Validity and measurement equivalence of EQ-5D-5L questionnaire among heart failure patients in Malaysia: a cohort study.

AIM: This study aimed to examine the validity of EQ-5D-5L among HFrEF patients in Malaysia, and to explore the measurement equivalence of three main language versions. METHODS: We surveyed HFrEF patients from two hospitals in Malaysia, using Malay, English or Chinese versions of EQ-5D-5L. EQ-5D-5L dimensional scores were converted to utility scores using the Malaysian value set. A confirmatory factor analysis longitudinal model was constructed. The utility and visual analog scale (VAS) scores were evaluated for validity (convergent, known-group, responsiveness), and measurement equivalence of the three language versions. RESULTS: 200 HFrEF patients (mean age = 61 years), predominantly male (74%) of Malay ethnicity (55%), completed the admission and discharge EQ-5D-5L questionnaire in Malay (49%), English (26%) or Chinese (25%) languages. 173 patients (86.5%) were followed up at 1-month post-discharge (1MPD). The standardized factor loadings and average variance extracted were ≥ 0.5 while composite reliability was ≥ 0.7, suggesting convergent validity. Patients with older age and higher New York Heart Association (NYHA) class reported significantly lower utility and VAS scores. The change in utility and VAS scores between admission and discharge was large, while the change between discharge and 1MPD was minimal. The minimal clinically important difference for utility and VAS scores was ±0.19 and ±11.01, respectively. Malay and English questionnaire were equivalent while the equivalence of Malay and Chinese questionnaire was inconclusive. LIMITATION: This study only sampled HFrEF patients from two teaching hospitals, thus limiting the generalizability of results to the entire heart failure population. CONCLUSION: EQ-5D-5L is a valid questionnaire to measure health-related quality of life and estimate utility values among HFrEF patients in Malaysia. The Malay and English versions of EQ-5D-5L appear equivalent for clinical and economic assessments.

EQ-5D is the most commonly used questionnaire to measure patients' health-related quality of life in clinical trials and health technology assessments. To increase confidence over clinical trial findings that heart failure interventions improve health-related quality of life and quality-adjusted life years (number of years alive with equivalence health-related quality of life), the questionnaire used to measure health-related quality of life needs to be validated in the specific population. Since EQ-5D-5L has not been validated in Malaysia's heart failure with reduced ejection fraction (HFrEF) population, this study evaluated the psychometric properties (validity) of EQ-5D-5L among HFrEF patients in Malaysia and the equivalence of different versions of languages (i.e. Malay, Chinese and English) of EQ-5D-5L in measuring the health-related quality of life. The findings suggested that EQ-5D-5L is a valid questionnaire to measure the health-related quality of life in HFrEF patients and estimate the quality-adjusted life years. The Malay and English versions of EQ-5D-5L appear to be equivalent for use in clinical trials and health technology assessments.

Economic Evaluations of Digital Health Interventions for Patients With Heart Failure: Systematic Review.

BACKGROUND: Digital health interventions (DHIs) have shown promising results in enhancing the management of heart failure (HF). Although health care interventions are increasingly being delivered digitally, with growing evidence on the potential cost-effectiveness of adopting them, there has been little effort to collate and synthesize the findings. OBJECTIVE: This study's objective was to systematically review the economic evaluations that assess the adoption of DHIs in the management and treatment of HF. METHODS: A systematic review was conducted using 3 electronic databases: PubMed, EBSCOhost, and Scopus. Articles reporting full economic evaluations of DHIs for patients with HF published up to July 2023 were eligible for inclusion. Study characteristics, design (both trial based and model based), input parameters, and main results were extracted from full-text articles. Data synthesis was conducted based on the technologies used for delivering DHIs in the management of patients with HF, and the findings were analyzed narratively. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed for this systematic review. The reporting quality of the included studies was evaluated using the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) guidelines. RESULTS: Overall, 27 economic evaluations were included in the review. The economic evaluations were based on models (13/27, 48%), trials (13/27, 48%), or a combination approach (1/27, 4%). The devices evaluated included noninvasive remote monitoring devices (eg, home telemonitoring using digital tablets or specific medical devices that enable transmission of physiological data), telephone support, mobile apps and wearables, remote monitoring follow-up in patients with implantable medical devices, and videoconferencing systems. Most of the studies (24/27, 89%) used cost-utility analysis. The majority of the studies (25/27, 93%) were conducted in high-income countries, particularly European countries (16/27, 59%) such as the United Kingdom and the Netherlands. Mobile apps and wearables, remote monitoring follow-up in patients with implantable medical devices, and videoconferencing systems yielded cost-effective results or even emerged as dominant strategies. However, conflicting results were observed, particularly in noninvasive remote monitoring devices and telephone support. In 15% (4/27) of the studies, these DHIs were found to be less costly and more effective than the comparators (ie, dominant), while 33% (9/27) reported them to be more costly but more effective with incremental cost-effectiveness ratios below the respective willingness-to-pay thresholds (ie, cost-effective). Furthermore, in 11% (3/27) of the studies, noninvasive remote monitoring devices and telephone support were either above the willingness-to-pay thresholds or more costly than, yet as effective as, the comparators (ie, not cost-effective). In terms of reporting quality, the studies were classified as good (20/27, 74%), moderate (6/27, 22%), or excellent (1/27, 4%). CONCLUSIONS: Despite the conflicting results, the main findings indicated that, overall, DHIs were more cost-effective than non-DHI alternatives. TRIAL REGISTRATION: PROSPERO CRD42023388241; https://tinyurl.com/2p9axpmc.

The IMPROVE trial: study protocol for a pragmatic cluster randomised controlled trial to assess the effectiveness of using lay health workers to improve uptake and completion of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease.

BACKGROUND: Pulmonary rehabilitation (PR) is a programme of exercise and education and the most effective treatment for the symptoms and disability associated with chronic obstructive pulmonary disease. However, the benefits of PR are limited by poor uptake and completion. This trial will determine whether using trained volunteer lay health workers, called "PR buddies," improves uptake and completion of PR and is cost-effective. This trial protocol outlines the methods for evaluating effectiveness, cost-effectiveness, and acceptability. METHODS: The IMPROVE trial is a pragmatic, open, cluster randomised controlled trial planned in 38 PR services across England and Wales. PR services will be randomised to either intervention arm-offering support from PR buddies to patients with chronic obstructive pulmonary disease-or to usual care as the control arm. PR staff in trial sites randomised to the intervention arm will receive training in recruiting and training PR buddies. They will deliver training to volunteers, recruited from among people who have recently completed PR in their service. The 3-day PR-buddy training programme covers communication skills, confidentiality, boundaries of the PR-buddy role and behaviour change techniques to help patients overcome obstacles to attending PR. An internal pilot will test the implementation of the trial in eight sites (four intervention sites and four in control arm). The primary outcome of the trial is the uptake and completion of PR. A process evaluation will investigate the acceptability of the intervention to patients, PR staff and the volunteer PR buddies, and intervention fidelity. We will also conduct a cost-effectiveness analysis. DISCUSSION: Improving outcomes for chronic obstructive pulmonary disease and access to PR are priorities for the UK National Health Service (NHS) in its long-term plan. The trial hypothesis is that volunteer PR buddies, who are recruited and trained by local PR teams, are an effective and cost-effective way to improve the uptake and completion rates of PR. The trial is pragmatic, since it will test whether the intervention can be incorporated into NHS PR services. Information obtained in this trial may be used to influence policy on the use of PR buddies in PR and other similar services in the NHS. TRIAL REGISTRATION: ISRCTN12658458. Registered on 23/01/2023.

Genetic-Guided Pharmacotherapy for Coronary Artery Disease: A Systematic and Critical Review of Economic Evaluations.

BACKGROUND: Genetic-guided pharmacotherapy (PGx) is not recommended in clinical guidelines for coronary artery disease (CAD). We aimed to examine the extent and quality of evidence from economic evaluations of PGx in CAD and to identify variables influential in changing conclusions on cost-effectiveness. METHODS AND RESULTS: From systematic searches across 6 databases, 2 independent reviewers screened, included, and rated the methodological quality of economic evaluations of PGx testing to guide pharmacotherapy for patients with CAD. Of 35 economic evaluations included, most were model-based cost-utility analyses alone, or alongside cost-effectiveness analyses of PGx testing to stratify patients into antiplatelets (25/35), statins (2/35), pain killers (1/35), or angiotensin-converting enzyme inhibitors (1/35) to predict CAD risk (8/35) or to determine the coumadin doses (1/35). To stratify patients into antiplatelets (96/151 comparisons with complete findings of PGx versus non-PGx), PGx was more effective and more costly than non-PGx clopidogrel (28/43) but less costly than non-PGx prasugrel (10/15) and less costly and less effective than non-PGx ticagrelor (22/25). To predict CAD risk (51/151 comparisons), PGx using genetic risk scores was more effective and less costly than clinical risk score (13/17) but more costly than no risk score (16/19) or no treatment (9/9). The remaining comparisons were too few to observe any trend. Mortality risk was the most common variable (47/294) changing conclusions. CONCLUSIONS: Economic evaluations to date found PGx to stratify patients with CAD into antiplatelets or to predict CAD risk to be cost-effective, but findings varied based on the non-PGx comparators, underscoring the importance of considering local practice in deciding whether to adopt PGx.

Measuring the impact of monoclonal antibody therapies.

Objective: Monoclonal antibody (Mab) treatments have significantly improved the quality and quantity of life, but they are some of the most expensive treatments, resulting in a degree of hesitancy to introduce new Mab agents. A system for estimating the effect of Mab drugs, in general, would optimally inform health strategy and fully realize how a single scientific discovery can deliver health benefits. We evaluated such a method with several well-established Mab regimens. Methods: We selected five different Mab regimens in oncology and rheumatology in England. We carried out two systematic literature reviews and meta-analyses to assess health outcomes (Health Assessment Questionnaire-Disability Index for rheumatoid arthritis; overall mortality for melanoma) from real-world data and compared them to the outcomes from randomized control trials (RCTs). We applied economic modeling to estimate the net monetary benefits for health outcomes for the estimated patient population size for each Mab regimen. Results: Meta-analyses of 27 eligible real-world data (RWD) sets and 26 randomized controlled trial (RCT) sets found close agreement between the observed and expected health outcomes. A Markov model showed the net positive monetary benefit in three Mab regimens and the negative benefit in two regimens. However, because of limited access to NHS data, the economic model made several assumptions about the number of treated patients and the cost of treatment to the NHS, the accuracy of which may affect the estimation of the net monetary benefit. Conclusion: RCT results reliably inform the real-world experience of Mab treatments. Calculation of the net monetary benefit by the algorithm described provides a valuable overall measure of the health impact, subject to the accuracy of data inputs. This study provides a compelling case for building a comprehensive, systematized, and accessible database and related analytics, on all Mab treatments within health services.

A Longitudinal Evaluation of the Preferences of Patients With Advanced Cancer for Quality of Life and Survival in Malaysia: A Discrete Choice Experiment.

OBJECTIVES: This study aims to quantify the preferences of patients with advanced cancer for quality of life (QoL) outcomes versus survival extension in Malaysia. The secondary aim of this study is to explore the change in preferences over time. METHODS: A discrete choice experiment was developed to include 7 attributes valued in cancer management: physical, psychological and social functioning, pain control, survival, place of death, and cost. Patients were recruited via convenience sampling from 2 Malaysian public hospitals. The survey questionnaire was administered to patients within 6 months of their cancer diagnosis with a follow-up 3 months later. Conditional logit regression was used to estimate the preference weight, relative attribute importance, and willingness to pay. RESULTS: One hundred valid responses were collected at baseline and 45 at follow-up. Respondents placed higher values on QoL improvements from severe to moderate or mild levels and to achieve home death over survival extension from 6 to 18 months. However, additional improvements (from moderate to mild) in some of the QoL outcomes were not valued as highly as life extension from 12 to 18 months, showing that it was vital for patients to avoid being in "severe" health dysfunction. Improving physical dysfunction from severe to mild yielded 3 times as much value as additional 1-year survival. After 3 months, the respondents' preferences changed significantly, with increased relative attribute importance of physical functioning, pain control, and cost. CONCLUSIONS: As QoL outcomes are valued more than survival, palliative care should be introduced as early as possible to alleviate suffering related to advanced cancer.

Continuous Positive Airway Pressure plus Mandibular Advancement Therapy (PAPMAT): study protocol for an adaptive randomised crossover trial comparing the benefits and costs of combining two established treatments for obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) involves repeated breathing pauses during sleep due to upper airway obstruction. It causes excessive daytime sleepiness and has other health impacts. Continuous positive airway pressure (CPAP) therapy is effective first line treatment for moderate to severe OSA. Unfortunately, many patients have difficulty tolerating CPAP and pressure intolerance is probably an important contributing factor. Mandibular advancement devices (MAD) are an alternative to CPAP. They are worn in the mouth during sleep to reduce airway obstruction. There is some evidence that, when used in combination with CPAP, MADs improve airway anatomy enough to reduce the CPAP pressure required to treat OSA and that this combination therapy could improve CPAP adherence. METHODS: Consecutive patients starting on CPAP for moderate to severe OSA will be recruited at a regional NHS sleep service. Patients with high CPAP pressure requirements after initial titration, who satisfy all entry criteria and consent to participate, will undertake a 2-arm randomised crossover trial. The arms will be (i) standalone CPAP and (ii) CPAP + MAD therapy. Each arm will last 12 weeks, including 2 weeks acclimatisation. CPAP machines will be auto-titrating and with facility for data download, so the impact of MAD on CPAP pressure requirements and CPAP adherence can be easily measured. The primary outcome will be CPAP adherence. Secondary outcomes will include measures of OSA severity, patient-reported outcome measures including subjective daytime sleepiness, quality of life, and treatment preference at the trial exit and health service use. Cost-effectiveness analyses will be undertaken. DISCUSSION: If the intervention is shown to be effective and cost-effective in improving adherence in this standard CPAP-eligible OSA patient population it would be relatively straightforward to introduce into existing OSA treatment pathways, within the wider NHS and more widely. Both MAD and CPAP are already used by sleep services so their combination would require only minor adjustments to existing clinical pathways. It would be straightforward to disseminate the results of the study through regional, national, and international respiratory meetings. The health economics analysis would provide cost-effectiveness data to inform service planning and clinical guidelines through policy briefing papers, including those by NICE and SIGN. TRIAL REGISTRATION: PAPMAT was registered with ISRCTN prior to recruitment beginning (ISRCTN Registry 2021): https://www.isrctn.com/ISRCTN33966032 . Registered on 17th November 2021.

A Systematic Literature Review of Gaps and Challenges in Value Assessment of Biosimilars: An ISPOR Special Interest Group Report.

OBJECTIVES: This study aims to provide an overview of the gaps and challenges in the value assessment of biosimilars and to identify potential approaches to address them. METHODS: A multidisciplinary, international team of biosimilar experts identified gaps and challenges. A systematic review was conducted of the peer-reviewed literature in PubMed, EMBASE, Web of Science Core Collection, EBSCOhost Business Source Complete; and of the gray literature. Preliminary results were presented at ISPOR conferences and this article benefited from 2 review rounds among ISPOR Biosimilar Special Interest Group members. RESULTS: Given that a biosimilar is highly similar to its reference biologic, health technology assessment agencies should accept the comparability exercise approved by regulatory authorities and, thus, conduct a price comparison when biosimilar reimbursement is requested for the same indication as the reference biologic. If the reference biologic is not reimbursed or is not the standard of care, a full economic evaluation of the biosimilar versus a relevant comparator needs to be conducted. To date, little consideration has been given to specific challenges, such as how biosimilar value assessment can account for the nocebo effect, potential differences between biologic-naive and biologic-experienced patients, the availability of intravenous and subcutaneous administration forms or different administration devices for the same active compound, value-added services, and the contribution of biosimilars for generating health gain at the population level. CONCLUSIONS: There is a need to gather further insights in the methodology of value assessment for biosimilars, and health technology assessment agencies need to develop more elaborate guidance on biosimilar value assessment in specific circumstances.

Conjoint analyses of patients' preferences for primary care: a systematic review.

BACKGROUND: While patients' preferences in primary care have been examined in numerous conjoint analyses, there has been little systematic effort to synthesise the findings. This review aimed to identify, to organise and to assess the strength of evidence for the attributes and factors associated with preference heterogeneity in conjoint analyses for primary care outpatient visits. METHODS: We searched five bibliographic databases (PubMed, Embase, PsycINFO, Econlit and Scopus) from inception until 15 December 2021, complemented by hand-searching. We included conjoint analyses for primary care outpatient visits. Two reviewers independently screened papers for inclusion and assessed the quality of all included studies using the checklist by ISPOR Task Force for Conjoint Analysis. We categorized the attributes of primary care based on Primary Care Monitoring System framework and factors based on Andersen's Behavioural Model of Health Services Use. We then assessed the strength of evidence and direction of preference for the attributes of primary care, and factors affecting preference heterogeneity based on study quality and consistency in findings. RESULTS: Of 35 included studies, most (82.4%) were performed in high-income countries. Each study examined 3-8 attributes, mainly identified through literature reviews (n = 25). Only six examined visits for chronic conditions, with the rest on acute or non-specific / other conditions. Process attributes were more commonly examined than structure or outcome attributes. The three most commonly examined attributes were waiting time for appointment, out-of-pocket costs and ability to choose the providers they see. We identified 24/58 attributes with strong or moderate evidence of association with primary care uptake (e.g., various waiting times, out-of-pocket costs) and 4/43 factors with strong evidence of affecting preference heterogeneity (e.g., age, gender). CONCLUSIONS: We found 35 conjoint analyses examining 58 attributes of primary care and 43 factors that potentially affect the preference of these attributes. The attributes and factors, stratified into evidence levels based on study quality and consistency, can guide the design of research or policies to improve patients' uptake of primary care. We recommend future conjoint analyses to specify the types of visits and to define their attributes clearly, to facilitate consistent understanding among respondents and the design of interventions targeting them. Word Count: 346/350 words. TRIAL REGISTRATION: On Open Science Framework: https://osf.io/m7ts9.

A Comparison of the Content and Consistency of Methodological Quality and Transferability Checklists for Reviewing Model-Based Economic Evaluations.

OBJECTIVES: The aim of this study was to examine whether and how the content of six checklists (Caro, Consensus on Health Economic Criteria [CHEC]-Extended, European Network of Health Economic Databases [EURONHEED], National Institute for Health and Care Excellence [NICE], Philips, Welte) affect the consistency in findings on methodological quality and transferability, using 10 model-based economic evaluations of genetic-guided pharmacotherapy for venous thromboembolism. METHODS: Each checklist was categorised by domain (structure, data, consistency, etc.) and type of assessment (presence vs. appropriateness) and was applied to each study by two independent reviewers who agreed on ratings via consensus, and discussion with a third reviewer when necessary. Methodological quality scores and rankings were examined using Spearman correlation tests, with subgroup analyses for domains and types of assessment. We compared overall ratings of transferability qualitatively, including how content may affect what is considered 'transferable'. RESULTS: The checklists had similar proportions of items judging presence and appropriateness, but varying proportions of items across domains. For methodological quality, ranking consistencies were the highest between CHEC-Extended-Philips, Philips-NICE and NICE-Caro, with similar consistencies for domains and type of assessment. For transferability, NICE and Caro identified the same study, which scored high on EURONHEED, as transferable to the UK, while Welte, which considered methodological quality, identified none as transferable. CONCLUSIONS: We found that the choice of checklist can affect findings on study quality and decisions about whether study results are transferable, indicating that different checklists may shortlist different sets of studies in formulating policy recommendations, leading to different policy decisions. Our systematic approach for evaluating the content of methodological quality and transferability checklists of economic evaluations can be extended to other checklists.

Genetic-Guided Pharmacotherapy for Atrial Fibrillation: A Systematic and Critical Review of Economic Evaluations.

OBJECTIVES: This study aimed to examine the extent and quality of evidence from economic evaluations (EEs) of genetic-guided pharmacotherapy (PGx) for atrial fibrillation (AF) and to identify variables influential in changing base-case conclusions. METHODS: From systematic searches, we included EEs of existing PGx testing to guide pharmacotherapy for AF, without restrictions on population characteristics or language. Articles excluded were genetic tests used to guide device-based therapy or focused on animals. RESULTS: We found 18 EEs (46 comparisons), all model-based cost-utility analysis with or without cost-effectiveness analysis mostly from health system's perspectives, of PGx testing to determine coumadin/direct-acting anticoagulant (DOAC) dosing (14 of 18), to stratify patients into coumadin/DOACs (3 of 18), or to increase patients' adherence to coumadin (1 of 18) versus non-PGx. Most PGx to determine coumadin dosing found PGx more costly and more effective than standard or clinical coumadin dosing (19 of 24 comparisons) but less costly and less effective than standard DOAC dosing (14 of 14 comparisons). The remaining comparisons were too few to observe any trend. Of 61 variables influential in changing base-case conclusions, effectiveness of PGx testing was the most common (37%), accounted for in the models using time-based or medication-based approaches or relative risk. The cost of PGx testing has decreased and plateaued over time. CONCLUSIONS: EEs to date only partially inform decisions on selecting optimal PGx testing for AF, because most evidence focuses on PGx testing to determine coumadin dosing, but less on other purposes. Future EE may refer to the list of influential variables and the approaches used to account for the effect of PGx testing to inform data collection and study design.

Development and validation of an interpretable machine learning scoring tool for estimating time to emergency readmissions.

Background: Emergency readmission poses an additional burden on both patients and healthcare systems. Risk stratification is the first step of transitional care interventions targeted at reducing readmission. To accurately predict the short- and intermediate-term risks of readmission and provide information for further temporal risk stratification, we developed and validated an interpretable machine learning risk scoring system. Methods: In this retrospective study, all emergency admission episodes from January 1st 2009 to December 31st 2016 at a tertiary hospital in Singapore were assessed. The primary outcome was time to emergency readmission within 90 days post discharge. The Score for Emergency ReAdmission Prediction (SERAP) tool was derived via an interpretable machine learning-based system for time-to-event outcomes. SERAP is six-variable survival score, and takes the number of emergency admissions last year, age, history of malignancy, history of renal diseases, serum creatinine level, and serum albumin level during index admission into consideration. Findings: A total of 293,589 ED admission episodes were finally included in the whole cohort. Among them, 203,748 episodes were included in the training cohort, 50,937 episodes in the validation cohort, and 38,904 in the testing cohort. Readmission within 90 days was documented in 80,213 (27.3%) episodes, with a median time to emergency readmission of 22 days (Interquartile range: 8-47). For different time points, the readmission rates observed in the whole cohort were 6.7% at 7 days, 10.6% at 14 days, 13.6% at 21 days, 16.4% at 30 days, and 23.0% at 60 days. In the testing cohort, the SERAP achieved an integrated area under the curve of 0.737 (95% confidence interval: 0.730-0.743). For a specific 30-day readmission prediction, SERAP outperformed the LACE index (Length of stay, Acuity of admission, Charlson comorbidity index, and Emergency department visits in past six months) and the HOSPITAL score (Hemoglobin at discharge, discharge from an Oncology service, Sodium level at discharge, Procedure during the index admission, Index Type of admission, number of Admissions during the last 12 months, and Length of stay). Besides 30-day readmission, SERAP can predict readmission rates at any time point during the 90-day period. Interpretation: Better performance in risk prediction was achieved by the SERAP than other existing scores, and accurate information about time to emergency readmission was generated for further temporal risk stratification and clinical decision-making. In the future, external validation studies are needed to evaluate the SERAP at different settings and assess their real-world performance. Funding: This study was supported by the Singapore National Medical Research Council under the PULSES Center Grant, and Duke-NUS Medical School.

Genetic-guided pharmacotherapy for venous thromboembolism: a systematic and critical review of economic evaluations.

Despite the known contributions of genes, genetic-guided pharmacotherapy has not been routinely implemented for venous thromboembolism (VTE). To examine evidence on cost-effectiveness of genetic-guided pharmacotherapy for VTE, we searched six databases, websites of four HTA agencies and citations, with independent double-reviewers in screening, data extraction, and quality rating. The ten eligible studies, all model-based, examined heterogeneous interventions and comparators. Findings varied widely; testing was cost-saving in two base-cases, cost-effective in four, not cost-effective in three, dominated in one. Of 22 model variables that changed decisions about cost-effectiveness, effectiveness/relative effectiveness of the intervention was the most frequent, albeit of poor quality. Studies consistently lacked details on the provision of interventions and comparators as well as on model development and validation. Besides improving the reporting of interventions, comparators, and methodological details, future economic evaluations should examine strategies recommended in guidelines and testing key model variables for decision uncertainty, to advise clinical implementations.

Optimal cut-off points for adherence measure among patients with type 2 diabetes in primary care clinics: a retrospective analysis.

BACKGROUND: Medication adherence measures are often dichotomized to classify patients into those with good or poor adherence using a cut-off value ⩾80%, but this cut-off may not be universal across diseases or medication classes. This study aimed to examine the cut-off value that optimally distinguish good and poor adherence by using the medication possession ratio (MPR) and proportion of days covered (PDC) as adherence measures and glycated hemoglobin (HbA1c) as outcome measure among type 2 diabetes mellitus (T2DM) patients. METHOD: We used pharmacy dispensing data of 1461 eligible T2DM patients from public primary care clinics in Malaysia treated with oral antidiabetic drugs between January 2018 and May 2019. Adherence rates were calculated during the period preceding the HbA1c measurement. Adherence cut-off values for the following conditions were compared: adherence measure (MPR versus PDC), assessment period (90-day versus 180-day), and HbA1c target (⩽7.0% versus ⩽8.0%). RESULTS: The optimal adherence cut-offs for MPR and PDC in predicting HbA1c ⩽7.0% ranged between 86.1% and 98.3% across the two assessment periods. In predicting HbA1c ⩽8.0%, the optimal adherence cut-offs ranged from 86.1% to 92.8%. The cut-off value was notably higher with PDC as the adherence measure, shorter assessment period, and a stricter HbA1c target (⩽7.0%) as outcome. CONCLUSION: We found that optimal adherence cut-off appeared to be slightly higher than the conventional value of 80%. The adherence thresholds may vary depending on the length of assessment period and outcome definition but a reasonably wise cut-off to distinguish good versus poor medication adherence to be clinically meaningful should be at 90%.

A New Procedure to Assess When Estimates from the Cumulative Link Model Can Be Interpreted as Differences for Ordinal Scales in Quality of Life Studies.

PURPOSE: Assessing the clinical importance of an exposure effect on a quality of life (QoL) score often requires quantifying the effect in terms of a difference in scores. Using the linear regression model (LRM) for this purpose assumes the ordinal score is a proxy for an underlying continuous variable, but the analysis offers no assessment for the validity of the assumption. We propose an approach that assesses the proxy assumption and estimates the exposure effect by using the cumulative link model (CLM). PATIENTS AND METHODS: CLM is a well-established regression model that assumes an ordinal score is an ordered category generated from applying thresholds to a latent continuous variable. Our approach assesses the proxy assumption by testing whether these thresholds are equidistant. We compared the performance of CLM and LRM using simulated ordinal data and illustrated their application to the effect of time since diagnosis on five subscales of fatigue among breast cancer survivors measured using the Multidimensional Fatigue Inventory. RESULTS: CLM had good performance in estimating the difference in means with simulated ordinal data satisfying the proxy assumption, even when the outcome had only a few categories. When the proxy assumption was inadequate, both the CLM and LRM had biased estimates with poor coverage. The proxy assumption was appropriate for four of the five subscales in our real data application to fatigue scores, which highlighted the importance of assessing the proxy assumption to avoid reporting invalid estimates in terms of the difference in scores. CONCLUSION: The proxy assumption is critical to the interpretation of the exposure effect on the difference in mean QoL scores. CLM offers a valid test for the presence of an association, a method for assessing the proxy assumption, and when the assumption is adequate, an assessment for clinical significance using the difference in means.

Examining the heterogeneity inexcess risks of coronary heart disease, stroke, dialysis, and lower extremity amputation associated with type 2 diabetes mellitus across demographic subgroups in an Asian population: A population-based matched cohort study.

AIMS: To examine whether the excess risks of coronary heart disease (CHD), stroke, dialysis, and lower extremity amputation (LEA) associated with type 2 diabetes mellitus (T2DM) differ across age, sex, and ethnicity in Singapore. METHODS: Using a 10-year administrative data, we matched individuals with T2DM using nearest neighbour matching, to those without, in 1:2 ratio. To examine whether the excess risks were heterogeneous across age, sex, and ethnicity, we generated interaction terms of age, sex, and ethnicity with T2DM status in Cox proportional hazard (PH) models. RESULTS: The main analyses included ~1 million person years, comprising 66,099 and 120,485 individuals with and without T2DM, respectively. The associations of T2DM with CHD and dialysis, split into two time periods to address violation of PH assumption, were higher with older age in short-term but lower with older age in long-term. The association of T2DM with stroke and LEA were lower with older age. The associations of T2DM with CHD and stroke were also consistently higher in women than men. The associations of T2DM with LEA were higher in ethnic Malays than ethnic Chinese. CONCLUSIONS: The excess risks of CHD, stroke, dialysis, and LEA associated with T2DM were heterogeneous across some demographic subgroups.

Risk of malignancies in patients with spondyloarthritis treated with biologics compared with those treated with non-biologics: a systematic review and meta-analysis.

BACKGROUND: The aim of our study was to synthesize evidence on the occurrence of malignancy in spondyloarthritis (SpA), from randomized controlled trials (RCTs) comparing biologics with non-biologics and biologics to each other. METHODS: We systematically searched Medline, Cochrane Library, EMBASE, Scopus and ClinicalTrials.gov from inception until 31 October 2018. RCTs with ⩾24-week follow-up were included. We extracted data using standardized forms and assessed the risk of bias using the Cochrane Risk of Bias Tool. We performed pair-wise meta-analyses and network meta-analyses to compare the risk of malignancy for each biologics class and SpA type. We reported the Peto odds ratio (OR) of any malignancy along with 95% confidence intervals (95% CI). Bayesian posterior probabilities comparing risk of malignancy of each biologic class with non-biologics were computed as supplementary measures. RESULTS: Fifty-four trials were included; most (44/54) had follow-up <1 year. Among 14,245 patients, 63 developed a malignancy. While most Peto ORs were >1, they had wide 95% CI and p >0.05. The overall Peto OR comparing biologics with non-biologics was 1.42 (95% CI 0.80-2.53). Only interleukin-17 inhibitors in peripheral SpA had p <0.05 (Peto OR 2.77, 95% CI 1.07-7.13); the posterior probability that the risk was higher than non-biologics was 98%. Stratified analyses revealed no consistent trend by prior exposure to biologics, duration of follow-up, study quality, study-arm crossover, analytical approaches and type of malignancy. CONCLUSIONS: Our findings indicate no overall elevated risk of malignancy with biologics in SpA. As our meta-analyses are unable to conclude on the long-term risk, long-term pharmacovigilance of biologics in SpA may still be warranted.

Psychological Resilience as an Emergent Characteristic for Well-Being: A Pragmatic View.

Currently, there is no clear agreement on the definition and conceptualization for psychological resilience (PR) in old age. Adopting a pragmatic view, this article elucidates the definition and conceptualization of PR by (1) extracting existing PR concepts that are relevant to aging, and (2) elucidating the contributing and delimiting factors for developing and sustaining PR as guided by the biopsychosocial framework. In addition, a comprehensive review of the tools used to measure PR was conducted to examine how scholars have conceptualized PR. Consequently, the renewed understanding defines PR as an emergent construct which is malleable, enduring, and can be developed and sustained by a dynamic interplay of biological, psychological, spiritual, and social factors. Correlates in terms of physical and mental well-being in the context of aging are identified.

The direct and indirect costs of axial spondyloarthritis (axSpA) in Singapore.

OBJECTIVE: To estimate the economic annual direct and indirect costs of axial spondyloarthritis (axSpA) in Singapore, and to identify factors associated with these costs. METHODS: A retrospective, cross-sectional, Institutional Review Board-approved study was conducted. A questionnaire was administered to the patients between 2013 and 2016 from the Singapore General Hospital (SGH) spondyloarthritis registry. Direct medical costs and indirect costs were estimated using the SGH database and the human capital approach respectively. Multivariate analyses using generalized linear model with gamma distribution and a log-linked function was conducted to identify factors associated with these total, direct and indirect costs. All costs were adjusted to 2017 using the Singapore Consumer Price Index and converted to 2017 US dollars (USD) by purchasing power parity. RESULTS: A total of 135 consecutive patients were included in the study, with a mean age of 40.4 ± 13.2 years. The overall annual total economic cost to society was around USD 74 790 820, with annual direct cost being the main component of total cost (90.8%). Annual direct cost was around USD 67 931 457, while annual indirect cost was around USD 6 855 951. Presence of extra-spinal symptoms (ever) was associated with an increase in total and direct costs. Higher education level and Patient Global Assessment were associated with an increase in indirect costs. Lack of employment was associated with a decrease in indirect costs. CONCLUSION: The disease burden of axSpA in Singapore is not trivial given that the disease is relatively common. This highlights the need for measures to accommodate patients with axSpA economically in Singapore.

The Association Between Psychological Resilience and Physical Function Among Older Adults With Hip Fracture Surgery.

OBJECTIVES: To examine the associations of prefracture psychological resilience and prefracture general mental health with physical function among older adults with hip fracture surgery. DESIGN: Single-center observational study. INTERVENTION: None. SETTING AND PARTICIPANTS: Patients aged ≥50 years who underwent first hip fracture surgery between January 2017 and December 2017 (N = 152). METHODS: We used data collected prospectively from the hospital's hip fracture registry. We performed generalized estimating equations to examine the associations of prefracture psychological resilience (10-item Connor-Davidson Resilience Scale) and prefracture general mental health (Short Form-36 mental health subscale) with physical function (Short Form-36 physical functioning subscale) at 4 time points-prefracture (based on recall), and 1.5, 3, and 6 months after surgery. RESULTS: Prefracture psychological resilience had an association with physical function; a 1-unit increase in psychological resilience score was associated with 1.15 units [95% confidence interval (CI) 0.71, 1.59] higher physical function score across 4 time points. In contrast, the association between general mental health and physical function varied over time; a 1-unit increase in general mental health score was associated with 0.42 units (95% CI 0.18, 0.66) higher physical function score at prefracture, 0.02 units (95% CI -0.18, 0.22) lower at 1.5 months, 0.23 units (95% CI -0.03, 0.49) higher at 3 months, and 0.39 units (95% CI 0.09, 0.68) higher at 6 months after surgery. CONCLUSIONS AND IMPLICATIONS: Psychological resilience is associated with physical function among older adults with hip fracture surgery, independent from general mental health. Our findings suggest the potential for interventions targeting psychological resilience for these patients and call for more studies on psychological factors affecting physical function recovery after hip fracture surgery.