glance 25 million people have diabetes - 1 in 12 adults 5% of worldwide expenditure USD 28.7 billions International Diabetes Federation, 6 th Edition, 2014
Undiagnosed disease Expert Committee on Diagnosis and Classification of Diabetes Mellitus A1C 6.5% The test should be performed in a laboratory using a method that is NGSP* certified and standardized to the DCCT assay OR FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h OR Two-hour PG 200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water OR In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose 200 mg/dl (11.1 mmol/l) * National Glycohemoglobin Standardized Program Diabetes Care 38, Supplement 1, January 2015
Undiagnosed disease Prevalence of undiagnosed diabetes in Mexico National Health and Nutrition Survey (ENSANUT) 2006 subsample of 4,687 participants without previous diagnosis of diabetes IFG - 5.2 % Abdominal obesity was the antrhopometric measure strongly associated with undiagnosed diabetes
Collection of intravenous and capillary blood tests: hemoglobin, HbA1c, total cholesterol, high density cholesterol, vitamin D, thyroid-stimulating hormone (TSH), and CRP - ISPM Blood pressure Undiagnosed disease Sub-sample (N=2086) Anthropometric measures: weight, height, knee height, waist and hip circumference Physical performance measures: balance, walk test, and muscle strength The targeted sub-sample was the full sample in four states: Rural state Urban state High-US-migration state High diabetes state
Sample Total sample N = 18,465 Sub-sample N = 2086 Age 50 years N = 1930 Sample= 1861 - Missing in HbA1c = 46 - Self-reported diabetes in 2001 or 2002 = 14 - Missing information in selfreported diabetes 2012 = 8 No - Self-reported Diabetes N = 1440 Yes - Self-reported Diabetes N = 421
Undiagnosed disease Outcome Undiagnosed diabetes - A1c 6.5% (Finger Prick) - AC1 Now - NGSP certified Advantage: - No need for fasting - Average of glucose in the last 4 months Limitations: - Conditions that affect red blood cell turnover (hemolysis, blood loss) and hemoglobin variants - Patients with Kidney disease - High cost
Undiagnosed disease Overall percent of undiagnosed diabetes % 80 70 60 50 40 30 20 10 0 76.7 Normal (HbA1C < 6.5) 23.3 Undiagnosed diabetes (HbA1c >=6.5)
Undiagnosed disease Descriptive characteristics Normal (HbA1c 6.5) Undiagnosed diabetes (HbA1c 6.5) Age (years) mean (SD) 63.6 (9.9) 63.7 (9.6) 50 to < 60 476 (43.1) 130 (38.7) 60 to < 70 338 (30.6) 122 (36.3) 70 to < 80 196 (17.8) 59 (17.6) >=80 94 (8.5) 25 (7.4) Female 619 (56.1) 202 (60.1) Married 726 (65.8) 230 (68.5) Years of formal education 6.1 (4.9) 5.8 (4.3) mean (SD) * No education 174 (15.9) 42 (12.5) 1-5 years 309 (28.3) 100 (29.8) 6 years 236 (21.6) 90 (26.9) >=7 years 374 (34.2) 103 (30.8) * p-value < 0.05
Undiagnosed disease Descriptive characteristics Normal (HbA1c 6.5) Undiagnosed diabetes (HbA1c 6.5) Family history of diabetes 320 (30.8) 110 (34.2) Residence (urban versus 634 (57.4) 199 (59.2) rural) High U.S. migration state * 638 (57.8) 156 (46.4) Family history of diabetes 196 (17.8) 59 (17.6) Physical Activity 94 (8.5) 25 (7.4) Smoking Status Never 677 (61.3) 211 (62.8) Ever 282 (25.5) 79 (23.5) Current 145 (13.1) 46 (13.7) Hypertension 412 (37.5) 134 (40.0) Stroke 18 (1.6) 5 (1.5) Heart Attack 28 (2.5) 8 (2.4) * p-value < 0.05
Undiagnosed disease Descriptive characteristics BMI(Kg/m 2 ) category * Normal (HbA1c 6.5) Undiagnosed diabetes (HbA1c 6.5) Normal (18.5 to <25) 308 (28.4) 41 (12.4) Overweight (25 to <30) 434 (39.9) 125 (37.8) Obese ( 30) 344 (31.7) 165 (49.9) High Waist Circumference * 596 (54.7) 245 (73.8) High Waist Hip Ratio 944 (86.7) 304 (91.6) Physician visits 863 (78.2) 273 (81.3) Insurance coverage 918 (83.3) 287 (85.4) Diabetes screening 732 (66.3) 236 (70.2) * p-value < 0.05 High WC = >102 cm in men and >88 cm in women. High WHR = >90 in men and >85 in women
Undiagnosed disease Multivariate analysis OR (95% CI) Physical activity 0.69 (0.53-0.91) High U.S. migration state 0.53 (0.40-0.70) BMI(Kg/m 2 ) category Normal (18.5 to <25) Reference Overweight (25 to <30) 1.74 (1.10 2.77) Obese ( 30) 2.56 (1.51 4.36) High Waist Circumference 1.59 (1.05 2.42) High WC = >102 cm in men and >88 cm in women
Surrogate marker Glycemic control Diabetes (N=421) % 80 70 60 50 40 30 20 10 0 27.1 72.9 Good control (HbA1c < 7) Poor control (HBA1c >=7) Decreased risk of microvascular complications
Multivariate analysis Good glycemic control HbA1c <7 OR (95% CI) Age 65 years 2.35 (1.34 4.13) Residence (urban versus rural) 2.00 (1.22 3.29) Diabetes treatment None Reference Oral hypoglycemic 0.42 (0.19 0.95) Insulin or /and oral hypoglycemic 0.14 (0.05 0.41)
% 80 70 60 50 40 30 20 10 0 Self-reported diabetes 23.2 % 27.1 Good control (HbA1c < 7) 72.9 Poor control (HBA1c >=7) No Self-reported diabetes 76.8 % 20.1 Normal HbA1c < 5.7 56.5 Prediabetes HbA1c -5.7-6.4) 23.3 Undiagnosed Diabetes - HbA1c >= 6.5
Undiagnosed disease Summary Percent of undiagnosed diabetes (23.3%) Physical activity and high migration state - less risk for undiagnosed diabetes Total and abdominal obesity - high risk for undiagnosed diabetes Only 23.3 % - good glycemic control aged 65 years and older and urban residence
Undiagnosed disease Implications (Diabetes prevention) Weight loss of 7% of body weight Increase physical activity to at least 150 min/week of moderate activity such as walking Metformin therapy for prevention of type 2 diabetes may be considered in those with IGT, IFG, or an A1C 5.7 6.4%, especially for those with BMI 35 kg/m2 and those aged 60 years Screening for and treatment of modifiable risk factors for CVD is suggested Better control of diabetes
Acknowledgment This study was supported by the National Institutes of Health (R01-AG018016, R. Wong, PI)