Mapping the value for money of precision medicine: a systematic literature review and meta-analysis.

Objective: This study aimed to quantify heterogeneity in the value for money of precision medicine (PM) by application types across contexts and conditions and to quantify sources of heterogeneity to areas of particular promises or concerns as the field of PM moves forward. Methods: A systemic search was performed in Embase, Medline, EconLit, and CRD databases for studies published between 2011 and 2021 on cost-effectiveness analysis (CEA) of PM interventions. Based on a willingness-to-pay threshold of one-time GDP per capita of each study country, the net monetary benefit (NMB) of PM was pooled using random-effects meta-analyses. Sources of heterogeneity and study biases were examined using random-effects meta-regressions, jackknife sensitivity analysis, and the biases in economic studies checklist. Results: Among the 275 unique CEAs of PM, publicly sponsored studies found neither genetic testing nor gene therapy cost-effective in general, which was contradictory to studies funded by commercial entities and early stage evaluations. Evidence of PM being cost-effective was concentrated in a genetic test for screening, diagnosis, or as companion diagnostics (pooled NMBs, $48,152, $8,869, $5,693, p < 0.001), in the form of multigene panel testing (pooled NMBs = $31,026, p < 0.001), which only applied to a few disease areas such as cancer and high-income countries. Incremental effectiveness was an essential value driver for varied genetic tests but not gene therapy. Conclusion: Precision medicine's value for money across application types and contexts was difficult to conclude from published studies, which might be subject to systematic bias. The conducting and reporting of CEA of PM should be locally based and standardized for meaningful comparisons.

Health Services Use and Functional Recovery Following Blunt Trauma in Older Persons - A National Multicentre Prospective Cohort Study.

OBJECTIVE: Frailty is associated with morbidity and mortality in older injured patients. However, for older blunt-trauma patients, increased frailty may not manifest in longer length of stay at index admission. We hypothesized that owing to time spent in hospital from readmissions, frailty would be associated with less total time at home in the 1-year postinjury period. DESIGN: Prospective, nationwide, multicenter cohort study. SETTING AND PARTICIPANTS: All Singaporean residents aged ≥55 years admitted for blunt trauma with an Injury Severity Score (ISS) or New Injury Severity Score (NISS) ≥10 from March 2016 to July 2018. METHODS: Frailty (by modified Fried criteria) was assessed at index admission, based on questions on preinjury weight loss, slowness, exhaustion, physical activity, and grip strength at the time of recruitment. Low time at home was defined as >14 hospitalized days within 1 year postinjury. The contribution of planned and unplanned readmission to time at home postinjury was explored. Functional trajectory (by Barthel Index) over 1 year was compared by frailty. RESULTS: Of the 218 patients recruited, 125 (57.3%) were male, median age was 72 years, and 48 (22.0%) were frail. On univariate analysis, frailty [relative to nonfrail: odds ratio (OR) 3.45, 95% confidence interval (CI) 1.33-8.97, P = .01] was associated with low time at home. On multivariable analysis, after inclusion of age, gender, ISS, intensive care unit admission, and surgery at index admission, frailty (OR 5.21, 95% CI 1.77-15.34, P < .01) remained significantly associated with low time at home in the 1-year postinjury period. Unplanned readmissions were the main reason for frail participants having low time at home. Frail participants had poorer function in the 1-year postinjury period. CONCLUSIONS AND IMPLICATIONS: In the year following blunt trauma, frail older patients experience lower time at home compared to patients who were not frail at baseline. Screening for frailty should be considered in all older blunt-trauma patients, with a view to being prioritized for postdischarge support.

Resuming elective surgery after COVID-19: A simulation modelling framework for guiding the phased opening of operating rooms.

OBJECTIVE: To develop a 2-stage discrete events simulation (DES) based framework for the evaluation of elective surgery cancellation strategies and resumption scenarios across multiple operational outcomes. MATERIALS AND METHODS: Study data was derived from the data warehouse and domain knowledge on the operational process of the largest tertiary hospital in Singapore. 34,025 unique cases over 43 operating rooms (ORs) and 18 surgical disciplines performed from 1 January 2019 to 31 May 2020 were extracted for the study. A clustering approach was used in stage 1 of the modelling framework to develop the groups of surgeries that followed distinctive postponement patterns. These clusters were then used as inputs for stage 2 where the DES model was used to evaluate alternative phased resumption strategies considering the outcomes of OR utilization, waiting times to surgeries and the time to clear the backlogs. RESULTS: The tool enabled us to understand the elective postponement patterns during the COVID-19 partial lockdown period, and evaluate the best phased resumption strategy. Differences in the performance measures were evaluated based on 95% confidence intervals. The results indicate that two of the gradual phased resumption strategies provided lower peak OR and bed utilizations but required a longer time to return to BAU levels. Minimum peak bed demands could also be reduced by approximately 14 beds daily with the gradual resumption strategy, whilst the maximum peak bed demands by approximately 8.2 beds. Peak OR utilization could be reduced to 92% for gradual resumption as compared to a minimum peak of 94.2% with the full resumption strategy. CONCLUSIONS: The 2-stage modelling framework coupled with a user-friendly visualization interface were key enablers for understanding the elective surgery postponement patterns during a partial lockdown phase. The DES model enabled the identification and evaluation of optimal phased resumption policies across multiple important operational outcome measures. LAY ABSTRACT: During the height of the COVID-19 pandemic, most healthcare systems suspended their non-urgent elective surgery services. This strategy was undertaken as a means to expand surge capacity, through the preservation of structural resources (such as operating theaters, ICU beds, and ventilators), consumables (such as personal protective equipment and medications), and critical healthcare manpower. As a result, some patients had less-essential surgeries postponed due to the pandemic. As the first wave of the pandemic waned, there was an urgent need to quickly develop optimal strategies for the resumption of these surgeries. We developed a 2-stage discrete events simulation (DES) framework based on 34,025 unique cases over 43 operating rooms (ORs) and 18 surgical disciplines performed from 1 January 2019 to 31 May 2020 captured in the Singapore General Hospital (SGH) enterprise data warehouse. The outcomes evaluated were OR utilization, waiting times to surgeries and time to clear the backlogs. A user-friendly visualization interface was developed to enable decision makers to determine the most promising surgery resumption strategy across these outcomes. Hospitals globally can make use of the modelling framework to adapt to their own surgical systems to evaluate strategies for postponement and resumption of elective surgeries.

Association between housing type and accelerated biological aging in different sexes: moderating effects of health behaviors.

INTRODUCTION: Despite associated with multiple geriatric disorders, whether housing type, an indicator of socioeconomic status (SES) and environmental factors, is associated with accelerated biological aging is unknown. Furthermore, although individuals with low-SES have higher body mass index (BMI) and are more likely to smoke, whether BMI and smoking status moderate the association between SES and biological aging is unclear. We examined these questions in urbanized low-SES older community-dwelling adults. METHODS: First, we analyzed complete blood count data using the cox proportional hazards model and derived measures for biological age (BA) and biological age acceleration (BAA, the higher the more accelerated aging) (N = 376). Subsequently, BAA was regressed on housing type, controlling for covariates, including four other SES indicators. Interaction terms between housing type and BMI/smoking status were separately added to examine their moderating effects. Total sample and sex-stratified analyses were performed. RESULTS: There were significant differences between men and women in housing type and BAA. Compared to residents in ≥3 room public or private housing, older adults resided in 1-2 room public housing had a higher BAA. Furthermore, BMI attenuated the association between housing type and BAA. In sex-stratified analyses, the main and interaction effects were only significant in women. In men, smoking status instead aggravated the association between housing type and BAA. CONCLUSION: Controlling for other SES indicators, housing type is an independent socio-environmental determinant of BA and BAA in a low-SES urbanized population. There were also sex differences in the moderating effects of health behaviors on biological aging.

Long-term quality of life, sexual health and gastrointestinal function following colorectal cancer resection in an Asian cohort.

AIM: As populations age and cancer management improves, long-term survivorship and quality-of-life (QOL) outcomes are becoming equally important as oncological results. Data from Asian populations are scarce. We aimed to evaluate the sexual health, gastrointestinal function and QOL amongst colorectal cancer survivors in a tertiary referral centre in Singapore. METHOD: Adults who had undergone elective curative surgery for non-metastatic colorectal cancer at least 2 years prior were included. Exclusion criteria were cognitive disease, serious postoperative complications or recurrent cancer. Participants were invited to complete the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires EORTC-QLQ-C30 and QLQ-CR29. Using multiple bivariate analysis, r scores were used to examine relationship trends between QOL domains and survivor sociodemographic and disease-specific characteristics. RESULTS: From February 2017 to July 2019, 400 responses were recorded. Median age and follow-up duration were 64 years (range 32-90) and 78 months (interquartile range 49-113) respectively. Patients who had Stage III cancer had better overall QOL scores compared to Stage I/II. Rectal (vs. colon) cancer negatively influenced sexual health and gastrointestinal function, but did not appear to affect overall QOL. Amongst our cohort, 57% (n = 129) of men and 43% (n = 75) of women were sexually active. Markers of socioeconomic status, including employment, education and housing type, were found to significantly impact perception of various aspects of QOL. CONCLUSION: Knowledge of factors which influence well-being can identify individuals who may benefit from tailored management strategies. Regular patient-doctor contact may play a role in building and maintaining positive perspectives of cancer survivors. Normative data should be obtained from local populations to facilitate future comparative research.

Frailty and length of stay in older adults with blunt injury in a national multicentre prospective cohort study.

BACKGROUND: Patients suffering moderate or severe injury after low falls have higher readmission and long-term mortality rates compared to patients injured by high-velocity mechanisms such as motor vehicle accidents. We hypothesize that this is due to higher pre-injury frailty in low-fall patients, and present baseline patient and frailty demographics of a prospective cohort of moderate and severely injured older patients. Our second hypothesis was that frailty was associated with longer length of stay (LOS) at index admission. METHODS: This is a prospective, nation-wide, multi-center cohort study of Singaporean residents aged ≥55 years admitted for ≥48 hours after blunt injury with an injury severity score or new injury severity score ≥10, or an Organ Injury Scale ≥3, in public hospitals from 2016-2018. Demographics, mechanism of injury and frailty were recorded and analysed by Chi-square, or Kruskal-Wallis as appropriate. RESULTS: 218 participants met criteria and survived the index admission. Low fall patients had the highest proportion of frailty (44, 27.3%), followed by higher level fallers (3, 21.4%) and motor vehicle accidents (1, 2.3%) (p < .01). Injury severity, extreme age, and surgery were independently associated with longer LOS. Frail patients were paradoxically noted to have shorter LOS (p < .05). CONCLUSION: Patients sustaining moderate or severe injury after low falls are more likely to be frail compared to patients injured after higher-velocity mechanisms. However, this did not translate into longer adjusted LOS in hospital at index admission.

The Role of Prefracture Health Status in Physical and Mental Function After Hip Fracture Surgery.

OBJECTIVES: To examine the associations of 3 measures of prefracture health status (physical function, mental function, and comorbidity count) with trajectories of physical and mental function at 1.5, 3, 6, and 12 months after hip fracture surgery. DESIGN: Single-center observational study. SETTING: Singapore General Hospital (an acute hospital). PARTICIPANTS: Patients aged ≥60 years who underwent first hip fracture surgery between June 2011 and July 2016 (N = 928). INTERVENTION: None. MEASUREMENTS: We used data collected prospectively from the hospital's hip fracture registry. We used the Short Form-36 (SF-36) Physical Component Summary (PCS) and Mental Component Summary (MCS) as indicators of physical and mental function, respectively, collected at admission and at 1.5, 3, 6, and 12 months after hip fracture surgery. Comorbidity count at admission was the sum from a list of 10 common diseases associated with poorer physical function. RESULTS: Prefracture physical function and prefracture mental function demonstrated time-varying associations (interaction P < .001 and P = .001, respectively) with postfracture physical function; the associations were small initially but increased in strength up to 6 months and stabilized thereafter. In contrast, the strength of the association between comorbidity count and postfracture physical function were time-invariant (-0.52, P = .027). The strength of the associations between all 3 measures of prefracture health status and postfracture mental function were also constant over time (0.09, P = .004, for physical function; 0.38, P < .001, for mental function; -0.70, P = .034, for comorbidity count). CONCLUSIONS/IMPLICATIONS: The time-varying associations between prefracture health status and postfracture physical function suggest that even for patients with good prefracture health status, initial recovery may be slow. Our findings can be useful to clinicians and therapists in their prognostic evaluations and in management of patients' expectation for recovery.

One-year and three-year mortality prediction in adult major blunt trauma survivors: a National Retrospective Cohort Analysis.

BACKGROUND: Survivors of trauma are at increased risk of dying after discharge. Studies have found that age, head injury, injury severity, falls and co-morbidities predict long-term mortality. The objective of our study was to build a nomogram predictor of 1-year and 3-year mortality for major blunt trauma adult survivors of the index hospitalization. METHODS: Using data from the Singapore National Trauma Registry, 2011-2013, we analyzed adults aged 18 and over, admitted after blunt injury, with an injury severity score (ISS) of 12 or more, who survived the index hospitalization, linked to death registry data. The study population was randomly divided 60/40 into separate construction and validation datasets, with the model built in the construction dataset, then tested in the validation dataset. Multivariable logistic regression was used to analyze 1-year and 3-year mortality. RESULTS: Of the 3414 blunt trauma survivors, 247 (7.2%) died within 1 year, and 551 (16.1%) died within 3 years of injury. Age (OR 1.06, 95% CI 1.05-1.07, p < 0.001), male gender (OR 1.53, 95% CI 1.12-2.10, p < 0.01), low fall from 0.5 m or less (OR 3.48, 95% CI 2.06-5.87, p < 0.001), Charlson comorbidity index of 2 or more (OR 2.26, 95% CI 1.38-3.70, p < 0.01), diabetes (OR 1.31, 95% CI 1.68-2.52, p = 0.04), cancer (OR 1.76, 95% CI 0.94-3.32, p = 0.08), head and neck AIS 3 or more (OR 1.79, 95% CI 1.13-2.84, p = 0.01), length of hospitalization of 30 days or more (OR 1.99, 95% CI 1.02-3.86, p = 0.04) were predictors of 1-year mortality. This model had a c-statistic of 0.85. Similar factors were found significant for the model predictor of 3-year mortality, which had a c-statistic of 0.83. Both models were validated on the second dataset, with an overall accuracy of 0.94 and 0.84 for 1-year and 3-year mortality respectively. CONCLUSIONS: Adult survivors of major blunt trauma can be risk-stratified at discharge for long-term support.

Lifetime cost-effectiveness analysis of ticagrelor in patients with acute coronary syndromes based on the PLATO trial: a Singapore healthcare perspective.

INTRODUCTION: Ticagrelor is a novel antiplatelet drug developed to reduce atherothrombosis. The PLATO trial compared ticagrelor and aspirin to clopidogrel and aspirin in patients with acute coronary syndromes (ACS). Ticagrelor was found to be superior in the primary composite endpoint of cardiovascular death, myocardial infarction or stroke, without increasing major bleeding events. The current study estimates the lifetime cost-effectiveness of ticagrelor relative to generic clopidogrel from a Singapore public healthcare perspective. METHODS: This study used a two-part cost-effectiveness model. The first part was a 12-month decision tree (using PLATO trial data) to estimate the rates of major cardiovascular events, healthcare costs and health-related quality of life. The second part was a Markov model estimating lifetime quality-adjusted survival and costs conditional on events during the initial 12 months. Daily drug costs applied were SGD 1.05 (generic clopidogrel) and SGD 6.00 (ticagrelor). Cost per quality-adjusted life years (QALY) was estimated from a Singapore public healthcare perspective using life tables and short-term costs from Singapore, and long-term costs from South Korea. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Ticagrelor was associated with a lifetime QALY gain of 0.13, primarily driven by lower mortality. The resulting incremental cost per QALY gained was SGD 10,136.00. Probabilistic sensitivity analysis indicated that ticagrelor had a > 99% probability of being cost-effective, given the lower recommended WHO willingness-to-pay threshold of one GDP/capita per QALY. CONCLUSION: Based on PLATO trial data, one-year treatment with ticagrelor versus generic clopidogrel in patients with ACS, relative to WHO reference standards, is cost-effective from a Singapore public healthcare perspective.