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

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

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 Definition Working Group, convened by the National Institutes of Health

Director's Initiative on Biomarkers and Surrogate Endpoints - 1998

Biomarkers

Biomarkers

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 (prostate- specific antigen concentration in blood used to reflect extent of tumor growth and metastasis)

Applications in disease detection and monitoring of health status

Biomarkers

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

Applications in disease detection and monitoring of health status

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

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

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 Disadvantages Objective assessment Timing is critical

Precision of measurement Expensive (costs for analyses)

Reliable; validity can be established Storage (longevity of samples)

Less biased than questionnaires Laboratory errors

Disease mechanisms often studied Normal range difficult to establish

Homogeneity of risk or disease Ethical responsibility

Biomarkers Biomarkers of aging under investigation in laboratory and epidemiologic research

Biomarker Measured aspect of aging Associated disease if high

Associated disease if low

Interleukin – 6 Inflammation, infection, oxidation

CVD, cancer, diabetes, sarcopenia, frailty, cognitive decline

C-reactive protein Inflammation, infection, oxidation, liver function

CVD, cancer, diabetes, sarcopenia, frailty, cognitive decline

Liver disease

Aortic calcification Arteriosclerosis Arteriosclerosis

Pulse wave velocity

Arterial stiffness Hypertension

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 diabetes: Findings from the Mexican

Health and Aging Study

Undiagnosed disease

Use as a diagnostic tool for the identification of those patients with a disease or abnormal condition

Global diabetes prevalence

International Diabetes Federation, 6th 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, 6th 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, 6th 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)

Diabetes Care 38, Supplement 1, January 2015

Undiagnosed disease

* National Glycohemoglobin Standardized Program

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

Undiagnosed disease

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

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

Sub-sample (N=2086) Undiagnosed disease

Sample

Sub-sample N = 2086

Age ≥ 50 years N = 1930 - Missing in HbA1c = 46

- Self-reported diabetes in 2001 or 2002 = 14 - Missing information in self-reported diabetes 2012 = 8

No - Self-reported Diabetes N = 1440

Yes - Self-reported Diabetes N = 421

Total sample N = 18,465

Sample= 1861

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

76.7

23.3

01020304050607080

%

Normal (HbA1C <6.5)

Undiagnoseddiabetes (HbA1c

>=6.5)

Undiagnosed disease

Descriptive characteristics Undiagnosed disease

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 mean (SD) *

6.1 (4.9) 5.8 (4.3)

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 Undiagnosed disease

Normal (HbA1c ≥ 6.5)

Undiagnosed diabetes (HbA1c ≥ 6.5)

Family history of diabetes 320 (30.8) 110 (34.2) Residence (urban versus rural)

634 (57.4) 199 (59.2)

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

Normal (HbA1c ≥ 6.5)

Undiagnosed diabetes (HbA1c ≥ 6.5)

BMI(Kg/m2) category * Normal (18.5 to 88 cm in women. High WHR = >90 in men and >85 in women

* p-value < 0.05

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/m2) category

Normal (18.5 to 88 cm in women

Undiagnosed disease

27.1

72.9

01020304050607080

%

Good control (HbA1c < 7) Poor control (HBA1c >=7)

Glycemic control Diabetes (N=421)

Surrogate marker

Decreased risk of microvascular complications

Multivariate analysis Good glycemic control HbA1c

27.1

72.9

20.1

56.5

23.30

10

20

30

40

50

60

70

80

Good control(HbA1c < 7)

Poor control(HBA1c >=7)

Normal HbA1c< 5.7

PrediabetesHbA1c -5.7 -

6.4)

UndiagnosedDiabetes -

HbA1c >= 6.5

%

Self-reported diabetes 23.2 %

No Self-reported diabetes 76.8 %

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

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

Implications (Diabetes prevention)

Undiagnosed disease

Acknowledgment This study was supported by the National Institutes of Health (R01-AG018016, R.

Wong, PI)

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