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      Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials

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          Abstract

          Introduction

          This study estimated the minimal clinically important difference (MCID) for Mini Mental State Examination, Clinical Dementia Rating Scale sum of boxes, and Functional Activities Questionnaire across the Alzheimer's disease (AD) spectrum.

          Methods

          Retrospective analysis of the National Alzheimer's Coordinating Center Uniform Data Set (9/2005-9/2016) and MCID for clinical outcomes were estimated using anchor-based (clinician's assessment of meaningful decline) and distribution-based (1/2 baseline standard deviation) approaches, stratified by severity of cognitive impairment.

          Results

          On average, a 1-3 point decrease in Mini Mental State Examination, 1-2 point increase in Clinical Dementia Scale sum of boxes, and 3-5 point increase in Functional Activities Questionnaire were indicative of a meaningful decline. The MCID values generally increased by disease severity; the effect size and standardized response mean for those with meaningful decline were consistently in the acceptable ranges for MCID.

          Discussion

          These findings can inform design and interpretation of future clinical trials.

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          Most cited references10

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          Measurement of health status. Ascertaining the minimal clinically important difference.

          In recent years quality of life instruments have been featured as primary outcomes in many randomized trials. One of the challenges facing the investigator using such measures is determining the significance of any differences observed, and communicating that significance to clinicians who will be applying the trial results. We have developed an approach to elucidating the significance of changes in score in quality of life instruments by comparing them to global ratings of change. Using this approach we have established a plausible range within which the minimal clinically important difference (MCID) falls. In three studies in which instruments measuring dyspnea, fatigue, and emotional function in patients with chronic heart and lung disease were applied the MCID was represented by mean change in score of approximately 0.5 per item, when responses were presented on a seven point Likert scale. Furthermore, we have established ranges for changes in questionnaire scores that correspond to moderate and large changes in the domains of interest. This information will be useful in interpreting questionnaire scores, both in individuals and in groups of patients participating in controlled trials, and in the planning of new trials.
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            Methods to explain the clinical significance of health status measures.

            One can classify ways to establish the interpretability of quality-of-life measures as anchor based or distribution based. Anchor-based measures require an independent standard or anchor that is itself interpretable and at least moderately correlated with the instrument being explored. One can further classify anchor-based approaches into population-focused and individual-focused measures. Population-focused approaches are analogous to construct validation and rely on multiple anchors that frame an individual's response in terms of the entire population (eg, a group of patients with a score of 40 has a mortality of 20%). Anchors for population-based approaches include status on a single item, diagnosis, symptoms, disease severity, and response to treatment. Individual-focused approaches are analogous to criterion validation. These methods, which rely on a single anchor and establish a minimum important difference in change in score, require 2 steps. The first step establishes the smallest change in score that patients consider, on average, to be important (the minimum important difference). The second step estimates the proportion of patients who have achieved that minimum important difference. Anchors for the individual-focused approach include global ratings of change within patients and global ratings of differences between patients. Distribution-based methods rely on expressing an effect in terms of the underlying distribution of results. Investigators may express effects in terms of between-person standard deviation units, within-person standard deviation units, and the standard error of measurement. No single approach to interpretability is perfect. Use of multiple strategies is likely to enhance the interpretability of any particular instrument.
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              Minimally important differences were estimated for the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) instrument using a combination of distribution- and anchor-based approaches.

              To estimate minimally important differences (MIDs) on the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) instrument using anchor- and distribution-based methods. Preliminary MIDs were generated for FACT-C scores based on published results for two samples (n = 60 and n = 63) from the FACT-C validation study. Preliminary MIDs were confirmed using data from a Phase II randomized controlled clinical trial (n = 104) and a population-based observational study (n = 568). MIDs were estimated for the colorectal cancer subscale (CCS); the FACT-C Trial Outcome Index (TOI-C), which is the sum of the CCS, physical well-being, and functional well-being subscales; and the FACT-C total score. Both cross-sectional and longitudinal analyses were used. MIDs were stable across the different patient samples. The recommended MIDs ranged from 2 to 3 points for the CCS, 4 to 6 points for the TOI-C, and 5 to 8 points for the FACT-C total score. MIDs can enhance the interpretability of FACT-C scores, and they can be used to provide a basis for sample size estimation and to determine clinical benefit in combination with other measures of efficacy. General guidelines for estimating MIDs for other FACT instruments are suggested.
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                Author and article information

                Contributors
                Journal
                Alzheimers Dement (N Y)
                Alzheimers Dement (N Y)
                Alzheimer's & Dementia : Translational Research & Clinical Interventions
                Elsevier
                2352-8737
                02 August 2019
                2019
                02 August 2019
                : 5
                : 354-363
                Affiliations
                [a ]Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
                [b ]Analysis Group, Inc., Boston, MA, USA
                Author notes
                []Corresponding author. Tel.: +(617)425-8315; Fax: +(617)425-8001. Urvi.desai@ 123456analysisgroup.com
                Article
                S2352-8737(19)30036-8
                10.1016/j.trci.2019.06.005
                6690415
                31417957
                20369607-bb47-4e34-b782-8550500d11b7
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                alzheimer's disease,mcid,mmse,cdr,faq,meaningful decline
                alzheimer's disease, mcid, mmse, cdr, faq, meaningful decline

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