Identification and Validation of Biomarkers in Disease States

Transcription

1 Identification and Validation of Biomarkers in Disease States Patrick J. Stover, PhD Vice Chancellor and Dean for Agriculture and Life Sciences

2 Disclosures AFFILIATION/FINANCIAL INTERESTS (prior 12 months) ORGANIZATION Grants/Research Support: Scientific Advisory Board/Consultant: Speakers Bureau: NIH: T32-DK R37DK58144; ODS Supplement HD NHSc; Biofortis, Marabou Foundation; National Academy of Sciences Chronic Disease Endpoints Committee None Stock Shareholder: TIAA Owner MetabolicSolutions LLC 2

3 Biomarkers and Classifying and Evaluating Human Nutrient Needs DRIs based on Chronic Disease Endpoints Nutrients Dose-Response Chronic Disease Special Nutrient Requirements Disease Severity Dose-Response Disease Nutrients Disease Classify Individuals 3

4 Iodine: J Nutr 2014 Folate: J Nutr 2015 Zinc: J Nutr Vit A: J Nutr Vit B12: In preparation Iron: In preparation

5 Biomarkers of Nutrition for Development (BOND) Program Biomarker: A distinct biological or biologically derived molecule found in blood, other body fluids, or tissues that is a sign of a process, event, condition, or disease. Within the context of nutrition, measuring nutrient-specific biomarkers can determine: Exposure Status Function Effect 5

6 Biomarkers and Surrogate Endpoints for Establishing Nutrient Requirements in Disease Clinical Health Outcome A Validated Surrogate Biomarker(s) that directly relates a nutrient intake level to a health outcome along a causal pathway A Non-validated Intermediate Functional Biomarker(s) that may not necessarily be related to a clinical outcome but that report on a doseresponse relationship between a nutrient intake level and a physiological response(s) 6

7 Disease influences whole-body nutrient status and/or specific tissue nutrient status Maceyka et al, 2012 Trends in Cell Biology: 22, p50 7

8 Classifying and Evaluating Human Nutrient Needs Indicators Groups Health Disease Prevention *Disease Management Primary - Secondary Tertiary Acute - Chronic Whole Body Nutritional Status* Normal Physiological Function* Clinical Outcomes* Predictive Biomarkers* * Co-morbidities *Tissue Specific Nutritional Status *Restoration of Function *Tissue Regeneration Dietary Reference Intakes Special Nutritional Requirements 50% of the US adult population suffers from a chronic disease Prev. Chronic. Dis. 2014, 11, E62

9 Analytic Framework Applicable to Assessment of Nutrients I Exposure IVa II Indicator Markers Exposure III Validated Surrogate Outcomes Whole Body?? V Tissue?? Cell? Non Validated Intermediate Markers IV IIa? IIIa Clinical Outcome Primary Disease Disease Progression / Comorbidity I. Association of exposure with clinical outcomes of interest II. Association of exposure with validated surrogate outcomes of interest (functional biomarker) III. Association of exposure with intermediate biomarker of interest (to clinical outcome) IV. Association of exposure indicators to clinical outcomes of interest V. Association of exposure indicator to surrogate outcome of interest Russell et al Am J Clin Nutr

10 Classifying and Evaluating Brain Folate Needs in Disease Blood Nutrient Biomarkers (whole body) BBB Functional Biomarkers CSF Nutrient Biomarkers (Brain) Blood Nutrient Biomarkers BBB Functional Biomarkers CSF Nutrient Biomarkers RBC Folate Folate Receptor α autoantibodies CSF Folate Serum Folate S100β GFAP Homocysteine Homocysteine Inflammatory markers 10

11 Classifying and Evaluating Human Nutrient Needs in Disease Classify Disease (Individual or Population) Biomarker of Primary Disease (Prognostic Biomarkers) Biomarker(s) of Responsive Nutrient Deficiencies (Predictive Biomarkers) Precision Medicine as a Model? Nature Medicine (Mar. 2011): p304. Biomarker of Nutrition Adequacy in Disease Exposure Status Function Clinical Improvement (Related to the Disease-induced Nutritional Deficiency) 11

12 Precision Nutrition As disease progresses in severity, are nutrient needs altered? If Disease-Nutrient Need relationship is stable, then classification of clinical subgroups for Special Nutrient Requirements may be possible. If Disease-Nutrient Need relationship is dynamic, then monitoring is needed. - Real Time Personalized Readouts of Health/Disease and Nutrition/Physiology Data will be readily accessible! What guidance will we (or the cell phone) give?

13 Disease can Independently Modify Nutritional Status and Nutrition Biomarkers Nutrient Status Nutrient Biomarkers Inflammation Inflammation modifies the nutrientbiomarker relationship because: Acute and chronic inflammation can modify nutrient biomarker measures. Inflammation can have a direct effect on actual nutrient status. 13

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15 Complex Interactions Between Inflammation and Nutrition The prevalence of low TBI is underestimated if it is not adjusted by inflammation, particularly in children living in areas with a high prevalence of inflammation. 15

16 Chronic Disease Endpoints - Challenges of Prevention - Chronic Diseases are complex traits age, diet, genetics, epigenetics, environment Few chronic diseases are affected by: single nutrients single pathways Consider systems/networks over pathways Establish system readouts as biomarkers (integrative biomarkers) Consider DRIs as ranges in lieu of point estimates Understand biomarkers of aging system decay GRADE standards of evidence Food as Medicine

17 System Biomarkers of Central Metabolism 17

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21 A Platform for Rapid Exploration of Aging and Diseases in a Naturally Short-Lived Vertebrate Cell 160, , 2015

22 The Epigenetic Landscape Decays with Age Nature Reviews Mol. Cell Biol 2015, Vol 16,

23 Neurodegeneration: DNA Damage and Biomarkers DNA damage and DNA repair are common hallmarks of neurodegenerative disorders including Alzheimer s, Parkinson s, and neuromuscular disorders (Hoch, et. al. (2017) Nature 541: 87-91; Ross and Truant (2017) Nature 541: ). DNA damage of stem cells and the stem cell niche may affect tissue regeneration and repair. 23

24 Folate functions in 1-C transfers THF + Formate (from mitochondria) 5-CH 3 -THF RFC 5-CH 3 -THF Cellular Methylation 10-Formyl-THF Purines 5-CH 3 -THF MTHFD1 5,10-CH-THF MTHFR B-2 5,10-CH 2 -THF 5-CH 3 -THF dump Glycine B-6 SHMT Serine TS THF Thymidylate DHFR DHF DHFR Folic Acid FA FR Methionine MTR B12 Homocysteine CBS B-6 SAM X MTs CH SAH 3 -X Cystathionine PCFT FA 5-CH 3 -THF 24

25 DNA Damage in Diabetics is Responsive to Very High Dose Folic Acid Diabetics exhibit more DNA damage; normalizes after 30 days treatment with high-dose folic acid (15 mg/day). Diabetics may have special nutritional needs to correct this biomarker of DNA damage in buccal cells. DNA damage may be a good predictive biomarker for folic acid nutritional needs in diabetes. Buccal cells may be a proxy for peripheral nerve? % of cells with mutation Frequency of nuclear abnormalities Healthy controls Diabetic patients Diabetic patients taking folic acid Mutat Res Genet Toxicol Environ Mutagen Feb;797:1-8

26 Martha Field Karsten Hiller