Charlson Comorbidity Index: A Critical Review of Clinimetric Properties.

The present critical review was conducted to evaluate the clinimetric properties of the Charlson Comorbidity Index (CCI), an assessment tool designed specifically to predict long-term mortality, with regard to its reliability, concurrent validity, sensitivity, incremental and predictive validity. The original version of the CCI has been adapted for use with different sources of data, ICD-9 and ICD-10 codes. The inter-rater reliability of the CCI was found to be excellent, with extremely high agreement between self-report and medical charts. The CCI has also been shown either to have concurrent validity with a number of other prognostic scales or to result in concordant predictions. Importantly, the clinimetric sensitivity of the CCI has been demonstrated in a variety of medical conditions, with stepwise increases in the CCI associated with stepwise increases in mortality. The CCI is also characterized by the clinimetric property of incremental validity, whereby adding the CCI to other measures increases the overall predictive accuracy. It has been shown to predict long-term mortality in different clinical populations, including medical, surgical, intensive care unit (ICU), trauma, and cancer patients. It may also predict in-hospital mortality, although in some instances, such as ICU or trauma patients, the CCI did not perform as well as other instruments designed specifically for that purpose. The CCI thus appears to be clinically useful not only to provide a valid assessment of the patient's unique clinical situation, but also to demarcate major diagnostic and prognostic differences among subgroups of patients sharing the same medical diagnosis.

Fragility indices for only sufficiently likely modifications.

The fragility index is a clinically meaningful metric based on modifying patient outcomes that is increasingly used to interpret the robustness of clinical trial results. The fragility index relies on a concept that explores alternative realizations of the same clinical trial by modifying patient measurements. In this article, we propose to generalize the fragility index to a family of fragility indices called the incidence fragility indices that permit only outcome modifications that are sufficiently likely and provide an exact algorithm to calculate the incidence fragility indices. Additionally, we introduce a far-reaching generalization of the fragility index to any data type and explain how to permit only sufficiently likely modifications for nondichotomous outcomes. All of the proposed methodologies follow the fragility index concept.

On clinical trial fragility due to patients lost to follow up.

BACKGROUND: Clinical trials routinely have patients lost to follow up. We propose a methodology to understand their possible effect on the results of statistical tests by altering the concept of the fragility index to treat the outcomes of observed patients as fixed but incorporate the potential outcomes of patients lost to follow up as random and subject to modification. METHODS: We reanalyse the statistical results of three clinical trials on coronary artery bypass grafting (CABG) to study the possible effect of patients lost to follow up on the treatment effect statistical significance. To do so, we introduce the LTFU-aware fragility indices as a measure of the robustness of a clinical trial's statistical results with respect to patients lost to follow up. RESULTS: The analyses illustrate that clinical trials can either be completely robust to the outcomes of patients lost to follow up, extremely sensitive to the outcomes of patients lost to follow up, or in an intermediate state. When a clinical trial is in an intermediate state, the LTFU-aware fragility indices provide an interpretable measure to quantify the degree of fragility or robustness. CONCLUSIONS: The LTFU-aware fragility indices allow researchers to rigorously explore the outcomes of patients who are lost to follow up, when their data is the appropriate kind. The LTFU-aware fragility indices are sensitivity measures in a way that the original fragility index is not.

The fragility index can be used for sample size calculations in clinical trials.

OBJECTIVE: The fragility index is a clinically interpretable metric increasingly used to interpret the robustness of clinical trials results that is generally not incorporated in sample size calculation and applied post-hoc. In this manuscript, we propose to base the sample size calculation on the fragility index in a way that supplements the classical prefixed alpha and power cutoffs and we provide a dedicated R software package for the design and analysis tools. STUDY DESIGN AND SETTING: This approach follows from a novel hypothesis testing framework that is based on the fragility index and builds on the classical testing approach. As case studies, we re-analyse the design of two important trials in cardiovascular medicine, the FAME and FAMOUS-NSTEMI trials. RESULTS: The analyses show that approach returns sample sizes which results in a higher power for the P value based test and most importantly a lower and context dependent Type I error rate for the fragility index based test compared to standard tests. CONCLUSION: Our method allows clinicians to control for the fragility index during clinical trial design.

Examining the correlation between Altmetric Attention Score and citation count in the gynecologic oncology literature: Does it have an impact?

We sought to determine the correlation between Altmetric Attention Score and traditional bibliometrics in the gynecologic oncology literature. We identified the 10 most-cited gynecologic oncology articles from 5 major gynecology journals and 10 major "oncology" journals that publish on gynecologic oncology during 2014, 2016, and 2018. Article citation count and Altmetric Attention Score (AAS), as well as journal impact factor (IF) and date of Twitter account development were recorded. Pearson's correlation coefficient was used to describe the relationship between AAS, tweets, IF, and citation count. While the median citation counts significantly decreased for the top-cited gynecologic oncology articles from 2014 to 2018 (p < 0.001), the corresponding median AAS continuously increased during this period (p = 0.008). For articles published in 2014 and 2018, there was a strong positive relationship between the median citation count and the median AAS (2014: r = 0.92; 2018: r = 0.97), as well as between the IF (r = 0.78 and r = 0.89, respectively); these correlations were moderate to weak in 2016 (r = 0.5 and r = 0.41, respectively). There was a continuously increasing strong positive correlation from 2014 to 2018 between journal IF and median AAS (2014: r = 0.75; 2016: r = 0.82; 2018: r = 0.92). Gynecologic oncology articles published in higher impact journals are associated with increased social media visibility and attention. Our data support the idea that early online attention scores, like the AAS, might be useful for predicting future citation counts for oncology publications in general and gynecologic oncology specifically.

Clinimetric Criteria for Patient-Reported Outcome Measures.

Patient-reported outcome measures (PROMs) are self-rated scales and indices developed to improve the detection of the patients' subjective experience. Given that a considerable number of PROMs are available, it is important to evaluate their validity and usefulness in a specific research or clinical setting. Published guidelines, based on psychometric criteria, do not fit in with the complexity of clinical challenges, because of their quest for homogeneity of components and inadequate attention to sensitivity. Psychometric theory has stifled the field and led to the routine use of scales widely accepted yet with a history of poor performance. Clinimetrics, the science of clinical measurements, may provide a more suitable conceptual and methodological framework. The aims of this paper are to outline the major limitations of the psychometric model and to provide criteria for clinimetric patient-reported outcome measures (CLIPROMs). The characteristics related to reliability, sensitivity, validity, and clinical utility of instruments are critically reviewed, with particular reference to the differences between clinimetric and psychometric approaches. Of note is the fact that PROMs, rating scales, and indices developed according to psychometric criteria may display relevant clinimetric properties. The present paper underpins the importance of the clini-metric methodology in choosing the appropriate PROMs. CLIPROM criteria may also guide the development of new indices and the validation of existing PROMs to be employed in clinical settings.

Methodologic Considerations on Four Cardiovascular Interventions Trials With Contradictory Results.

BACKGROUND: Contradictory findings from randomized trials addressing similar research questions are not uncommon in medicine. Although differing results may reflect true differences in the treatment effects or in the deliverability of the intervention, more commonly it is as a consequence of small but important discrepancies in study design. METHODS: The writing group selected 4 recent trials with apparently contradictory results (2 on revascularization for left main coronary stenosis and 2 on treatment of secondary mitral regurgitation). Detailed methodologic analysis was performed to elucidate the difference in findings. RESULTS: Differences in the definition of the primary outcome are the most likely explanation for the contradictory findings of NOBLE versus EXCEL. Differences in study design (leading to substantially different patient populations) and in outcome definition might explain the discrepant findings of MITRA-FR versus COAPT. CONCLUSIONS: As shown by the comparative analysis of NOBLE and EXCEL and MITRA-FR and COAPT, changes in study design, outcome definitions, and patient population can markedly affect the outcome of randomized clinical trials.

Clinical and metabolic characteristics of the Diabetes Intervention Accentuating Diet and Enhancing Metabolism (DIADEM-I) randomised clinical trial cohort.

OBJECTIVES: Diabetes Intervention Accentuating Diet and Enhancing Metabolism-I (DIADEM-I) is the first randomised controlled trial (RCT) in the Middle East and North Africa (MENA) region testing the effectiveness of an intensive lifestyle intervention (ILI) for weight loss and diabetes remission. We report on the recruitment process and baseline characteristics of the DIADEM-I cohort based on origin (Middle East vs North Africa), and waist circumference. DESIGN: DIADEM-I is an open-label randomised, controlled, parallel group RCT recruiting young individuals (18-50 years) with early type 2 diabetes (≤3 years since diagnosis) originating from MENA. Individuals from primary care were randomised to usual medical care or ILI (total dietary replacement phase using meal replacement products, followed by staged food reintroduction and physical activity support). The primary outcome is weight loss at 12 months. Other outcomes are glycaemic control and diabetes remission. SETTING: Primary care, Qatar. PARTICIPANTS: 147 (73% men) randomised within DIADEM-I who were included in the final trial data analysis. OUTCOME MEASURES: Recruitment metrics, and baseline clinical and metabolic characteristics. RESULTS: Of 1498 people prescreened, 267 (18%) were invited for screening and 209 (78%) consented. 173 (83%) were eligible. 15 (7%) withdrew before randomisation and the remaining 158 were randomised. Mean age was 42.1 (SD 5.6) years and mean body mass index was: 36.3 (5.5) kg/m2 (women) and 34.4 (5.4) kg/m2 (men). Mean diabetes duration was 1.8 (1.0) years and mean glycosylated haemoglobin (HbA1c) was 7.0% (1.30) (52.5 mmol/mol (SD 14.3)). Participants originated from 13 countries. Those from North Africa reported greater physical activity and had lower family history of diabetes. 90% of subjects were taking diabetes medications and 31% antihypertensives. Those with greater waist circumference had significantly higher insulin resistance and lower quality of life. CONCLUSION: Recruitment of participants originating from the MENA region into the RCT was successful, and study participation was readily accepted. While DIADEM-I participants originated from 13 countries, there were few baseline differences amongst participants from Middle East versus North Africa, supporting generalisability of RCT results. TRIAL REGISTRATION NUMBER: ISRCTN20754766; NCT03225339.

Overall and Cause-Specific Mortality in Randomized Clinical Trials Comparing Percutaneous Interventions With Coronary Bypass Surgery: A Meta-analysis.

Importance: Mortality is a common outcome in trials comparing percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG). Controversy exists regarding whether all-cause mortality or cardiac mortality is preferred as a study end point, because noncardiac mortality should be unrelated to the treatment. Objective: To evaluate the difference in all-cause and cause-specific mortality in randomized clinical trials (RCTs) comparing PCI with CABG for the treatment of patients with coronary artery disease. Data Sources: MEDLINE (1946 to the present), Embase (1974 to the present), and the Cochrane Library (1992 to the present) databases were searched on November 24, 2019. Reference lists of included articles were also searched, and additional studies were included if appropriate. Study Selection: Articles were considered for inclusion if they were in English, were RCTs comparing PCI with drug-eluting or bare-metal stents and CABG for the treatment of coronary artery disease, and reported mortality and/or cause-specific mortality. Trials of PCI involving angioplasty without stenting were excluded. For each included trial, the publication with the longest follow-up duration for each outcome was selected. Data Extraction and Synthesis: For data extraction, all studies were reviewed by 2 independent investigators, and disagreements were resolved by a third investigator in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline. Data were pooled using fixed- and random-effects models. Main Outcomes and Measures: The primary outcomes were all-cause and cause-specific (cardiac vs noncardiac) mortality. Subgroup analyses were performed for PCI trials using drug-eluting vs bare-metal stents and for trials involving patients with left main disease. Results: Twenty-three unique trials were included involving 13 620 unique patients (6829 undergoing PCI and 6791 undergoing CABG; men, 39.9%-99.0% of study populations; mean age range, 60.0-71.0 years). The weighted mean (SD) follow-up was 5.3 (3.6) years. Compared with CABG, PCI was associated with a higher rate of all-cause (incidence rate ratio, 1.17; 95% CI, 1.05-1.29) and cardiac (incidence rate ratio, 1.24; 95% CI, 1.05-1.45) mortality but also noncardiac mortality (incidence rate ratio, 1.19; 95% CI, 1.00-1.41). Conclusions and Relevance: Percutaneous coronary intervention was associated with higher all-cause, cardiac, and noncardiac mortality compared with CABG at 5 years. The significantly higher noncardiac mortality associated with PCI suggests that even noncardiac deaths after PCI may be procedure related and supports the use of all-cause mortality as the end point for myocardial revascularization trials.

The Impact of Social and Clinical Complexity on Diabetes Control Measures.

PURPOSE: In an age of value-based payment, primary care providers are increasingly scrutinized on performance metrics that assess quality of care, including the outcomes of their patient population in key areas such as diabetes control. Although such measures often adjust for patient clinical risk factors or clinical complexity, most do not account for the social complexity of patient populations, despite research demonstrating the strong association between social factors and health. METHODS: Using patient electronic health record data from 2 large community health center networks serving safety net patients, we assessed the effect of both clinical and social risk factors on poor glucose control among diabetics. Logistic regression results were used to estimate the impact of adjusting for both clinical and social complexity on provider performance metrics. Clinical complexity was measured at the patient-level using the Charlson Comorbidity Index. Social complexity was measured at the community-level using the Social Deprivation Index. RESULTS: Clinical complexity alone was not consistently associated with poor diabetes control (ie, HbA1c > 9%) in diabetic patients with HbA1c testing during the study period. However, increasing social complexity was significantly associated with higher rates of poor diabetic control in both cohorts. After adding adjustment for social complexity down to the national median score, our models suggest that approximately 25% of providers would have 1 to 2% improvement in the assessment of their diabetes control measures, with 45% showing a 2 to 5% improvement, and 5% showing more than a 5% improvement. CONCLUSIONS: Providers caring for patients with greater social risk factors may benefit from having their performance metrics adjusted for the social complexity of their patient populations.

Characteristics of Contemporary Randomized Clinical Trials and Their Association With the Trial Funding Source in Invasive Cardiovascular Interventions.

Importance: Changes in evidence-based practice and guideline recommendations depend on high-quality randomized clinical trials (RCTs). Commercial device and pharmaceutical manufacturers are frequently involved in the funding, design, conduct, and reporting of trials, the implications of which have not been recently analyzed. Objective: To evaluate the design, outcomes, and reporting of contemporary randomized clinical trials of invasive cardiovascular interventions and their association with the funding source. Design, Setting, and Participants: This cross-sectional study analyzed published RCTs between January 1, 2008, to May 31, 2019. The trials included those involving coronary, vascular and structural interventional cardiology, and vascular and cardiac surgical procedures. Main Outcomes and Measures: We assessed (1) trial characteristics, (2) finding of a statistically significant difference in the primary end point favoring the experimental intervention, (3) reporting of implied treatment advantage in trials without significant differences in primary end point, (4) existence of major discrepancies between registered and published primary outcomes, (5) number of patients whose outcomes would need to switch from a nonevent to an event to convert a significant difference in primary end point to nonsignificant, and (6) association with funding source. Results: Of the 216 RCTs analyzed, 115 (53.2%) reported having commercial sponsorship. Most trials had 80% power to detect an estimated treatment effect of 30%, and 128 trials (59.3%) used composite primary end points. The median (interquartile range [IQR]) sample size was 502 (204-1702) patients, and the median (IQR) follow-up duration was 12 (1.0-14.4) months. Overall, 123 trials (57.0%) reported a statistically significant difference in the primary outcome favoring the experimental intervention; reporting strategies that implied an advantage were identified in 55 (65.5%) of 84 trials that reported nonsignificant differences. Commercial sponsorship was associated with a statistically significantly greater likelihood of favorable outcomes reporting (exponent of regression coefficient ß, 2.80; 95% CI, 1.09-7.18; P = .03) and with the reporting of findings that are inconsistent with the trial results. Discrepancies between the registered and published primary outcomes were found in 82 trials (38.0%), without differences in trial sponsorship. A median (IQR) number of 5 (2.8-12.5) patients experiencing a different outcome would have change statistically significant results to nonsignificant. Commercial sponsorship was associated with a greater number of patients (exponent of regression coefficient ß, 1.29; 95% CI, 1.00-1.66; P = .04). Conclusions and Relevance: These results suggest that contemporary RCTs of invasive cardiovascular interventions are relatively small and fragile, have short follow-up, and have limited power to detect large treatment effects. Commercial support appeared to be associated with differences in trial design, results, and reporting.

Effect of intensive lifestyle intervention on bodyweight and glycaemia in early type 2 diabetes (DIADEM-I): an open-label, parallel-group, randomised controlled trial.

BACKGROUND: Type 2 diabetes is affecting people at an increasingly younger age, particularly in the Middle East and in north Africa. We aimed to assess whether an intensive lifestyle intervention would lead to significant weight loss and improved glycaemia in young individuals with early diabetes. METHODS: This open-label, parallel-group, randomised controlled trial (DIADEM-I), done in primary care and community settings in Qatar, compared the effects of an intensive lifestyle intervention with usual medical care on weight loss and glycaemic outcomes in individuals with type 2 diabetes, aged 18-50 years, with a short diabetes duration (≤3 years), had a BMI of 27·0 kg/m2 or more, and who were from the Middle East and north Africa region. Participants were randomly allocated (1:1) either to the intensive lifestyle intervention group or the usual medical care control group by a computer-generated sequence and an online randomisation service. The intensive lifestyle intervention comprised a total diet replacement phase, in which participants were given formula low-energy diet meal replacement products followed by gradual food reintroduction combined with physical activity support, and a weight-loss maintenance phase, involving structured lifestyle support. Participants in the control group received usual diabetes care, which was based on clinical guidelines. The primary outcome was weight loss at 12 months after receiving the assigned intervention. Our analysis was based on the intention-to-treat principle. Key secondary outcomes included diabetes control and remission. The trial was registered with the ISRCTN registry, ISRCTN20754766, and ClinicalTrials.gov, NCT03225339. FINDINGS: Between July 16, 2017, and Sept 30, 2018, we enrolled and randomly assigned 158 participants (n=79 in each group) to the study. 147 participants (70 in the intervention group and 77 in the control group) were included in the final intention-to-treat analysis population. Between baseline and 12 months, the mean bodyweight of participants in the intervention group reduced by 11·98 kg (95% CI 9·72 to 14·23) compared with 3·98 kg (2·78 to 5·18) in the control group (adjusted mean difference -6·08 kg [95% CI -8·37 to -3·79], p<0·0001). In the intervention group, 21% of participants achieved more than 15% weight loss between baseline and 12 months compared with 1% of participants in the control group (p<0·0001). Diabetes remission occurred in 61% of participants in the intervention group compared with 12% of those in the control group (odds ratio [OR] 12·03 [95% CI 5·17 to 28·03], p<0·0001). 33% of participants in the intervention group had normoglycaemia compared with 4% of participants in the control group (OR 12·07 [3·43 to 42·45], p<0·0001). Five serious adverse events were reported in four participants in the control group; four admissions to hospital because of unanticipated events (supraventricular tachycardia, abdominal pain, pneumonia, and epididymo-orchitis), and one admission to hospital for an anticipanted event (hyperglycaemia). INTERPRETATION: Our findings show that the intensive lifestyle intervention led to significant weight loss at 12 months, and was associated with diabetes remission in over 60% of participants and normoglycaemia in over 30% of participants. The provision of this lifestyle intervention could allow a large proportion of young individuals with early diabetes to achieve improvements in key cardiometabolic outcomes, with potential long-term benefits for health and wellbeing. FUNDING: Qatar National Research Fund.

Randomized Trials in Cardiac Surgery: JACC Review Topic of the Week.

Compared with randomized controlled trials (RCTs) in medical specialties, RCTs in cardiac surgery face specific issues. Individual and collective equipoise, rapid evolution of the surgical techniques, as well as difficulties in obtaining funding, and limited education in clinical epidemiology in the surgical community are among the most important challenges in the design phase of the trial. Use of complex interventions and learning curve effect, differences in individual operators' expertise, difficulties in blinding, and slow recruitment make the successful completion of cardiac surgery RCTs particularly challenging. In fact, over the course of the last 20 years, the number of cardiac surgery RCTs has declined significantly. In this review, a team of surgeons, trialists, and epidemiologists discusses the most important challenges faced by RCTs in cardiac surgery and provides a list of suggestions for the successful design and completion of cardiac surgery RCTs.

Big Data Analytics and the Struggle for Equity in Health Care: The Promise and Perils.

Big data is both a product and a function of technology and the ever-growing analytic and computational power. The potential impact of big data in health care innovation cannot be ignored. The technology-mediated transformative potential of big data is taking place within the context of historical inequities in health and health care. Although big data analytics, properly applied, hold great potential to target inequities and reduce disparities, we believe that the realization of this potential requires us to explicitly address concerns of fairness, equity, and transparency in the development of big data tools. To mitigate potential sources of bias and inequity in algorithmic decision-making, a multipronged and interdisciplinary approach is required, combining insights from data scientists and domain experts to design algorithmic decision-making approaches that explicitly account and correct for these issues.