1. Frailty – an overview Kenneth Rockwood MD, FRCPC, FRCP, FCAHS Professor of Geriatric Medicine Dalhousie University Halifax, Nova Scotia, Canada

2. Frailty - summary Frailty is a state of vulnerability to adverse outcomes. The risk of all adverse outcomes increases with age; frailty refers to the fact that not all people of the same age have the same risk of adverse outcomes. There are varying ways to operationalize frailty.

3. A Frailty “phenotype” A person can be said to be frail if they have any 3 of the following features: – They move slowly. – They have a weak handgrip. – They have reduced their level of activity. – They have (unintentionally) lost weight. – They feel exhausted. » Fried et al., J Gerontol Med Sc 2001

4. Frailty - summary Frailty can be operationalized as deficit accumulation in a frailty index. The behaviour of the frailty index shows: – A characteristic pattern to accumulation. – A characteristic rate of deficit accumulation. – A limit to deficit accumulation. – Characteristic, gradual change, with average decline, but considerable individual fluctuation.

5. As people get older, they are more likely to die 0102030405060708090100 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0102030405060708090100 0.002 0.007 0.018 0.050 0.135 0.368 Age (years) The Rate of Mortality (1/y) Log scale Gompertz’s Law Mortality rate is a measure of the number of deaths in some population, scaled to the size of that population, per unit time.

6. As people get older, on average, the cost of care increases

7. Age (years) Proportion As people get older, fitness declines and frailty increases. Green- Fit Red: frail 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 102030405060708090

8. Ageing is a system phenomenon: The building blocks of life do not age http://www.cerritos.edu/earth-science/images/radioa1.gif

9. Understanding ageing as a system phenomenon requires modeling of complex processes Inouye et al. J Am Geriatr Soc 2007;55(5):794-6 Mitnitski et al. J Am Geriatric Soc 2005;53:2184-2189. Mitnitski & Rockwood, Exp Gerontol 2007;42:241-6. Model of frailty www.hopkinsmedicine.org

10. Medicine and the legacy of reductionism Reductionism: “An attempt or tendency to explain a complex set of facts, entities, phenomena, or structures by another, simpler set.”

11. Geriatric medicine and the challenge of complexity Rockwood et al. Can Med Association 1994; 150:499-507 Rockwood et al. J Am Geriatric Society 1996; 44:578-82 Health Attitudes toward Health and health practices Resources Caregiver Illness Disability Dependence on Others Burden on the caregiver

12. Increasing impairment increases health risks in community-dwelling older adults Rockwood et al. Lancet 1999;353:205-6

13. Frailty as deficit accumulation: Most problems accumulate with age (Canadian National Population Health Survey, n= 66,580) Proportion of the individuals with deficit 020406080100 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 arthritis 020406080100 0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 vision problems 020406080100 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 Mobility disability 020406080100 0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 thyroid problems Age (years) Rockwood & Mitnitski Rev Clin Gerontol 2007;18:1-12.

14. The Frailty Index showed a characteristic distribution for community-dwelling older adults Level of the Frailty Index 00.10.20.30.40.50.60.7 0 100 200 300 400 500 600 700 800 900 Number of Subjects

15. Mitnitski, et al., J Am Geriatr Soc, 2005;53:2184-9 Mean accumulation of deficits Legend 65 707580859095 ALSA CSHA-screen CSHA-exam NHANES NPHS SOPS Breast cancer CSHA-inst Myoc Infarct US-LTHS H70-75 0.1 0.2 0.3 0.5 1.0 0.05 Age (years) Clinical and institutional samples, n=2,573 The slope is ~0.03 Community samples n=33,559 Log scale 2. Deficits accumulate characteristically, both between groups (community vs. institution/ clinical) and within groups* Slope <0.01

16. 3. At any age, women accumulate more deficits than do men. 4. For men & women, deficit accumulation is highly correlated (r>0.95) with mortality Mitnitski et al. J Am Geriatr Soc, 2005;53:2184-9

17. Frailty can be graded, with increasing grades reflecting worse survival. Cut points: 0.03, 0.08, 0.14, 0.20, 0.25, 0.34; n= 416, 732, 471, 368, 236, 259, 258

18. Impact of age and frailty on survival: At low levels of deficit accumulation, age matters. At high levels of frailty, age matters less.

19. 5. There is a limit to frailty. Canadian Study of Health & Aging, N=8,547 Of 8,547 people at baseline, only 18 had >17/31 possible deficits, and only 7 (of 5586) had >17/31 at follow-up Survival limit close to the frailty Index of about 0.7 A limit to of the number of deficits suggests exhaustion of reserve capacity – is it operationalizable clinically? Mitnitski, Bao, Rockwood. Mech Ageing Dev 2006;127:490-3. Rockwood & Mitnitski Mech Ageing Dev 2006;127:494-6.

20. “Frailty as deficit accumulation” allows analysis of complexity: Failure kinetics of systems with variable reserve From Gavrilov & Gavrilova Sci Aging Knowledge Env, 2003; 28:1-10

21. 8. The FI-CGA can loss be used to measure loss of redundancy in relation to deficit accumulation Age, years Panel B 707580859095100 -3 -2.5 -2 -1.5 -0.5 0 Rockwood, Rockwood, Mitnitski., J Am Geriatrics Soc, 2010;58:318-323. Log of the Frailty Index Gavrilov & Gavrilova Sci Aging Knowledge Env, 2003; 28:1-10

22. 010203040506070 0 0.2 0.4 0.6 0.8 1 7. Frailty predicts mortality better than age. Age FI-CGA 70 80 90 100 0.1 0.2 0.3 0.40.5 Survival time (months) Survival probability 010203040506070 0 0.2 0.4 0.6 0.8 1 Rockwood, Rockwood, Mitnitski, J Am Geriatric Soc 2010;58:318-323.

23. Frailty kinetics: Loss of redundancy with in age association with deficit accumulation Searle et al., CSHA data, unpublished.

24. Summary to now Frailty can be understood by counting deficits in a frailty index. A frailty index derived from routinely collected clinical data can offer insights into the biology of aging using mathematics of complex systems.

25. What else can we learn clinically from other complex systems applications What else can we learn clinically from other complex systems applications?

26. A Frailty Index can be constructed clinically, from the items recorded in a Comprehensive Geriatric Assessment

27. Measuring mobility: the HABAM The Hierarchy of Balance & Mobility In bed-mobility – Cannot move off pressure points – Moves side to side – Can push to sit up – Can swing legs over the side MacKnight & Rockwood Age Ageing 1995;24:126-30 MacKnight & Rockwood J Clin Epidemiol 2000;53:1242-7 Rockwood et al. J Am Geriatr Soc, 2008; 56:1213-1217-24

28. Hierarchical Assessment of Balance and Mobility: embracing complexity through pattern recognition in a state variable Rockwood et al., J Am Geriatr Soc, 2008;56:1213-1217

29. Mean HABAM scores over the first 14 days of hospitalization, by outcome Hubbard et al., submitted

30. Risk of death within 30 days in relation to HABAM scores Absolute risk of death of patients who score the lowest on each of the HABAM domains at any point of the hospital stay: 45% (36-54). » Hubbard et al., submitted. Relative risk of death of patients whose HABAM scores decline in the first 48 hours, versus those in whom the scores stay the same or improve: 27.2 (19.4-35.6). » Rockwood, Rockwood & Mitnitski, submitted.

31. Mean changes hide important variability: individuals show variable trajectories of deficit accumulation. 65707580859095 0 5 10 15 20 25 30 65707580859095 0 5 10 15 20 25 30 65707580859095 0 5 10 15 20 25 30 65707580859095 0 5 10 15 20 25 30 Age (years) Number of accumulated health deficits Iterations of 40 randomly selected people (from 8,547) assessed 3 times over 10 years Average trajectory Individual trajectories

32. Schematic representation of transitions as a Markov Chain* S 0 S 1 S 2 S n D D D D absorbing state *Mitnitski et al., Mech Ageing Dev 2006;127:490-3 Mitnitski et al., Exp Geront 2007:42:241-6

33. Transition matrix between the different number of deficits during 5 years (example)* 4 35 93 112 75 34 38 11 3 6 2 0 1 0 0 1 0 1 0 93 2 from to 265  * http://myweb.dal.ca/amitnits/mad-appendix.htmhttp://myweb.dal.ca/amitnits/mad-appendix.htm 原始状态原始状态 新状态

34. 5-year transitions between different states of health (empty circles), replicated 5 years later (solid circles)* Legend: Empty circles: CSHA-1  CSHA-2 Solid circles: CSHA-2  CSHA-3 Goodness of fit r = 0.99 *Mitnitski, Bao, Rockwood., Mech Ageing Dev 2006, 127;490-493 Number of deficits The model

35. How transitions can be displayed (instead of the previous table) This picture shows three lines from the table (previous page) The Poisson Distribution 前面的表可以较简单地用曲线表示 波松分布可以描述

36. Four parameters of the model and their interpretation 0510 0 0.2 Average number of deficits given zero deficits at baseline 010 0 0.2 0.4 The difference between the average number of deficits at the two incremental deficit numbers at baseline 010 n The intercept and the slope in the probability of death as a function of the number of deficits at baseline

37. Mitnitski & Rockwood BMC Geriatrics 2008; Feb 18;8:3 Cognitive deficits change much as other deficits do: 5-year transitions, CSHA

38. 0.10.20.30.40.50.60.7 0 0.2 0.4 0.6 0.8 1 0 Frailty Index Death Rate over 8 years women men Mortality in relation to frailty in the Beijing Longitudinal Study of Aging. Is frailty more lethal in China?

39. List of Frailty States : 1. Very Fit 2. Well 3. Managing Well 4. Vulnerable 5. Mildly Frail 6. Moderately Frail 7. Severely Frail 8. Very Severely Frail 9. Terminally ill © Geriatric Medicine Research Unit, Dalhousie University, 2008

40. 2. Well – People who have no active disease symptoms but are less fit than category 1. Often, they exercise or are very active occasionally, e.g. seasonally. Frailty Index score is <0.10. Well older adults share most attributes of the very fit, except for regular, vigorous exercise. Like them, some may complain of memory symptoms, but without objective deficits.

41. 6. Moderately Frail – People need help with all outside activities and with keeping house. Inside, they often have problems with stairs and need help with bathing and might need minimal assistance (cuing, standby) with dressing. Often rate health no better than ‘fair’. Typically, walking is slow. Frailty index ~0.35 – 0.45.

42. Frailty can be understood through deficit accumulation. The analysis of deficit accumulation shows that lessons from complex systems can be applied to the management of frailty. Summary - 1

43. Summary - 2 There is a limit to frailty. Pattern recognition makes management easier. Frailty is a state variable over long periods. Mobility & balance is a state variable over short periods. Changes in frailty states typically are gradual.

44. Acknowledgments Funding sources: Canadian Institutes of Health Research Fountain Innovation Fund of the QEII Health Sciences Foundation Mathematics of Information Technology and Computer Science program, National Research Council Alzheimer Society of Canada Dalhousie Medical Research Foundation Colleagues & students: Arnold Mitnitski Nadar Fallah Xiaowei Song Ruth Hubbard Melissa Andrew Michael Rockwood Samuel Searle Paige Moorhouse, Laurie Mallery