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Dose-Response Relation between Physical Activity and Health: An Observational Epidemiologic Perspective

Dose-Response Relation between Physical Activity and Health: An Observational Epidemiologic Perspective. I-Min Lee, MD, ScD. Clinical Trials vs. Observational Studies.

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Dose-Response Relation between Physical Activity and Health: An Observational Epidemiologic Perspective

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  1. Dose-Response Relation betweenPhysical Activity and Health: An Observational Epidemiologic Perspective I-Min Lee, MD, ScD

  2. Clinical Trials vs. Observational Studies “The paradox of the clinical trial is that it is the best way to assess whether an intervention works, but is arguably the worst way to assess who will benefit from it.” “It must be recognised explicitly that, in order to apply the results of the trials to individual patients, there must be a parallel investment in observational studies – both quantitative and qualitative.” Mant; Lancet 1999;353:743-6

  3. Research Direction 1950’s to Does PA decrease risk early 1990’s of chronic diseases? early 1990’s We know PA decreases onwards risk of chronic diseases: - how much? - how intense? - what duration? - etc. “dose-response”

  4. Dose-Response: Definition • “Describes the change in effect … caused by differing levels of exposure to a stressor”; central to determining safe and hazardous levels for drugs and pollutants (Wikipedia) • PubMed search for “dose response” and “exercise” – studies as far back as 1967, but mainly related to drug effects; e.g., effect of beta-blocker on exercise tolerance in angina patients • In the mid-1980’s, we begin to see the term used for the study of different doses of PA • ? Influence of medical/epidemiologic principles

  5. What Do We Know (2000)? “Most of the evidence currently available seems to be related to the effects (benefits or risks) of regular physical activity rather than to the relationship between dose and response.” Dose-Response Issues Concerning PA and Health: An Evidence-Based Symposium (Hockley Valley, Canada, 2000)

  6. What Do We Know (2007)? “Participation in aerobic and muscle-strengthening physical activities above minimum recommended amounts provides additional health benefits ...” It is well-documented that PA of longer duration or higher intensity is associated with additional risk decrements but the exact shape of the … curve remains unclear and may vary depending on the health outcome of interest and baseline PA level …” Physical activity and public health: Updated recommendation for adults from ACSM/AHA. Haskell et al, MSSE 2007;39:1423-34

  7. Why the Interest in Dose-Response?

  8. 1. Knowledge is useful in clinical and public health setting 2. Dose-response is one criterion used to judge cause-and-effect relation in observational studies (most studies of PA-chronic disease are observational) 3. Dose-response can help us understand the biology underlying physical activity-disease relation

  9. Above average Immuno-surveillance Average Infection risk Below average Sedentary Moderate Very High Exercise Workload Nieman DC, MSSE 2000;32:S406-S411

  10. Issues to Consider in Studies of Dose-Response

  11. Definition of Physical Activity • “Physical activity” is ambiguous; need to specify which measure is of interest (total volume? intensity? duration?) • Analogy: I want to study the dose-response between “diet” and health (total calories? fat calories? meat intake? etc.)

  12. Translation of Physical Activity from Epidemiologic Studies • Most epi studies use questionnaires • Questionnaire usually tested for reliability (repeatability) and validity (“correctness”) • But, note that high correlations for validity don’t necessarily mean the absolute values (e.g, comparing questionnaire and doubly-labeled water) agree

  13. E.g., Harvard alumni questionnaire: comparing qx estimate and doubly-labeled water, r = 0.67 • Qx estimate of PA = 716 kcal/day • But, doubly-labeled water estimate of PA (total EE minus RMR) = 802 kcal/day • Not surprising, since qx estimates walking, stairs, sports/recreation ONLY • (Doubly-labeled water minus TEE) calculates ALL physical activity (including, e.g., brushing teeth, fixing meals, etc.)

  14. Inter-relations among PA components (1) • Inter-relations among PA components contribute to complexity of analyses • Appropriate analyses need to be conducted, to get “right” answer • E.g., if we see these rates of disease associated with different PA intensities: no activity 15/10,000 (referent) mod intensity 12/10,000 (p=0.32) vig intensity 5/10,000 (p=0.02) • What interpretations are possible, and what are the implications?

  15. Inter-relations among PA components (2) • In randomized trials, consider this in design of the intervention arms • Not possible in observational studies, so control for this in analyses. The aim is to mimic the controlled environment in a randomized trial.

  16. Choice of Cutpoints (1) • Continuous measure of PA, or categories? • Continuous measure: • - if non-linear relation, yields little • additional info • - interpretation less understandable • Categorical measure: • - allows visualization of disease rates • in each category

  17. Choice of Cutpoints (2) • If categorical, how many groups? • Quantiles (e.g., tertiles, quintiles) • “Natural” breaks according to research interest • “Natural” breaks on numerical scale • Driven by biology

  18. C Increasing rates of disease A B Increasing doses of activity Shape of the Curve (1)

  19. Shape of the Curve (2) • Most investigators test for linear trend on log scale • Note that a straight line on the log scale translates to an exponential curve on the natural scale • However, for small effects (RR between 0.5 and 1, or 1 and 2), curves on log and natural scales look similar • Other shapes of the curve are possible (e.g., regression splines)

  20. Spline Regression Model (cubic spline, 4 knots) Hu FB et al, JAMA 2000;283:2961-7

  21. Shape of the Curve (3) • Individual studies have their own ways of assessing and categorizing PA • This makes it difficult to combine data across studies to synthesize info on the shape of the dose-response curve for a particular health outcome • Investigators have done the best they can for meta-analyses, but may be combining disparate categories

  22. E.g., “quintiles” of PA do not mean the same thing in different studies: Finnish men (twin study): Q1: <4.0 MET-hr/wk Q2: 4.1-9.0 Q3: 9.1-17.4 Q4: 17.5-34.1 Q5: 31.5+ US women (Nurses’ Health Study): Q1: <2.5 MET-hr/wk Q2: 2.5-7.2 Q3: 7.3-13.4 Q4: 13.5-23.3 Q5: 23.4+ Men in Q5 expended 60% more energy than women in Q5

  23. Dose-response curves for physical activity and physical fitness in relation to CVD Williams PT, MSSE 2001;33:754-761

  24. Population under Study • Physical activity varies according to age, sex, race, etc. • Thus the range of activity in different populations being studied may vary • This may have an impact on the dose-response curve observed in any single study • (Which is why combining data across studies is needed to get a good idea of the complete dose-response curve)

  25. Hypothetical Spectrum of Response P, trend <0.001 Event Rate Sample 1 Sample 2 Physical Activity Doses

  26. In Sample 1: • Less active population (could be older persons, women) • We likely would choose Group 1 as our reference (a very sluggardly group!) • We would see nice dose-response

  27. In Sample 2: • More active population (could be younger persons, men) • We likely would choose Group 5 as our reference (a pretty active group) • We would see little dose-response

  28. Dose-Response for Volume of Physical Activity

  29. Dose-Response for Volume • Probably the simplest measure to analyze • Any assessment of PA, no matter how simple, gives an idea of the volume of PA even if estimation of the actual energy expended cannot be made • E.g., “none”, “a little”, “a lot”

  30. Garfinkel et al, Cancer 1988;62:1844-1850

  31. Harvard Alumni Health Study P, trend <0.001 Age-Std Death Rate/10,000 Physical Activity, Kcal/Week Lee et al, JAMA 1995;273:1179-1184

  32. Mortality Rates by Tertiles of Free-Living Activity Energy Expenditure Health ABC Study 302 healthy adults, 70-82 y, followed ~6 y, 55 deaths Manini et al, JAMA 2006;296:171-9

  33. Dose-Response for Intensity of Physical Activity

  34. Dose-Response for Intensity • 2 issues to be concerned about: confounding by volume of PA, and confounding by activities of other intensities • Analogous to confounding by total caloric intake and confounding by other nutrients in diet studies • Can borrow methods from diet studies to control for these issues

  35. Standard multivariate model

  36. Health Professionals’ Follow-Up Study Tanasescu et al, JAMA 2002;288:1994-2000

  37. “Energy decomposition” method

  38. Harvard Alumni Health Study Multivariate RR’s for Mortality: Lee et al, JAMA 1995;273:1179-1184

  39. Notes: • It is not sufficient to note that the coefficient (RR) for vigorous activities is significant, while that for non-vigorous activities is non-significant • What is important is: are the coefficients (I.e., [vig] versus  [nonvig]) DIFFERENT from each other?

  40. Harvard Alumni Health Study P, trend = 0.32 P, trend = 0.007 Physical Activity, Kcal/Week Lee et al, JAMA 1995;273:1179-1184

  41. Restriction/Stratification

  42. Women's Health Study P, trend <0.001 RR* of CHD Walking, Hr/Wk * multivariate; among women without vigorous activity Lee et al, JAMA 2001; 285:1447-1454

  43. Harvard Alumni Health Study * Among 17,321 men, 1195 performed only non-vigorous activities (380 deaths) Lee et al, JAMA 1995;273:1179-1184

  44. The updated physical activity recommendation (2007 ACSM/AHA) allows for combining moderate and vigorous activities – What data support this?

  45. WHI Observational Cohort ~ 10 MET-hr ~ 12.5 MET-hr Manson et al, NEJM 2002;347:716-25

  46. Dose-Response for Duration (Frequency) of Physical Activity

  47. Dose-Response for Duration • Same issue: we are concerned about confounding by total volume of PA • Close correlation between volume of energy expended and duration or frequency of PA • Longer duration, more frequent bouts result in greater energy expended • To isolate dose-response for duration or frequency, analysis must control for volume of energy expended

  48. Dose-Response for Duration • This answers the question: For two persons expending the same volume of energy, does the one exercising in long bouts/less frequently benefit more than the one exercising in short bouts/more frequently? • Almost no data on this from observational studies • (In randomized clinical trials, by design, investigator can control for total volume of energy expended)

  49. Harvard Alumni Health Study Duration (min)Age-Adjusted RR(95% CI) No sports/rec 1.00 (ref) 1-15 0.85 (0.55-1.31) 16-30 0.76 (0.57-1.03) 31-45 0.85 (0.58-1.24) 46-60 0.80 (0.59-1.10) >60 0.78 (0.62-0.98) p, trend = 0.04 Lee et al, Circulation 2000;102:981-986

  50. Harvard Alumni Health Study Duration (min)Bivariate RR*(95% CI)No sports/rec 1.00 (ref) 1-15 0.94 (0.61-1.47) 16-30 0.92 (0.65-1.30) 31-45 1.07 (0.68-1.67) 46-60 1.02 (0.69-1.50) >60 1.05 (0.73-1.49) p, trend = 0.68 * adjusted for age and volume of PA

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