The minimal important difference (MID) is a phrase with instant appeal in a field struggling to interpret health-related quality of life and other patient-reported outcomes. The terminology can be ...confusing, with several terms differing only slightly in definition (e.g., minimal clinically important difference, clinically important difference, minimally detectable difference, the subjectively significant difference), and others that seem similar despite having quite different meanings (minimally detectable difference versus minimum detectable change). Often, nuances of definition are of little consequence in the way that these quantities are estimated and used. Four methods are commonly employed to estimate MIDs: patient rating of change (global transition items); clinical anchors; standard error of measurement; and effect size. These are described and critiqued in this article. There is no universal MID, despite the appeal of the notion. Indeed, for a particular patient-reported outcome instrument or scale, the MID is not an immutable characteristic, but may vary by population and context. At both the group and individual level, the MID may depend on the clinical context and decision at hand, the baseline from which the patient starts, and whether they are improving or deteriorating. Specific estimates of MIDs should therefore not be overinterpreted. For a given health-related quality-of-life scale, all available MID estimates (and their confidence intervals) should be considered, amalgamated into general guidelines and applied judiciously to any particular clinical or research context.
Purpose
Patient-reported outcome measures (PROMs) are increasingly used in clinical settings to inform individual patient care. In-depth understanding of end-users’ experiences may help identify ...factors that promote or hinder their use in clinical decision-making. We aimed to examine stakeholder perceptions of the utility of using PROMs in clinical practice based on real-life experience.
Methods
Systematic review searching Medline, Embase and PsychINFO from inception to May 2021. Qualitative studies examining patients’ and/or clinicians’ experiences of using PROMs in clinical settings were included. Study screening and data extraction were performed by two independent reviewers. Qualitative data from included studies was analysed thematically.
Results
Of 2388 abstracts retrieved, 52 articles reporting 50 studies met eligibility. Five key benefits were identified: (1) promotes active patient involvement (enables goal setting and discussion of sensitive topics); (2) enhances the focus of consultations (prioritizes patient needs); (3) improves quality of care (enables tailored, holistic care and prompts action); (4) enables standardized monitoring of patient outcomes; and (5) enhances the patient–clinician relationship (provides reassurance). Perceived limitations included the capacity of PROMs to shift the focus of consultations; inaccurately estimate problems; raise unrealistic expectations for care; inhibit patient–clinician interaction; lack clinically meaningful information; and not be suitable for all patients.
Conclusion
Both patients and clinicians reported benefits of using PROMs across diverse health conditions and clinical settings, but also highlighted several limitations. These limitations shed some light on why PROM use may not always improve patient outcomes and provide considerations for the design and implementation of future PROM initiatives.
Patient-reported outcomes (PROs) can be included in clinical trials as primary or secondary endpoints and are increasingly recognized by regulators, clinicians, and patients as valuable tools to ...collect patient-centered data. PROs provide unique information on the impact of a medical condition and its treatment from the patient's perspective; therefore, PROs can be included in clinical trials to ensure the impact of a trial intervention is comprehensively assessed. This review first discusses examples of how PRO endpoints have added value to clinical trial interpretation. Second, it describes the problems with current practices in designing, implementing, and reporting PRO studies, and how these problems may be addressed by complying with guidance for protocol development, selecting appropriate PRO measures to match clinically motivated PRO hypotheses, minimizing the rates of avoidable missing PRO data, analyzing and interpreting PRO data, and transparently reporting PRO findings.
PURPOSE; To use published literature to estimate large, medium, and small differences in quality of life (QOL) data from the European Organisation for the Research and Treatment of Cancer Quality of ...Life Questionnaire Core 30 (EORTC QLQ-C30).
An innovative method combining systematic review of published studies, expert opinions, and meta-analysis was used to estimate large, medium, and small differences for QLQ-C30 scores. Published mean data were identified from the literature. Differences (contrasts) between groups (eg, between treatment groups, age groups, and performance status groups) were reviewed by 34 experts in QOL measurement and cancer treatment. The experts, blinded to actual QOL results, were asked to predict these differences. A large difference was defined as one representing unequivocal clinical relevance. A medium difference was defined as likely to be clinically relevant but to a lesser extent. A small difference was one believed to be subtle but nevertheless clinically relevant. A trivial difference was used to describe circumstances unlikely to have any clinical relevance. Actual QOL results were combined using meta-analytic techniques to estimate differences corresponding to small, medium, or large effects.
Nine hundred eleven articles were identified, leading to 152 relevant articles (2,217 contrasts) being reviewed by at least two experts. Resulting estimates from the meta-analysis varied depending on the subscale. Thus, the recommended minimum to detect medium differences ranges from 9 (cognitive functioning) to 19 points (role functioning).
Guidelines for the size of effects are provided for the QLQ-C30 subscales. These guidelines can be used for sample size calculations for clinical trials and can also be used to aid interpretation of differences in QLQ-C30 scores.
Patient-reported outcome (PRO) data from clinical trials can provide valuable evidence to inform shared decision making, labeling claims, clinical guidelines, and health policy; however, the PRO ...content of clinical trial protocols is often suboptimal. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was published in 2013 and aims to improve the completeness of trial protocols by providing evidence-based recommendations for the minimum set of items to be addressed, but it does not provide PRO-specific guidance.
To develop international, consensus-based, PRO-specific protocol guidance (the SPIRIT-PRO Extension).
The SPIRIT-PRO Extension was developed following the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework for guideline development. This included (1) a systematic review of existing PRO-specific protocol guidance to generate a list of potential PRO-specific protocol items (published in 2014); (2) refinements to the list and removal of duplicate items by the International Society for Quality of Life Research (ISOQOL) Protocol Checklist Taskforce; (3) an international stakeholder survey of clinical trial research personnel, PRO methodologists, health economists, psychometricians, patient advocates, funders, industry representatives, journal editors, policy makers, ethicists, and researchers responsible for evidence synthesis (distributed by 38 international partner organizations in October 2016); (4) an international Delphi exercise (n = 137 invited; October 2016 to February 2017); and (5) consensus meeting (n = 30 invited; May 2017). Prior to voting, consensus meeting participants were informed of the results of the Delphi exercise and given data from structured reviews evaluating the PRO protocol content of 3 defined samples of trial protocols.
The systematic review identified 162 PRO-specific protocol recommendations from 54 sources. The ISOQOL Taskforce (n = 21) reduced this to 56 items, which were considered by 138 international stakeholder survey participants and 99 Delphi panelists. The final wording of the SPIRIT-PRO Extension was agreed on at a consensus meeting (n = 29 participants) and reviewed by external group of experts during a consultation period. Eleven extensions and 5 elaborations to the SPIRIT 2013 checklist were recommended for inclusion in clinical trial protocols in which PROs are a primary or key secondary outcome. Extension items focused on PRO-specific issues relating to the trial rationale, objectives, eligibility criteria, concepts used to evaluate the intervention, time points for assessment, PRO instrument selection and measurement properties, data collection plan, translation to other languages, proxy completion, strategies to minimize missing data, and whether PRO data will be monitored during the study to inform clinical care.
The SPIRIT-PRO guidelines provide recommendations for items that should be addressed and included in clinical trial protocols in which PROs are a primary or key secondary outcome. Improved design of clinical trials including PROs could help ensure high-quality data that may inform patient-centered care.
Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant ...chemotherapy after chemoradiotherapy.
The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0–2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0–50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088.
Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years IQR 37 to 55; 663 72% were White, 121 13% were Black or African American, 53 6% were Asian, 24 3% were Aboriginal or Pacific islander, and 57 6% were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% 95% CI –6 to 7; hazard ratio 0·90 95% CI 0·70 to 1·17; p=0·81). In the safety population, the most common clinically significant grade 3–4 adverse events were decreased neutrophils (71 20% in the adjuvant chemotherapy group vs 34 8% in the chemoradiotherapy only group), and anaemia (66 18% vs 34 8%). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths.
Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting.
National Health and Medical Research Council and National Cancer Institute.
•Rat social isolation (SI) at weaning alters behavior and neurochemistry resembling schizophrenia.•The role of changed gut microbiota in development of the SI syndrome is examined herein.•SI ...increased activity, reduced associative learning, neurogenesis and hippocampal IL-6 and IL-10.•Correlations existed between microbiota, IL-6 and IL-10, conditioned freezing and exploration.•SI alters microbiota, cytokine and hippocampal function akin to schizophrenia pathophysiology.
Early-life stress is an established risk for the development of psychiatric disorders. Post-weaning isolation rearing of rats produces lasting developmental changes in behavior and brain function that may have translational pathophysiological relevance to alterations seen in schizophrenia, but the underlying mechanisms are unclear. Accumulating evidence supports the premise that gut microbiota influence brain development and function by affecting inflammatory mediators, the hypothalamic–pituitaryadrenal axis and neurotransmission, but there is little knowledge of whether the microbiota-gut-brain axis might contribute to the development of schizophrenia-related behaviors. To this end the effects of social isolation (SI; a well-validated animal model for schizophrenia)-induced changes in rat behavior were correlated with alterations in gut microbiota, hippocampal neurogenesis and brain cytokine levels. Twenty-four male Lister hooded rats were housed in social groups (group-housed, GH, 3 littermates per cage) or alone (SI) from weaning (post-natal day 24) for four weeks before recording open field exploration, locomotor activity/novel object discrimination (NOD), elevated plus maze, conditioned freezing response (CFR) and restraint stress at one week intervals. Post-mortem caecal microbiota composition, cortical and hippocampal cytokines and neurogenesis were correlated to indices of behavioral changes. SI rats were hyperactive in the open field and locomotor activity chambers traveling further than GH controls in the less aversive peripheral zone. While SI rats showed few alterations in plus maze or NOD they froze for significantly less time than GH following conditioning in the CFR paradigm, consistent with impaired associative learning and memory. SI rats had significantly fewer BrdU/NeuN positive cells in the dentate gyrus than GH controls. SI rats had altered microbiota composition with increases in Actinobacteria and decreases in the class Clostridia compared to GH controls. Differences were also noted at genus level. Positive correlations were seen between microbiota, hippocampal IL-6 and IL-10, conditioned freezing and open field exploration. Adverse early-life stress resulting from continuous SI increased several indices of ‘anxiety-like’ behavior and impaired associative learning and memory accompanied by changes to gut microbiota, reduced hippocampal IL-6, IL-10 and neurogenesis. This study suggests that early-life stress may produce long-lasting changes in gut microbiota contributing to development of abnormal neuronal and endocrine function and behavior which could play a pivotal role in the aetiology of psychiatric illness.
Summary Background Evidence for improved outcomes for people with dementia through provision of person-centred care and dementia-care mapping is largely observational. We aimed to do a large, ...randomised comparison of person-centred care, dementia-care mapping, and usual care. Methods In a cluster randomised controlled trial, urban residential sites were randomly assigned to person-centred care, dementia-care mapping, or usual care. Carers received training and support in either intervention or continued usual care. Treatment allocation was masked to assessors. The primary outcome was agitation measured with the Cohen-Mansfield agitation inventory (CMAI). Secondary outcomes included psychiatric symptoms including hallucinations, neuropsychological status, quality of life, falls, and cost of treatment. Outcome measures were assessed before and directly after 4 months of intervention, and at 4 months of follow-up. Hierarchical linear models were used to test treatment and time effects. Analysis was by intention to treat. This trial is registered with the Australia and New Zealand Clinical Trials Registry, number ACTRN12608000084381. Findings 15 care sites with 289 residents were randomly assigned. Pairwise contrasts revealed that at follow-up, and relative to usual care, CMAI score was lower in sites providing mapping (mean difference 10·9, 95% CI 0·7–21·1; p=0·04) and person-centred care (13·6, 3·3–23·9; p=0·01). Compared with usual care, fewer falls were recorded in sites that used mapping (0·24, 0·08–0·40; p=0·02) but there were more falls with person-centred care (0·15, 0·02–0·28; p=0·03). There were no other significant effects. Interpretation Person-centred care and dementia-care mapping both seem to reduce agitation in people with dementia in residential care. Funding Australian Health Ministers' Advisory Council.
PDF
