Application of the NIA-AA Research Framework: Towards a Biological Definition of Alzheimer's Disease Using Cerebrospinal Fluid Biomarkers in the AIBL Study.

BACKGROUND: The National Institute on Aging and Alzheimer's Association (NIA-AA) have proposed a new Research Framework: Towards a biological definition of Alzheimer's disease, which uses a three-biomarker construct: Aß-amyloid, tau and neurodegeneration AT(N), to generate a biomarker based definition of Alzheimer's disease. OBJECTIVES: To stratify AIBL participants using the new NIA-AA Research Framework using cerebrospinal fluid (CSF) biomarkers. To evaluate the clinical and cognitive profiles of the different groups resultant from the AT(N) stratification. To compare the findings to those that result from stratification using two-biomarker construct criteria (AT and/or A(N)). DESIGN: Individuals were classified as being positive or negative for each of the A, T, and (N) categories and then assigned to the appropriate AT(N) combinatorial group: A-T-(N)-; A+T-(N)-; A+T+(N)-; A+T-(N)+; A+T+(N)+; A-T+(N)-; A-T-(N)+; A-T+(N)+. In line with the NIA-AA research framework, these eight AT(N) groups were then collapsed into four main groups of interest (normal AD biomarkers, AD pathologic change, AD and non-AD pathologic change) and the respective clinical and cognitive trajectories over 4.5 years for each group were assessed. In two sensitivity analyses the methods were replicated after assigning individuals to four groups based on being positive or negative for AT biomarkers as well as A(N) biomarkers. SETTING: Two study centers in Melbourne (Victoria) and Perth (Western Australia), Australia recruited MCI individuals and individuals with AD from primary care physicians or tertiary memory disorder clinics. Cognitively healthy, elderly NCs were recruited through advertisement or via spouses of participants in the study. PARTICIPANTS: One-hundred and forty NC, 33 MCI participants, and 27 participants with AD from the AIBL study who had undergone CSF evaluation using Elecsys® assays. INTERVENTION (if any): Not applicable. MEASUREMENTS: Three CSF biomarkers, namely amyloid ß1-42, phosphorylated tau181, and total tau, were measured to provide the AT(N) classifications. Clinical and cognitive trajectories were evaluated using the AIBL Preclinical Alzheimer Cognitive Composite (AIBL-PACC), a verbal episodic memory composite, an executive function composite, California Verbal Learning Test - Second Edition; Long-Delay Free Recall, Mini-Mental State Examination, and Clinical Dementia Rating Sum of Boxes scores. RESULTS: Thirty-eight percent of the elderly NCs had no evidence of abnormal AD biomarkers, whereas 33% had biomarker levels consistent with AD or AD pathologic change, and 29% had evidence of non-AD biomarker change. Among NC participants, those with biomarker evidence of AD pathology tended to perform worse on cognitive outcome assessments than other biomarker groups. Approximately three in four participants with MCI or AD had biomarker levels consistent with the research framework's definition of AD or AD pathologic change. For MCI participants, a decrease in AIBL-PACC scores was observed with increasing abnormal biomarkers; and increased abnormal biomarkers were also associated with increased rates of decline across some cognitive measures. CONCLUSIONS: Increasing biomarker abnormality appears to be associated with worse cognitive trajectories. The implementation of biomarker classifications could help better characterize prognosis in clinical practice and identify those at-risk individuals more likely to clinically progress, for their inclusion in future therapeutic trials.

Risk of cardiac valvulopathy with use of bisphosphonates: a population-based, multi-country case-control study.

UNLABELLED: Analyses of healthcare data from 30 million individuals in three countries showed that current use of bisphosphonates may be associated with a small increased risk of cardiac valvulopathy (vs. those not exposed within the previous year), although confounding cannot be entirely ruled out. The observed tendency for decreased valvulopathy risk with cumulative duration of bisphosphonate use >6 months may even indicate a protective effect with prolonged use. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy. INTRODUCTION: A signal of cardiac valve disorders with use of bisphosphonates was identified in the literature and EudraVigilance database, which contains reports of suspected adverse drug reactions from worldwide sources. The aim of this study was to evaluate the association using population-based healthcare data. METHODS: This was a case-control study among users of bisphosphonates and other drugs for osteoporosis in six healthcare databases covering over 30 million individuals in Italy, Netherlands and the UK from 1996 to 2012. Prescriptions/dispensations were used to assess drug exposure. Newly diagnosed cases of cardiac valvulopathy were identified via disease codes/free-text search. Controls were matched to each case by age, sex, database and index date. Adjusted odds ratios (ORs) were estimated using conditional logistic regression for the pooled data and meta-analysis of individual database risk estimates. RESULTS: A small but statistically significant association was found between exposure to bisphosphonates as a class and risk of valvulopathy. Overall risk was 18 % higher (95 % CI 12-23 %) in those currently exposed to any bisphosphonate (mainly alendronate and risedronate) vs. those not exposed within the previous year. Risk of valve regurgitation was 14 % higher (95 % CI 7-22 %). Decreased valvulopathy risk was observed with longer cumulative duration of bisphosphonate use, compared to use of less than 6 months. Meta-analyses of database-specific estimates confirmed results from pooled analyses. CONCLUSIONS: The observed increased risks of cardiac valvulopathy with bisphosphonate use, although statistically significant, were quite small and unlikely to be clinically significant. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy and to investigate possible mechanisms for the association.

The incidence of Barrett's oesophagus and oesophageal adenocarcinoma in the United Kingdom and The Netherlands is levelling off.

BACKGROUND: Barrett's oesophagus (BO) is a risk factor for oesophageal adenocarcinoma (OAC). Several studies report increasing incidences of BO with substantial variation. AIM: To determine age- and sex-stratified incidence rates (IR) of BO and OAC. METHODS: Cohort study using two primary care databases in the United Kingdom (UK) and the Netherlands (NL) (2000-2012). BO and OAC cases were identified using disease-specific READ codes (UK) and free-text search with manual validation (NL). Age- and sex-specific incidence rates (IRs) were calculated for both BO and OAC. RESULTS: From the study population of 6,885,420 subjects in the UK, we identified 12,312 incident BO and 40 (0.3%) subsequent incident OAC cases. There were 1383 incident BO, and subsequent 5 (0.4%) incident OAC cases among the 1,487,191 subjects in the NL. The IR of BO increased linearly with age: 15.6/100,000 PYs (UK) and 23.7/100,000 PYs (NL) for patients aged 40-44 years, increasing to 85.6/100,000 PYs (UK) and 87.0/100,000 PYs (NL) for 70-74 years. In both the UK and the NL, IR of BO was 2-4 times higher in males than females across all age groups. With respect to calendar time, the IR of BO increased by 35% (UK) and 41% (NL) from 2000 to 2003, after which IRs remained stable until 2012. CONCLUSIONS: The incidence rates of BO in the UK and the NL increased until 2003, but levelled off thereafter. Around 0.3% of patients with BO developed OAC at least 1 year after BO diagnosis. These findings may help tailor endoscopic surveillance strategies among patients with BO.

Combining multiple healthcare databases for postmarketing drug and vaccine safety surveillance: why and how?

A growing number of international initiatives (e.g. EU-ADR, Sentinel, OMOP, PROTECT and VAESCO) are based on the combined use of multiple healthcare databases for the conduct of active surveillance studies in the area of drug and vaccine safety. The motivation behind combining multiple healthcare databases is the earlier detection and validation, and hence earlier management, of potential safety issues. Overall, the combination of multiple healthcare databases increases statistical sample size and heterogeneity of exposure for postmarketing drug and vaccine safety surveillance, despite posing several technical challenges. Healthcare databases generally differ by underlying healthcare systems, type of information collected, drug/vaccine and medical event coding systems and language. Therefore, harmonization of medical data extraction through homogeneous coding algorithms across highly different databases is necessary. Although no standard procedure is currently available to achieve this, several approaches have been developed in recent projects. Another main challenge involves choosing the work models for data management and analyses whilst respecting country-specific regulations in terms of data privacy and anonymization. Dedicated software (e.g. Jerboa) has been produced to deal with privacy issues by sharing only anonymized and aggregated data using a common data model. Finally, storage and safe access to the data from different databases requires the development of a proper remote research environment. The aim of this review is to provide a summary of the potential, disadvantages, methodological issues and possible solutions concerning the conduct of postmarketing multidatabase drug and vaccine safety studies, as demonstrated by several international initiatives.