Alexander J. Mogilner

Accumulation of deficits as a proxy measure of aging.

This paper develops a method for appraising health status in elderly people. A frailty index was defined as the proportion of accumulated deficits (symptoms, signs, functional impairments, and laboratory abnormalities). It serves as an individual state variable, reflecting severity of illness and proximity to death. In a representative database of elderly Canadians we found that deficits accumulated at 3% per year, and show a gamma distribution, typical for systems with redundant components that can be used in case of failure of a given subsystem. Of note, the slope of the index is insensitive to the individual nature of the deficits, and serves as an important prognostic factor for life expectancy. The formula for estimating an individuals life span given the frailty index value is presented. For different patterns of cognitive impairments the average within-group index value increases with the severity of the cognitive impairment, and the relative variability of the index is significantly reduced. Finally, the statistical distribution of the frailty index sharply differs between well groups (gamma distribution) and morbid groups (normal distribution). This pattern reflects an increase in uncompensated deficits in impaired organisms, which would lead to illness of various etiologies, and ultimately to increased mortality. The accumulation of deficits is as an example of a macroscopic variable, i.e., one that reflects general properties of aging at the level of the whole organism rather than any given functional deficiency. In consequence, we propose that it may be used as a proxy measure of aging.

Frailty, fitness and late-life mortality in relation to chronological and biological age

BackgroundPeople age at remarkably different rates, but how to estimate trajectories of senescence is controversial.MethodsIn a secondary analysis of a representative cohort of Canadians aged 65 and over (n = 2914) we estimated a frailty index based on the proportion of 20 deficits observed in a structured clinical examination. The construct validity of the index was examined through its relationship to chronological age (CA). The criterion validity was examined in its ability to predict mortality, and in relation to other predictions about aging. From the frailty index, relative (to CA) fitness and frailty were estimated, as was an individuals biological age.ResultsThe average value of the frailty index increased with age in a log-linear relationship (r = 0.91; p < 0.001). In a Cox regression analysis, biological age was significantly more highly associated with death than chronological age. The average increase in the frailty index (i.e. the average accumulation of deficits) amongst those with no cognitive impairment was 3 per cent per year.ConclusionsThe frailty index is a sensitive predictor of survival. As the index includes items not traditionally related to adverse health outcomes, the finding is compatible with a view of frailty as the failure to integrate the complex responses required to maintain function.

The mortality rate as a function of accumulated deficits in a frailty index.

In a representative Canadian population survey (n=66589) the proportion of accumulated deficits in a frailty index showed a linear relationship with mortality in a log-log plot, such that the mortality rate was a power-law function of the frailty index. Represented in this way, the frailty index readily summarizes individual differences in health status. The exponent and amplitude parameters of the power function are gender specific, reflecting that while, on average, women accumulate more deficits than men of the same age, their risk of mortality is lower. The dependence of the mortality rate on the frailty index points to the merit of the index as a simple and accessible tool for estimating individual risks of mortality.

Changes with age in the distribution of a frailty index.

Models of human mortality include a factor that summarises intrinsic differences in individual rates of ageing, commonly called frailty. Frailty also describes a clinical syndrome of apparent vulnerability. In a representative, cross-sectional, Canadian survey (n = 66,589) we calculated a frailty index as the mean accumulation of deficits and previously showed it to increase exponentially with age. Here, its density function exhibited a monotonic change in shape, being least skewed at the oldest ages. Although the shape gradually changed, the frailty index was well fitted by a gamma distribution. Of note, the variation coefficient, initially high, decreased from middle age on. Being able to quantify frailty means that health risks can be summarised at both the individual and group levels.

The Accumulation of Deficits with Age and Possible Invariants of Aging

This paper extends a method of apprising health status to a broad range of ages from adolescence to old age. The “frailty index” is based on the accumulation of deficits (symptoms, signs, disease classifications) as analyzed in the National Population Health Survey, a representative Canadian population sample (n = 81,859). The accumulation of deficits has both an age-independent (background) component and an age-dependent (exponential) component, akin to the well-known Gompertz-Makeham model for the risk of mortality. While women accumulate more deficits than men of the same age, on average, their rate of accumulation is lower, so the difference in the level of deficits between men and women decreases with age. Two possible invariants of the process of accumulation of deficits were found: (1) the age at which the average proportion of deficits coincides for men and women is 94 years, which closely matches the species-specific lifespan in humans (95 ± 2); (2) the value of the frailty index (proportion of deficits), which corresponds to that age (0.18). The similarity between mortality kinetics and the accumulation of deficits (frailty kinetics), and the coincidence of the time parameters in the frailty and mortality models make it possible to express mortality risk in terms of accumulated deficits. This provides a simple and accessible tool that might have potential in a number of biomedical applications.

Symptoms and Signs in Dementia Synergy and Antagonism

This paper addresses the synergy and antagonism between symptoms and signs among 2,914 elderly Canadians diagnosed in 15 categories, including no cognitive impairment, cognitive impairment but no dementia, mild, moderate and severe forms of Alzheimers disease and vascular dementia, 4 subtypes of possible Alzheimers disease, Parkinsons dementia, unspecified other dementias and unclassified dementias Attention is paid to the relationships between symptoms and signs rather than conventional analyses which assume independent signs. We demonstrate that dementia progression and specific aetiologies have characteristic patterns of decline and destruction from the strong synergy that exists between symptoms and signs among the population with no cognitive impairment. These findings have potential implications for the incorporation of new diagnostic criteria into existing databases.

Techniques for knowledge discovery in existing biomedical databases: Estimation of individual aging effects in cognition in relation to dementia

New interest is being expressed in the systematic application of modeling techniques to existing datasets. Under the rubric of Knowledge Discovery in Databases (KDD) large databases are being exploited for commercial and scientific purposes. This article reviews the development and applications of KDD techniques to dementia, using the longitudinal Canadian Study of Health and Aging dataset. KDD has demonstrated usefulness at the group level. For example, as in the course of functional impairment between Alzheimers disease and no cognitive impairment suggest damage control-protection mechanisms for the former compared with noncompensated random accumulation of deficits for the latter. At the individual level, KDD suggests that more precise diagnosis seems possible as well as individual life expectancy prediction. Biomedical databases appear to hold the potential for novel insights when explored by systematic modeling.

An Algorithmic Approach to the Differential Diagnosis of Dementia

The careful definition of cases is fundamental to diagnosis and to any study of cognitive, behavioural and functional problems in dementia. This paper presents an algorithmic approach which mimics a crucial component of diagnostic decision-making; symptoms and signs do not occur independently, but are conditioned on each other. First, we examine whether the conditioned items can be assembled to yield a differential diagnosis of dementia which corresponds to clinical diagnoses, and second, we explore whether subjects whose algorithmic profiles do not fit the clinical diagnoses form new discernable patterns. Such a technique offers two advantages: it allows for the development of validation protocols which are crucial to epidemiological studies, and it allows for the analysis of new patterns of signs and symptoms for emerging criteria of dementia subtypes. This approach has the potential to refine and enhance criteria for the differential diagnosis of dementia and to have an impact on case identification and assessment, particularly in large epidemiologic studies.

Data integration and knowledge discovery in biomedical databases. Reliable information from unreliable sources

To better understand information about human health from databases we analyzed three datasets collected for different purposes in Canada: a biomedical database of older adults, a large population survey across all adult ages, and vital statistics. Redundancy in the variables was established, and this led us to derive a generalized (macroscopic state) variable, being a fitness/frailty index that reflects both individual and group health status. Evaluation of the relationship between fitness/frailty and the mortality rate revealed that the latter could be expressed in terms of variables generally available from any cross-sectional database. In practical terms, this means that the risk of mortality might readily be assessed from standard biomedical appraisals collected for other purposes.