Biomarkers and Social Sciences

1. Biomarkers and Social Sciences Elliot Friedman Biomarkers, Genetics, and Social Sciences Workshop July 7, 2010

2. Biomarkers and social sciences • What is a “biomarker?” • Indicator of some biological process • Biological processes are designed to serve adaptive functions • Can become damaging to health under certain circumstances • A potential mechanistic link between social factors and health outcomes • How social factors may “get under the skin”

3. Example – social status and health • Health status is graded by social status • Living in poverty • 12 fewer years of life • 16 fewer years of disease/disability-free life

4. Social patterning of healthLife expectancy in England and Wales (1992-1996) Class I – V difference Men: 9.5 yrs Women: 6.4 yrs Source: Office of National Statistics Longitudinal Study Marmot, PerspectBiol Med, 2003

5. Example – social status and health • Health status is graded by social status • Living in poverty • 12 fewer years of life • 16 fewer years of disease/disability-free life • What accounts for social gradients in health? • Possible explanations • Differential access to health care • But gradient seen in countries with universal health care • Poorer health behavior among the poor • Explains only ~30% of the relationship • Psychosocial factors, especially stress

6. Psychological stress • What makes stress stressful? • i.e. under what circumstances would we expect to see changes in biology? • Transaction between individual and environment • Stressor • Controllability, predictability, severity • Individual • Genetic background • Life experiences • Coping resources • Appraisal of threat to physical or psychological integrity • Activation of stress response systems • Does the stress process offer insights into health disparities?

7. Stressor characteristics Individual attributes High predictability High control Low severity Positive appraisal Appropriate coping Health • Perceived threat accounts for link between education and physical health symptoms2 • Sense of control mediates link between income and health3 Those with <HS education experience a greater number of severe stressors on a day-to-day basis1 Stressor Low predictability Low control High severity Negative appraisal Mismatched coping Illness Cumulative experiences over the life-course 1Almeida et al., 2005; 2Almeida et al., 2005; 3Lachman & Weaver, 1998

8. Example – social status and health • Biomarkers • Should be associated with health outcomes of interest • Should exhibit patterning by social status • Associated with relevant psychosocial factors • Candidate biomarkers: • Neuroendocrine and autonomic hormones • Focus on cortisol • Inflammatory proteins

9. Organizational model:psychosocial factors and physiological dysregulation Social Status Psychosocial Processes Health Behaviors Neuroendocrine and autonomic regulatory systems Inflammatory proteins Disease

10. Plan for the afternoon • Part I Neuroendocrine and autonomic hormones • Part II Inflammatory proteins • Part III Multi-system dysregulation

11. Part INeuroendocrine and autonomic hormones

12. Hormones • Neuroendocrine • Hypothalamic-pituitary-adrenal (HPA) axis • Hormone product: cortisol • Autonomic • Sympathetic nervous system • Hormone products: epinephrine and norepinephrine • Parasympathetic nervous system • Hormone product: acetylcholine • Can also be measured indirectly • Control of heart rate

13. HPA Axis CRF – Corticotropin-releasing factor ACTH – Adrenocorticotropic hormone Cortisol

14. Stress response • External demand perceived as threatening • Need to marshal resources to adapt • Increase blood sugar • Increase heart rate and blood pressure • Inhibit non-essential functions • Digestion, protein synthesis, reproductive functions

15. Negative Feedback HIPPOCAMPUS In the presence of sustained exposure to cortisol, feedback is lost

16. Cortisol and hippocampal volume Lupien et al., Nat Neurosci., 1998

17. Measuring cortisol • Source of cortisol • Urine • Blood • Saliva • Type of measurement • Assessment of stable levels • Assessment of dynamic change

18. Measuring cortisol • Stable levels • Urinary cortisol • Integrative measure • Need to adjust for urine concentration • Typically by using creatinine levels • Blood or saliva Sapolsky et al (1997), Archives of General Psychiatry, 54: 1137-1143 Kiecolt-Glaser et al. (1984), Psychosomatic Medicine, 46: 15-23

19. Measuring cortisol Up to 50% increase in cortisol 30-45 min after awakening • Dynamic change • Diurnal rhythm • Cortisol awakening response (CAR) • Daily decline • Area under the curve (AUC)

20. Measuring cortisol • Dynamic change • Response to challenge • Amplitude of response • % of baseline • Duration of response • Time to return to baseline

21. Evaluating cortisol • What do the different assessments tell you? • Stable levels • Urinary sample is most reliable • Time scale: ½ to full day • Q: How do social factors relate to stable levels of cortisol? • Diurnal patterns • Time scale: hours; times of day • Q: How do social factors relate to dynamics of daily cortisol regulation? • Response to challenge • Time scale: minutes • Q: How do social factors relate to HPA system’s ability to respond to and recover from an acute challenge?

22. Cortisol as candidate biomarker • Cortisol is related to health outcomes • Cushing’s Disease associated with increased risk of cardiovascular disease • Daily cortisol rhythms linked to health

23. Cortisol and cancer survival Sephton et al.(2000), Journal of the National Cancer Institute, 92: 994-1000

24. Cortisol as candidate biomarker • Cortisol is related to health outcomes • Cushing’s Disease associated with increased risk of cardiovascular disease • Daily cortisol rhythms linked to health • Cortisol is patterned by social factors (including status)

25. Social factors and diurnal cortisol patterns Data from the Multi-Ethnic Study of Atherosclerosis (MESA; N = 935) Hajat et al (2010), Psychoneuroendocrinology, 35: 932-943

26. Social factors and diurnal cortisol patterns Data from the study of Coronary Artery Risk Development in Adolescents (CARDIA; N = 781) Cohen et al (2006), Psychosomatic Medicine, 68: 41-50

27. Cortisol as candidate biomarker • Cortisol is related to health outcomes • Cushing’s Disease associated with increased risk of cardiovascular disease • Daily cortisol rhythms linked to health • Cortisol is patterned by social factors (including status) • Associated with relevant psychosocial factors • Stressors increases cortisol levels • Social-evaluative threats are the most potent • Mitigating factors • Perceptions of control or predictability • Social support • Severe or chronic stress changes cortisol regulation • Flatter diurnal slopes • Amplified responses to acute stressors

28. Cortisol across the day Low employment grade High employment grade Steptoe et al., 2003

29. Using cortisol data • Tends to be positively skewed; often outliers • Trimming and log-transformations typically applied • Consider variables that affect cortisol and might represent confounds • Serious illness • Endocrine disorders • 3rd trimester of pregnancy • Steroid medications • Menstrual cycle timing • Body weight • Exercise levels • Caffeine intake • Smoking status • Medication use Common exclusion criteria Typically statistically controlled

30. Using cortisol data • Additional considerations • What time of day were data collected? • Important for blood and saliva in particular • For daily samples, how was collection time verified? • Critical for determining daily patterns, like CAR or decline

31. Importance of sample timing Kudielka et al (2003), Psychosomatic Medicine 65: 313-319

32. Age and the CAR:Rationale for multi-day cortisol sampling Data from the Survey of Mid-Life in the United States (MIDUS; N = 1,143 Almeida et al (2009), Psychology and Aging, 24: 819-827

33. Summary • Cortisol can be measured in many ways, each of which provide different sorts of information • Social adversity and poorer health outcomes typically associated with • Higher urinary levels • Flatter diurnal slopes; higher evening values • More pronounced reactivity to and delayed recovery from challenge • Patterns are similar for urinary epinephrine and norepinephrine and for some indices of autonomic function (e.g. control of heart rate)

34. Inflammatory proteins

35. What is inflammation? • Biological process • Important for host defense • Maladaptive if not contained in space and time • Blood-borne proteins • Pro-inflammatory cytokines • Interleukin-6 (IL-6) • Acute phase proteins • C-reactive protein (CRP) • Clotting factors • Fibrinogen • Health implications • Linked to morbidity and mortality • Increased risk of later cardiac events in healthy individuals • Increased risk of cardiac mortality in patients with CVD • Limited screening for CRP currently recommended • Sensitive to sociodemographic and psychosocial factors

36. Macrophage “Large eater” Innate immune system Many locations around body Initiates inflammatory response

37. Inflammatory response (local) CRP Fibrinogen IL-6

38. Inflammation • Local • Contained, short-lived • Proteins typically not detected in blood • Critical for host defense • Robust response indicative of optimal health • Systemic • Indicative of chronic disease or disease risk • Measurable blood levels of inflammatory proteins • Predictive of adverse health outcomes

39. Inflammation and cardiovascular disease

40. Social status and health • Inflammatory proteins as candidate biomarkers • Should be associated with health outcomes of interest

41. Inflammation as nexus Cardiovascular Disease Diabetes Inflammation Cancer E.g. Interleukin-6 (IL-6) Alzheimer’s Disease Rheumatoid arthritis

42. Social status and health • Inflammatory proteins as candidate biomarkers • Should be associated with health outcomes of interest • Should exhibit patterning by social status

43. SES and inflammation • Income and education • NHANES1; MESA2; Framingham offspring3; Heart and Soul Study4; Health, Aging, and Body Composition Study5; CARDIA6 • Occupational status7 • Community SES8 • Composite of income and education • Subjective social status9 • Hypothesized by Adler et al, 2000 • 1Alley et al., 2005; 2Ranjit et al., 2007; 3Loucks et al., 2006; 4Lubbock et al., 2005; 5Koster et al., 2006; 6Gruenewald et al., 2009; 7Owen et al., 2003; 8Petersen et al., 2008; 9Demakakos et al., Soc Sci Med, 2008

44. Education and inflammation in Framingham offspring Loucks et al., Am J. Epidemiol., 2006

45. Poverty and very high CRP (>10 mg/L) in NHANES IV Alley et al., Brain Behav. Immun., 2006

46. Subjective social status and inflammation in ELSA Demakakos et al., Soc Sci Med, 2008

47. Income and IL-6 Friedman & Herd (2010), Psychosomatic Medicine, 73: 290-300

48. Income and CRP Friedman & Herd (2010), Psychosomatic Medicine, 73: 290-300

49. Social status and health • Inflammatory proteins as candidate biomarkers • Should be associated with health outcomes of interest • Should exhibit patterning by social status • Associated with relevant psychosocial factors

50. Inflammation as nexus Cardiovascular Disease Age Diabetes Socioeconomic status Inflammation Social and familial relationships Cancer E.g. Interleukin-6 (IL-6) Alzheimer’s Disease Psychological functioning Rheumatoid arthritis Neurobiological functioning