Janice E. Graham

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.

STANDARDIZATION OF THE DIAGNOSIS OF DEMENTIA IN THE CANADIAN STUDY OF HEALTH AND AGING

Standardization of diagnostic procedures for cognitive impairment in large epidemiologic surveys remains difficult. This paper reports results of diagnostic standardization in a subsample of 2,914 elderly (age 65 years+) Canadians from the Canadian Study of Health and Aging (CSHA; n = 10,263). The objectives were to measure the consistency of the CSHA diagnosis as a test of validity; to assess inter-rater reliability, and to assess the impact of neuropsychological data on the diagnosis of dementia. The CSHA clinical assessment included a nurses examination, Modified Mini-Mental Status (3MS) exam and Cambridge Mental Disorders Examination, neuropsychological tests, medical history and examination, and laboratory investigations. A final diagnosis was reached in a consensus conference which incorporated preliminary diagnoses from both physicians and neuropsychologists. Computer algorithms, which were developed to check consistency between the clinical observations and the final diagnosis, demonstrated 98% concordance with DSM-III-R criteria for dementia and 92% with NINCDS-ADRADA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers Disease and Related Disorders Association) criteria for probable Alzheimers disease. Inter-rater agreement was high: kappa = 0.81 for dementia/no dementia; kappa = 0.74 for normal/cognitive impairment, not dementia/ dementia. Comparisons of diagnoses between raters by clinical specialty revealed few systematic differences. The impact of neuropsychological input on the physicians diagnosis was most marked in the borderline cases between diagnostic categories.

Actor-Network Theory: a tool to support ethical analysis of commercial genetic testing

Social, ethical and policy analysis of the issues arising from gene patenting and commercial genetic testing is enhanced by the application of science and technology studies, and Actor-Network Theory (ANT) in particular. We suggest the potential for transferring ANTs flexible nature to an applied heuristic methodology for gathering empirical information and for analysing the complex networks involved in the development of genetic technologies. Three concepts are explored in this paper—actor-networks, translation, and drift—and applied to the case of Myriad Genetics and their commercial BRACAnalysis genetic susceptibility test for hereditary breast cancer. Treating this test as an active participant in socio-technical networks clarifies the extent to which it interacts with, shapes and is shaped by people, other technologies, and institutions. Such an understanding enables more sophisticated and nuanced technology assessment, academic analysis, as well as public debate about the social, ethical and policy implications of the commercialization of new genetic technologies.|spagf|ro|epagf|

Goal setting and attainment in Alzheimer’s disease patients treated with donepezil

Objectives: To understand the treatment goals of Alzheimer’s disease (AD) patients, carers, and physicians; to estimate whether clinically important goals are met during treatment with donepezil; and to compare a measure of goal attainment with standard measures used to evaluate AD treatment. Methods: In a 12 month phase IV trial, 108 patients with mild to moderate AD, their primary carers, and treating physicians set goals assigned to five domains, using Goal Attainment Scaling (GAS) as the primary outcome. Goal attainment was assessed quarterly. GAS scores were correlated with standard outcomes, including the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-cog), and the Clinician’s Interview-Based Impression of Change-Plus (CIBIC-plus). Results: Physicians set fewer goals (342, mean (SD) per patient=3 (1)) than patients/carers (855, mean=9 (3)), particularly in leisure (20% by physicians compared with 76% by patients/carers), and social interaction (24% versus 49%). Physicians observed statistically significant improvement in global goal attainment for six months, and patients/carers for nine months. Patients/carers described consistent goal attainment, whereas physicians observed variable effects, such as decline in cognition but improved social interaction and behaviour. Physician global GAS scores correlated highly with the CIBIC-plus at weeks 12 (r= −0.82) and 52 (r=−0.80), but not with the ADAS-cog (r=0.12 and r=−0.45, respectively). Patient/carer global GAS scores correlated moderately with the physician’s CIBIC-plus (week 12 r=−0.51; week 52 r=−0.56), and nominally with the ADAS-cog. Conclusions: Patients/carers and physicians differ in their expectations and impressions of treatment effects. Clinically important changes correlated only modestly with psychometric tests. Attainment of treatment goals does not accord with a simplistic model in which successful AD treatment means that all declines uniformly improve.

Assessment of factors associated with complete immunization coverage in children aged 12-23 months: a cross-sectional study in Nouna district, Burkina Faso

BackgroundThe Expanded Program on Immunization (EPI) is still in need of improvement. In Burkina Faso in 2003, for example, the Nouna health district had an immunization coverage rate of 31.5%, compared to the national rate of 52%. This study identifies specific factors associated with immunization status in Nouna health district in order to advance improved intervention strategies in this district and in those with similar environmental and social contexts.MethodsA cross-sectional study was undertaken in 41 rural communities and one semi-urban area (urban in the text). Data on 476 children aged 12 to 23 months were analyzed from a representative sample of 489, drawn from the Nouna Health Research Centres Demographic Surveillance System (DSS) database. The vaccination history of these children was examined. The relationships between their immunization status and social, economic and various contextual variables associated with their parents and households were assessed using Chi square test, Pearson correlation and logistic regression.ResultsThe total immunization coverage was 50.2% (CI, 45.71; 54.69). Parental knowledge of the preventive value of immunization was positively related to complete immunization status (p = 0.03) in rural areas. Children of parents who reported a perception of communication problems surrounding immunization had a lower immunization coverage rate (p < 0.001). No distance related difference exists in terms of complete immunization coverage within villages and between villages outside the site of the health centres. Children of non-educated fathers in rural areas have higher rates of complete immunization coverage than those in the urban area (p = 0.028). Good communication about immunization and the importance of availability of immunization booklets, as well as economic and religious factors appear to positively affect childrens immunization status.ConclusionVaccination sites in remote areas are intended to provide a greater opportunity for children to access vaccination services. These efforts, however, are often hampered by the poor economic conditions of households and insufficient communication and knowledge regarding immunization issues. While comprehensive communication may improve understanding about immunization, it is necessary that local interventions also take into account religious specificities and critical economic periods. Particular approaches that take into consideration these distinctions need to be applied in both rural and urban settings.Abstract in FrenchSee the full article online for a translation of this abstract in French.

The clinical meaningfulness of ADAS-Cog changes in Alzheimer's disease patients treated with donepezil in an open-label trial

BackgroundIn 6-month anti-dementia drug trials, a 4-point change in the Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is held to be clinically important. We examined how this change compared with measures of clinical meaningfulness.MethodsThis is a secondary analysis of a 12 month open-label study of 100 patients (71 women) diagnosed with mild to moderate AD treated with 5–10 mg of donepezil daily. We studied the observed case, 6-month change from baseline on the ADAS-Cog, the Clinicians Interview Based Impression of Change-Plus Caregiver Input (CIBIC-Plus), patient-Goal Attainment Scaling (PGAS) and clinician-GAS (CGAS).ResultsAt 6 months, donepezil-treated patients (n = 95) were more likely to show no change (+/- 3 points) on the ADAS-Cog (56%) than to improve (20%) or decline (24%) by 4-points. ADAS-Cog change scores were little correlated with other measures: from -0.09 for PGAS to 0.27 for the CIBIC-Plus. While patients who improved on the ADAS-Cog were less likely to decline on the clinical measures (26%), 43% of patients who declined on the ADAS-Cog improved on at least two of the clinical measures.ConclusionThe ADAS-Cog did not capture all clinically important effects. In general, ADAS-Cog improvement indicates clinical improvement, whereas many people with ADAS-Cog decline do not show clinical decline. The open-label design of this study does not allow us to know whether this is a treatment effect, which requires further investigation.

Global challenges of implementing human papillomavirus vaccines

Human Papillomavirus vaccines are widely hailed as a sweeping pharmaceutical innovation for the universal benefit of all women. The implementation of the vaccines, however, is far from universal or equitable. Socio-economically marginalized women in emerging and developing, and many advanced economies alike, suffer a disproportionately large burden of cervical cancer. Despite the marketing of Human Papillomavirus vaccines as the solution to cervical cancer, the market authorization (licensing) of the vaccines has not translated into universal equitable access. Vaccine implementation for vulnerable girls and women faces multiple barriers that include high vaccine costs, inadequate delivery infrastructure, and lack of community engagement to generate awareness about cervical cancer and early screening tools. For Human Papillomavirus vaccines to work as a public health solution, the quality-assured delivery of cheaper vaccines must be integrated with strengthened capacity for community-based health education and screening.

Pharmacogenetics for off-patent antipsychotics: reframing the risk for tardive dyskinesia and access to essential medicines

First-generation antipsychotics (FGAs) induce tardive dyskinesia, a debilitating involuntary hyperkinetic movement disorder, in 20 – 50% of individuals with a psychotic illness during chronic treatment. There is presently no curative treatment or definitive predictive test for tardive dyskinesia. The authors note that the three antipsychotic drugs enlisted in the most recent (14th) World Health Organization Model List of Essential Medicines – chlorpromazine, fluphenazine and haloperidol – belong to the FGA therapeutic class. In this regard, the need to choose between the competing objectives of ensuring global access to affordable and efficacious medicines, such as FGAs, and the formidable long-term risk for tardive dyskinesia, may create an ethical conundrum. Pharmacogenetics has thus far been conceptually framed as a tool to individualise therapy with new drugs under patent protection. However, the authors suggest that pharmacogenetics may also improve access to pharmacotherapy through the reintroduction of affordable second-line generic drugs or FGAs with suboptimal safety, as first-line therapy, in targeted subpopulations in whom they present a lower risk for tardive dyskinesia. To impact positively on global public health and distributive justice, a directory complementary to the essential medicines library – one that enlists the ‘essential biomarkers’ required for optimal pharmacotherapy – may benefit patients who do not have adequate access to new antipsychotic medications. This review discusses pharmacogenetic associations of tardive dyskinesia that are in part supported by meta-analyses and the oxidative stress-neuronal degeneration hypothesis.

Anthropological contributions to the understanding of age-related cognitive impairment

Medical anthropology has not only helped us to understand the social, political, and ethical foundations of modern biomedicine, but also improved the identification and treatment of patients in various geographic, sociological, and medical contexts. In this article, we present an anthropological perspective on the understanding, diagnosis, and treatment of age-related cognitive impairment. The ubiquity of cognitive changes in the growing number of elderly people around the world, and the many diverse responses that human communities have taken to such challenges, require biocultural approaches. Anthropology can serve as an ally in accomplishing the goal of improving the quality of life of those with cognitive impairment by highlighting the role of sociocultural processes that influence the development, meaning, and experience of dementia. So too can it serve as a framework for criticism of biomedical research, theory, and practice.

Multigenic Control of Drug Response and Regulatory Decision-Making in Pharmacogenomics: The Need for an Upper-Bound Estimate of Genetic Contributions

Nature or nurture? To what extent genetics play a role in drug efficacy and safety? These questions are not new. They are however gaining increasing prominence with the implementation of pharmacogenomics in various facets of medicine ranging from therapeutics, drug development and regulatory science to research funding decisions. For predisposition to common complex diseases, twin and family studies have been the mainstay for estimating genetic components of the attendant risk. On the other hand, the rapid pace of drug development in the pharmaceutical industry and the need for faster regulatory decisions call for an approach of higher throughput to identify the compounds for which heritability is likely to play a significant role in their pharmacokinetics and/or pharmacodynamics. A second predicament related to multifactorial nature of drug effects is that one typically observes a considerable overlap in the distribution of drug response phenotypes among subpopulations identified by each pharmacogenomic biomarker. This is in sharp contrast to monogenic pharmacological traits wherein it is feasible to partition the patient populations into discrete subgroups by analysis of a single gene. Hence, as pharmacogenom ic investigation s progress from monogenic to increasingly multigenic or multifactoria l drug response phenotypes, the regulatory decision-makers are faced with a dilemma: How can a reviewer or a clinician determine if a given separation of a drug response profile by a pharmacogenomic biomarker is worthwhile for clinical implementation? The present manuscript makes an attempt to address these broad and emerging issues in pharmacogenomics and regulatory science. We propose that a comparison of inter- versus intra-subject variability in drug response under minimal environmental exposure may provide an upper- bound estimate of heritability of drug efficacy and safety. It is also argued that seemingly modest changes in population averages may underestimate the dramatic impact of a genetic biomarker at the tails of a population. To this end, a conceptual framework for graded risk assessment among subpopulations with overlapping quantitative phenotypes is presented. We conclude with a broader discussion of the evolution of genetic biomarkers from monogenic to multigenic traits in pharmacology, the associated ethical, social and therapeutic policy corollaries and the challenges lying ahead.