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Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI.

ABSTRACT: The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI).Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid A?1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms.Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency.These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials.

SUBMITTER: Caroli A

PROVIDER: S-EPMC4437812 | biostudies-literature | 2015 Apr-Jun

REPOSITORIES: biostudies-literature

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Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI.

Caroli Anna A Prestia Annapaola A Wade Sara S Chen Kewei K Ayutyanont Napatkamon N Landau Susan M SM Madison Cindee M CM Haense Cathleen C Herholz Karl K Reiman Eric M EM Jagust William J WJ Frisoni Giovanni B GB Frisoni Giovanni B GB

Alzheimer disease and associated disorders 20150401 2

<h4>Background</h4>The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI).<h4>Methods</h4>Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, ...[more]

PMID: 25437302

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Project description:BACKGROUND:Acute severe haemorrhage is a common complication of injury, childbirth, surgery, gastrointestinal pathologies and other medical conditions. Bleeding is a major cause of death, but patients also die from non-bleeding causes, the frequency of which varies by the site of haemorrhage and between populations. Because patients can bleed to death within hours, established interventions inevitably take priority over randomisation into a trial. These circumstances raise challenges in selecting appropriate outcome measures for clinical trials of haemostatic interventions. MAIN BODY:We use data from three large randomised controlled trials in acute severe haemorrhage (CRASH-2, WOMAN and HALT-IT) to explore the strengths and limitations of outcome measures commonly used in trials of haemostatic treatments, including all-cause and cause-specific mortality, blood transfusion and surgical interventions. Many deaths following acute severe haemorrhage are due to patient comorbidities or complications rather than bleeding. If non-bleeding deaths are unaffected by a haemostatic intervention, even large trials will have low power to detect an effect on all-cause mortality. Due to the dilution from deaths unaffected or reduced by the trial treatment, all-cause mortality can also obscure important harmful effects. Additionally, because the relative contributions of different causes of death vary within and between patient populations, all-cause mortality is not generalisable. Different causes of death occur at different time intervals from bleeding onset, with bleeding deaths generally occurring early. Time-specific mortality can therefore be used as a proxy for cause in un-blinded trials where bias is a concern or in situations where cause of death cannot be assessed. Urgent treatment is critical, and so post-randomisation blood transfusion and surgery are often planned before or at the time of randomisation and therefore cannot be influenced by the trial treatment. CONCLUSIONS:All-cause mortality has low power, lacks generalisability and can obscure harmful effects. Cause-specific mortality, such as death due to bleeding or thrombosis, avoids these drawbacks. In certain scenarios, time-specific mortality can be used as a proxy for cause-specific mortality. Blood transfusion and surgical procedures have limited utility as outcome measures in trials of haemostatic treatments.

Dataset Information

Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI.

Publications

Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI.

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