Cost-effectiveness of the McGill interactive pediatric oncogenetic guidelines in identifying Li-Fraumeni syndrome in female patients with osteosarcoma.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a penetrant cancer predisposition syndrome (CPS) associated with the development of many tumor types in young people including osteosarcoma and breast cancer (BC). The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) decision-support tool provides a standardized approach to identify patients at risk of CPSs. METHODS: We conducted a cost-utility analysis, from the healthcare payer perspective, to compare MIPOGG-guided, physician-guided, and universal genetic testing strategies to detect LFS in female patients diagnosed at an age of less than 18 years with osteosarcoma. We developed a decision tree and discrete-event simulation model to simulate the clinical and cost outcomes of the three genetic referral strategies on a cohort of female children diagnosed with osteosarcoma, especially focused on BC as subsequent cancer. Outcomes included BC incidence, quality-adjusted life-years (QALYs), healthcare costs, and incremental cost-utility ratios (ICURs). We conducted probabilistic and scenario analyses to assess the uncertainty surrounding model parameters. RESULTS: Compared to the physician-guided testing, the MIPOGG-guided strategy was marginally more expensive by $105 (-$516; $743), but slightly more effective by 0.003 (-0.04; 0.045) QALYs. Compared to MIPOGG, the universal testing strategy was $1333 ($732; $1953) more costly and associated with 0.011 (-0.043; 0.064) additional QALYs. The ICUR for the MIPOGG strategy was $33,947/QALY when compared to the physician strategy; the ICUR for universal testing strategy was $118,631/QALY when compared to the MIPOGG strategy. DISCUSSION: This study provides evidence for clinical and policy decision-making on the cost-effectiveness of genetic referral strategies to identify LFS in the setting of osteosarcoma. MIPOGG-guided strategy was most likely to be cost-effective at a willingness-to-pay threshold value of $50,000/QALY.

Application of Multi-Criteria Decision Analysis (MCDA) to Prioritize Real-World Evidence Studies for Health Technology Management: Outcomes and Lessons Learned by the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration.

Multi-criteria decision analysis (MCDA) is a value assessment tool designed to help support complex decision-making by incorporating multiple factors and perspectives in a transparent, structured approach. We developed an MCDA rating tool, consisting of seven criteria evaluating the importance and feasibility of conducting potential real-world evidence (RWE) studies aimed at addressing uncertainties stemming from initial cancer drug funding recommendations. In collaboration with the Canadian Agency for Drugs and Technologies in Health's Provincial Advisory Group, a validation exercise was conducted to further evaluate the application of the rating tool using RWE proposals varying in complexity. Through this exercise, we aimed to gain insight into consensus building and deliberation processes and to identify efficiencies in the application of the rating tool. An experienced facilitator led a multidisciplinary committee, consisting of 11 Canadian experts, through consensus building, deliberation, and prioritization. A total of nine RWE proposals were evaluated and prioritized as low (n = 4), medium (n = 3), or high (n = 2) priority. Through an iterative process, efficiencies and recommendations to improve the rating tool and associated procedures were identified. The refined MCDA rating tool can help decision-makers prioritize important and feasible RWE studies for research and can enable the use of RWE for the life-cycle evaluation of cancer drugs.

Cost and cost-effectiveness of immunotherapy in childhood ALL: A systematic review.

Survival rates for pediatric acute lymphoblastic leukemia (pALL) have improved dramatically; relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL) remains challenging. Immunotherapies are rapidly evolving treatments for r/r ALL with limited cost-effectiveness data. This study identifies existing economic evaluations of immunotherapy in pALL and summarizes cost-effectiveness. Medline, Embase, and other databases were searched from inception to October 2022. Cost-effectiveness analyses evaluating immunotherapy in pALL were included. Costs reported in 2021 USD. Of 2960 studies, 11 met inclusion criteria. Tisagenlecleucel was compared to standard of care, clofarabine monotherapy, clofarabine combination therapy, or blinatumomab. No studies have evaluated blinatumomab or inotuzumab ozogamicin. Six studies found tisagenlecleucel to be cost-effective, five of which were supported by Novartis. Four found that it had the potential to be cost-effective, and one found that it was not cost-effective. The cost-effectiveness of tisagenlecleucel was highly dependent on list price and cure rates. This study can inform the use of tisagenlecleucel in pALL.

Late mortality among 5-year survivors of childhood cancer: A systematic review and meta-analysis.

BACKGROUND: Childhood cancer survivors are at increased risk of late mortality (death ≥5 years after diagnosis) from cancer recurrence and treatment-related late effects. The authors conducted a systematic review and meta-analysis to provide comprehensive estimates of late mortality risk among survivors internationally and to investigate differences in risk across world regions. METHODS: Health sciences databases were searched for cohort studies comprised of 5-year childhood cancer survivors in which the risk of mortality was evaluated across multiple cancer types. Eligible studies assessed all-cause mortality risk in survivors relative to the general population using the standardized mortality ratio (SMR). The absolute excess risk (AER) was assessed as a secondary measure to examine excess deaths. Cause-specific mortality risk was also assessed, if reported. SMRs from nonoverlapping cohorts were combined in subgroup meta-analysis, and the effect of world region was tested in univariate meta-regression. RESULTS: Nineteen studies were included, and cohort sizes ranged from 314 to 77,423 survivors. Throughout survivorship, SMRs for all-cause mortality generally declined, whereas AERs increased after 15-20 years from diagnosis in several cohorts. All-cause SMRs were significantly lower overall in North American studies than in European studies (relative SMR, 0.63; 95% confidence interval, 0.49-0.80). SMRs for subsequent malignant neoplasms and for cardiovascular, respiratory, and external causes did not vary significantly between world regions. CONCLUSIONS: The current findings suggest that late mortality risk may differ significantly between world regions, but these conclusions are based on a limited number of studies with considerable heterogeneity. Reasons for regional differences remain unclear but may be better elucidated through future analyses of individual-level data.

Internal and external validation of an updated ICD-10-CA to AIS-2005 update 2008 algorithm.

BACKGROUND: Administrative data are a powerful tool for population-level trauma research but lack the trauma-specific diagnostic and injury severity codes needed for risk-adjusted comparative analyses. The objective of this study was to validate an algorithm to derive Abbreviated Injury Scale (AIS-2005 update 2008) severity scores from Canadian International Classification of Diseases (ICD-10-CA) diagnostic codes in administrative data. METHODS: This was a retrospective cohort study using data from the 2009 to 2017 Ontario Trauma Registry for the internal validation of the algorithm. This registry includes all patients treated at a trauma center who sustained a moderate or severe injury or were assessed by a trauma team. It contains both ICD-10-CA codes and injury scores assigned by expert abstractors. We used Cohen's kappa (𝜅) coefficient to compare AIS-2005 Update 2008 scores assigned by expert abstractors to those derived using the algorithm and the intraclass correlation coefficient to compare assigned and derived Injury Severity Scores. Sensitivity and specificity for detection of a severe injury (AIS score, ≥ 3) were then calculated. For the external validation of the algorithm, we used administration data to identify adults who either died in an emergency department or were admitted to hospital in Ontario secondary to a traumatic injury (2009-2017). Logistic regression was used to evaluate the discriminative ability and calibration of the algorithm. RESULTS: Of 41,869 patients in the Ontario Trauma Registry, 41,793 (99.8%) had at least one diagnosis matched to the algorithm. Evaluation of AIS scores assigned by expert abstractors and those derived using the algorithm demonstrated a high degree of agreement in identification of patients with at least one severe injury (𝜅 = 0.75; 95% confidence interval [CI], 0.74-0.76). Likewise, algorithm-derived scores had a strong ability to rule in or out injury with AIS ≥ 3 (specificity, 78.5%; 95% CI, 77.7-79.4; sensitivity, 95.1; 95% CI, 94.8-95.3). There was strong correlation between expert abstractor-assigned and crosswalk-derived Injury Severity Score (intraclass correlation coefficient, 0.80; 95% CI, 0.80-0.81). Among the 130,542 patients identified using administrative data, the algorithm retained its discriminative properties. CONCLUSION: Our ICD-10-CA to AIS-2005 update 2008 algorithm produces reliable estimates of injury severity and retains its discriminative properties with administrative data. Our findings suggest that this algorithm can be used for risk adjustment of injury outcomes when using population-based administrative data. LEVEL OF EVIDENCE: Diagnostic Tests/Criteria; Level II.

The PSY-SIM Model: Using Real-World Data to Inform Health Care Policy for Individuals With Chronic Psychotic Disorders.

BACKGROUND AND HYPOTHESIS: Few microsimulation models have been developed for chronic psychotic disorders, severe and disabling mental disorders associated with poor medical and psychiatric outcomes, and high costs of care. The objective of this work was to develop a microsimulation model for individuals with chronic psychotic disorders and to use the model to examine the impact of a smoking cessation initiative on patient outcomes. STUDY DESIGN: Using health records and survey data from Ontario, Canada, the PSY-SIM model was developed to simulate health and cost outcomes of individuals with chronic psychotic disorders. The model was then used to examine the impact of the Smoking Treatment for Ontario Patients (STOP) program from Ontario on the development of chronic conditions, life expectancy, quality of life, and lifetime health care costs. STUDY RESULTS: Individuals with chronic psychotic disorders had a lifetime risk of 63% for congestive heart failure and roughly 50% for respiratory disease, cancer and diabetes, and a life expectancy of 76 years. The model suggests the STOP program can reduce morbidity and lead to survival and quality of life gains with modest increases in health care costs. At a long-term quit rate of 4.4%, the incremental cost-effectiveness ratio of the STOP program was $41,936/QALY compared with status quo. CONCLUSIONS: Smoking cessation initiatives among individuals with chronic psychotic disorders can be cost-effective. These findings will be relevant for decision-makers and clinicians looking to improving health outcomes among this patient population.

Mismatch-repair deficiency, microsatellite instability, and lynch syndrome in ovarian cancer: A systematic review and meta-analysis.

OBJECTIVE: Investigating for mismatch repair protein deficiency (MMRd), microsatellite instability (MSI), and Lynch syndrome (LS) is widely accepted in endometrial cancer, but knowledge is limited on its value in epithelial ovarian cancer (EOC). The primary objective was to evaluate the prevalence of mismatch repair protein deficiency (MMRd), microsatellite instability (MSI)-high, and Lynch syndrome (LS) in epithelial ovarian cancer (EOC), as well as the diagnostic accuracy of LS screening tests. The secondary objective was to determine the prevalence of MMRd, MSI-high, and LS in synchronous ovarian endometrial cancer and in histological subtypes. METHODS: We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process and Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, and Embase databases. We included studies analysing MMR, MSI, and/or LS by sequencing. RESULTS: A total of 55 studies were included. The prevalence of MMRd, MSI-high, and LS in EOC was 6% (95% confidence interval (CI) 5-8%), 13% (95% CI 12-15%), and 2% (95% CI 1-3%) respectively. Hypermethylation was present in 76% of patients with MLH1 deficiency (95% CI 64-84%). The MMRd prevalence was highest in endometrioid (12%) followed by non-serous non-mucinous (9%) and lowest in serous (1%) histological subtypes. MSI-high prevalence was highest in endometrioid (12%) and non-serous non-mucinous (12%) and lowest in serous (9%) histological subtypes. Synchronous and endometrioid EOC had the highest prevalence of LS pathogenic variants at 7% and 3% respectively, with serous having lowest prevalence (1%). Synchronous ovarian and endometrial cancers had highest rates of MMRd (28%) and MSI-high (28%). Sensitivity was highest for IHC (91.1%) and IHC with MSI (92.8%), while specificity was highest for IHC with methylation (92.3%). CONCLUSION: MMRd and germline LS testing should be considered for non-serous non-mucinous EOC, particularly for endometrioid. PRECIS: The rates of mismatch repair deficiency, microsatellite instability high, and mismatch repair germline mutations are highest in endometrioid subtype and non-serous non-mucinous ovarian cancer. The rates are lowest in serous histologic subtype.

Financial toxicity among adolescent and young adult cancer survivors: A systematic review of educational attainment, employment, and income.

PURPOSE: To identify, evaluate and summarize the evidence on educational attainment, employment status and income of AYAs surviving cancer. METHODS: A search of six databases for articles published between 01/01/2010 and 03/31/2022 was performed. Articles with an AYA survivorship population, quantitative design and a cancer-free comparator group were included. Data extraction was conducted, and quality appraisal was completed using ROBINS-I. Results were summarized using a narrative synthesis. RESULTS: A total of 2801 articles were identified, of which 12 were included. Among the limited evidence, educational attainment did not differ from cancer-free peers. Survivors were more likely to be unemployed, have lower incomes and require social security for income supplementation. Evidence suggested that females, diagnosis of brain cancer and the presence of late-effects were among the risk factors for severe outcomes. CONCLUSIONS: Limited socioeconomic evidence exists for AYAs surviving cancer. Long-lasting financial toxicities occur and highlights a need for further investigation.

Healthcare utilization and costs associated with acute lymphoblastic leukemia in children with and without Down syndrome.

BACKGROUND: Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are at increased risk of treatment-related morbidity and mortality compared to non-DS-ALL, requiring increased supportive care. We examined the healthcare utilization and costs in DS-ALL patients to inform future evaluations of novel therapies. METHODS: A provincial registry identified all children (1-17 years) diagnosed with B-lineage ALL in Ontario, Canada between 2002 and 2012. Detailed demographic, disease, treatment, and outcome data were abstracted. Linkage to population-based health services databases identified all outpatient and emergency department (ED) visits, hospitalizations, and physician billings. Healthcare utilization costs were available for patients diagnosed during 2006-2012 using validated algorithms (2018 Canadian dollars). Healthcare utilization rates and costs were compared between DS and non-DS patients using regression models, adjusting for all covariates. RESULTS: Of 711 patients, 28 (3.9%) had DS. Adjusting for all covariates, children with DS-ALL experienced substantially higher rates of ED visits (rate ratio [RR] 1.5, 95% confidence interval [95% CI]: 1.2-2.0; p = .001) and inpatient days (RR 2.5, 95% CI: 1.4-4.5; p = .002) compared to non-DS children. Outpatient visit rates were similar (RR 1.1, 95% CI: 0.9-1.3; p = .41). Among patients with available cost data (N = 533, DS = 19), median 5-year healthcare utilization cost was $247,700 among DS patients (interquartile range [IQR]: 200,900-354,500) and $196,200 among non-DS patients (IQR: 148,900-280,300; p = .02). In adjusted analyses, DS-associated costs were 50% higher (RR 1.5, 95% CI: 1.2-1.9; p < .002). CONCLUSIONS: Healthcare utilization and treatment costs of DS-ALL patients are substantially higher than those of non-DS-ALL. Our data provide a baseline for future DS-specific cost-effectiveness studies.

Diagnostic accuracy of teleretinal screening for detection of diabetic retinopathy and age-related macular degeneration: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the diagnostic accuracy of teleretinal screening compared with face-to-face examination for detection of diabetic retinopathy (DR) and age-related macular degeneration (AMD). METHODS AND ANALYSIS: This study adhered to the Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA). A comprehensive search of OVID MEDLINE, EMBASE and Cochrane CENTRAL was performed from January 2010 to July 2021. QUADAS-2 tool was used to assess methodological quality and applicability of the studies. A bivariate random effects model was used to perform the meta-analysis. Referrable DR was defined as any disease severity equal to or worse than moderate non-proliferative DR or diabetic macular oedema (DMO). RESULTS: 28 articles were included. Teleretinal screening achieved a sensitivity of 0.91 (95% CI: 0.82 to 0.96) and specificity of 0.88 (0.74 to 0.95) for any DR (13 studies, n=7207, Grading of Recommendations, Assessment, Development and Evaluation (GRADE) low). Accuracy for referrable DR (10 studies, n=6373, GRADE moderate) was lower with a sensitivity of 0.88 (0.81 to 0.93) and specificity of 0.86 (0.79 to 0.90). After exclusion of ungradable images, the specificity for referrable DR increased to 0.95 (0.90 to 0.98), while the sensitivity remained nearly unchanged at 0.85 (0.76 to 0.91). Teleretinal screening achieved a sensitivity of 0.71 (0.49 to 0.86) and specificity of 0.88 (0.85 to 0.90) for detection of AMD (three studies, n=697, GRADE low). CONCLUSION: Teleretinal screening is highly accurate for detecting any DR and DR warranting referral. Data for AMD screening is promising but warrants further investigation. PROSPERO REGISTRATION NUMBER: CRD42020191994.

Clinical and economic impact of molecular testing for BRAF fusion in pediatric low-grade Glioma.

BACKGROUND: Treatment personalization via tumor molecular testing holds promise for improving outcomes for patients with pediatric low-grade glioma (PLGG). We evaluate the health economic impact of employing tumor molecular testing to guide treatment for patients diagnosed with PLGG, particularly the avoidance of radiation therapy (RT) for patients with BRAF-fusion. METHODS: We performed a model-based cost-utility analysis comparing two strategies: molecular testing to determine BRAF fusion status at diagnosis against no molecular testing. We developed a microsimulation to model the lifetime health and cost outcomes (in quality-adjusted life years (QALYs) and 2018 CAD, respectively) for a simulated cohort of 100,000 patients newly diagnosed with PLGG after their initial surgery. RESULTS: The life expectancy after diagnosis for individuals who did not receive molecular testing was 39.01 (95% Confidence Intervals (CI): 32.94;44.38) years and 40.08 (95% CI: 33.19;45.76) years for those who received testing. Our findings indicate that patients who received molecular testing at diagnosis experienced a 0.38 (95% CI: 0.08;0.77) gain in QALYs and $1384 (95% CI: $-3486; $1204) reduction in costs over their lifetime. Cost and QALY benefits were driven primarily by the avoidance of long-term adverse events (stroke, secondary neoplasms) associated with unnecessary use of radiation. CONCLUSIONS: We demonstrate the clinical benefit and cost-effectiveness of molecular testing in guiding the decision to provide RT in PLGG. While our results do not consider the impact of targeted therapies, this work is an example of the value of simulation modeling in assessing the long-term costs and benefits of precision oncology interventions for childhood cancer, which can aid decision-making about health system reimbursement.

Health care utilisation and costs associated with different treatment protocols for newly diagnosed childhood acute lymphoblastic leukaemia: A population-based study in Ontario, Canada.

BACKGROUND: Although different treatment protocols for childhood acute lymphoblastic leukaemia (ALL) all achieve high cure rates, their health care utilisation and costs have not been rigorously compared. METHODS: Disease, treatment, and outcome data were chart abstracted for all children with ALL in Ontario, Canada, diagnosed 2002-2012. Linkage to population-based databases identified health care utilisation. Utilisation-associated costs were determined through validated algorithms. Chemotherapy-associated costs were calculated separately. Health care utilisation and costs were compared between patients receiving Children's Oncology Group (COG) versus Dana-Farber Cancer Institute (DFCI)-based treatment. FINDINGS: Of 802 patients, 146 (18.2%) were treated on DFCI-based protocols. COG patients experienced significantly higher rates of emergency department (ED) visits (adjusted rate ratio [aRR]: 1.3, 95% confidence interval [CI]: 1.1-1.5; p = 0·01), whereas outpatient visit rates were 60% higher among DFCI patients (aRR: 1.6, 95% CI: 1.5-1.7, p < 0.0001). In adjusted analyses, DFCI-associated cost intensity was 70% higher (aRR: 1.7, 95% CI: 1.5-1.9; p < 0.0001), mainly attributable to outpatient visit costs. Total chemotherapy costs were higher among COG-treated patients ($39,400 ± $1100 versus $33,400 ± $2800; p = 0.02). Among PEG-ASNase-treated patients, total chemotherapy costs were highest among DFCI patients (median $54,200 ± $7400; p = 0.003 versus COG patients). INTERPRETATION: COG and DFCI treatments were associated with higher ED visit rates and higher outpatient visit rates, respectively. Overall utilisation-associated costs were increased in DFCI-treated patients. Administration of some intravenous chemotherapy at home and decreases in PEG-ASNase cost would decrease health care utilisation and costs for all patients and mitigate differences between COG and DFCI protocols. FUNDING: C17 Research Network.

Phase-specific risks of outpatient visits, emergency visits, and hospitalizations during Children's Oncology Group-based treatment for childhood acute lymphoblastic leukemia: A population-based study.

BACKGROUND: Therapy for childhood acute lymphoblastic leukemia (ALL) is associated with substantial health care utilization and burden on families. Little is known about health care utilization during specific treatment phases. PROCEDURES: We identified children with ALL diagnosed during 2002-2012 in Ontario, Canada and treated according to Children's Oncology Group (COG) protocols. Disease and treatment data were chart abstracted. Population-based health care databases identified all outpatient visits, emergency department (ED) visits, and hospitalizations. In addition to comparing standard and intensified versions of treatment phases, we compared patients receiving different steroids (dexamethasone vs. prednisone) and different versions of interim maintenance (IM) (Capizzi vs. high-dose methotrexate [HD-MTX]). RESULTS: Six hundred thirty-seven children met inclusion criteria. During intensified consolidation, 76.2% of patients were hospitalized at least once, compared to only 32.3% of patients receiving standard consolidation (p < .0001). Similarly, 72.9% of patients receiving intensified delayed intensification (DI) were hospitalized during this phase compared to 50.3% of patients receiving standard DI (p < .0001). Among patients receiving a four-drug induction, those receiving dexamethasone had an 85% higher rate of ED visits (adjusted rate ratio [aRR] 1.85, 95th confidence interval [95CI] 1.14-3.00; p = .01) and a 44% higher rate of hospitalization (aRR 1.44, 95CI 1.24-1.68) compared to those receiving prednisone. Among high-risk B-ALL and T-ALL patients in IM, Capizzi MTX was not associated with an increased rate of ED visits versus HD-MTX. CONCLUSIONS: These results can be used to inform anticipatory guidance for families, particularly those undergoing intensified therapy. Our results also suggest that increased toxicity rates associated with dexamethasone during Induction seen in clinical trials reflect real-world practice.

The intranasal dexmedetomidine plus ketamine for procedural sedation in children, adaptive randomized controlled non-inferiority multicenter trial (Ketodex): a statistical analysis plan.

BACKGROUND: Procedural sedation and analgesia (PSA) is frequently required to perform closed reductions for fractures and dislocations in children. Intravenous (IV) ketamine is the most commonly used sedative agent for closed reductions. However, as children find IV insertion a distressing and painful procedure, there is need to identify a feasible alternative route of administration. There is evidence that a combination of dexmedetomidine and ketamine (ketodex), administered intranasally (IN), could provide adequate sedation for closed reductions while avoiding the need for IV insertion. However, there is uncertainty about the optimal combination dose for the two agents and whether it can provide adequate sedation for closed reductions. The Intranasal Dexmedetomidine Plus Ketamine for Procedural Sedation (Ketodex) study is a Bayesian phase II/III, non-inferiority trial in children undergoing PSA for closed reductions that aims to address both these research questions. This article presents in detail the statistical analysis plan for the Ketodex trial and was submitted before the outcomes of the trial were available for analysis. METHODS/DESIGN: The Ketodex trial is a multicenter, four-armed, randomized, double-dummy controlled, Bayesian response adaptive dose finding, non-inferiority, phase II/III trial designed to determine (i) whether IN ketodex is non-inferior to IV ketamine for adequate sedation in children undergoing a closed reduction of a fracture or dislocation in a pediatric emergency department and (ii) the combination dose for IN ketodex that provides optimal sedation. Adequate sedation will be primarily measured using the Pediatric Sedation State Scale. As secondary outcomes, the Ketodex trial will compare the length of stay in the emergency department, time to wakening, and adverse events between study arms. DISCUSSION: The Ketodex trial will provide evidence on the optimal dose for, and effectiveness of, IN ketodex as an alternative to IV ketamine providing sedation for patients undergoing a closed reduction. The data from the Ketodex trial will be analyzed from a Bayesian perspective according to this statistical analysis plan. This will reduce the risk of producing data-driven results introducing bias in our reported outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04195256 . Registered on December 11, 2019.

Clinical and psychological outcomes of receiving a variant of uncertain significance from multigene panel testing or genomic sequencing: a systematic review and meta-analysis.

This study systematically reviewed and synthesized the literature on psychological and clinical outcomes of receiving a variant of uncertain significance (VUS) from multigene panel testing or genomic sequencing. MEDLINE and EMBASE were searched. Two reviewers screened studies and extracted data. Data were synthesized through meta-analysis and meta-aggregation. The search identified 4539 unique studies and 15 were included in the review. Patients with VUS reported higher genetic test-specific concerns on the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale than patients with negative results (mean difference 3.73 [95% CI 0.80 to 6.66] P = 0.0126), and lower than patients with positive results (mean difference -7.01 [95% CI -11.31 to -2.71], P = 0.0014). Patients with VUS and patients with negative results were similarly likely to have a change in their clinical management (OR 1.41 [95% CI 0.90 to 2.21], P = 0.182), and less likely to have a change in management than patients with positive results (OR 0.09 [95% CI 0.05 to 0.19], P < 0.0001). Factors that contributed to how patients responded to their VUS included their interpretation of the result and their health-care provider's counseling and recommendations. Review findings suggest there may be a need for practice guidelines or clinical decision support tools for VUS disclosure and management.

COVID-19: Adaptation of a model to predicting healthcare resources needs in Valle del Cauca, Colombia / COVID-19: Predicción de las necesidades de recursos sanitarios en el Valle del Cauca, Colombia

Abstract Background: Valle del Cauca is the region with the fourth-highest number of COVID-19 cases in Colombia (>50,000 on September 7, 2020). Due to the lack of anti-COVID-19 therapies, decision-makers require timely and accurate data to estimate the incidence of disease and the availability of hospital resources to contain the pandemic. Methods: We adapted an existing model to the local context to forecast COVID-19 incidence and hospital resource use assuming different scenarios: (1) the implementation of quarantine from September 1st to October 15th (average daily growth rate of 2%); (2-3) partial restrictions (at 4% and 8% growth rates); and (4) no restrictions, assuming a 10% growth rate. Previous scenarios with predictions from June to August were also presented. We estimated the number of new cases, diagnostic tests required, and the number of available hospital and intensive care unit (ICU) beds (with and without ventilators) for each scenario. Results: We estimated 67,700 cases by October 15th when assuming the implementation of a quarantine, 80,400 and 101,500 cases when assuming partial restrictions at 4% and 8% infection rates, respectively, and 208,500 with no restrictions. According to different scenarios, the estimated demand for reverse transcription-polymerase chain reaction tests ranged from 202,000 to 1,610,600 between September 1st and October 15th. The model predicted depletion of hospital and ICU beds by September 20th if all restrictions were to be lifted and the infection growth rate increased to 10%. Conclusion: Slowly lifting social distancing restrictions and reopening the economy is not expected to result in full resource depletion by October if the daily growth rate is maintained below 8%. Increasing the number of available beds provides a safeguard against slightly higher infection rates. Predictive models can be iteratively used to obtain nuanced predictions to aid decision-making

Resumen Introducción: Valle del Cauca es el departamento con el cuarto mayor número de casos de COVID-19 en Colombia (>50,000 en septiembre 7, 2020). Debido a la ausencia de tratamientos efectivos para COVID-19, los tomadores de decisiones requieren de acceso a información actualizada para estimar la incidencia de la enfermedad, y la disponibilidad de recursos hospitalarios para contener la pandemia. Métodos: Adaptamos un modelo existente al contexto local para estimar la incidencia de COVID-19, y la demanda de recursos hospitalarios en los próximos meses. Para ello, modelamos cuatro escenarios hipotéticos: (1) el gobierno local implementa una cuarentena desde el primero de septiembre hasta el 15 de octubre (asumiendo una tasa promedio de infecciones diarias del 2%); (2-3) se implementan restricciones parciales (tasas de infección del 4% y 8%); (4) se levantan todas las restricciones (tasa del 10%). Los mismos escenarios fueron previamente evaluados entre julio y agosto, y los resultados fueron resumidos. Estimamos el número de casos nuevos, el número de pruebas diagnósticas requeridas, y el numero de camas de hospital y de unidad de cuidados intensivos (con y sin ventilación) disponibles, para cada escenario. Resultados: El modelo estimó 67,700 casos a octubre 15 al asumir la implementación de una nueva cuarentena, 80,400 y 101,500 al asumir restricciones parciales al 4 y 8% de infecciones diarias, respectivamente, y 208,500 al asumir ninguna restricción. La demanda por pruebas diagnósticas (de reacción en cadena de la polimerasa) fue estimada entre 202,000 y 1,610,600 entre septiembre 1 y octubre 15, a través de los diferentes escenarios evaluados. El modelo estimó un agotamiento de camas de cuidados intensivos para septiembre 20 al asumir una tasa de infecciones del 10%. Conclusión: Se estima que el levantamiento paulatino de las restricciones de distanciamiento social y la reapertura de la economía no debería causar el agotamiento de recursos hospitalarios si la tasa de infección diaria se mantiene por debajo del 8%. Sin embargo, incrementar la disponibilidad de camas permitiría al sistema de salud ajustarse rápidamente a potenciales picos inesperados de infecciones nuevas. Los modelos de predicción deben ser utilizados de manera iterativa para depurar las predicciones epidemiológicas y para proveer a los tomadores de decisiones con información actualizada.

Understanding resource utilization and mortality in COPD to support policy making: A microsimulation study.

Chronic obstructive pulmonary disease (COPD) poses a significant but heterogeneous burden to individuals and healthcare systems. Policymakers develop targeted policies to minimize this burden but need personalized tools to evaluate novel interventions and target them to subpopulations most likely to benefit. We developed a platform to identify subgroups that are at increased risk of emergency department visits, hospitalizations and mortality and to provide stratified patient input in economic evaluations of COPD interventions. We relied on administrative and survey data from Ontario, Canada and applied a combination of microsimulation and multi-state modeling methods. We illustrated the functionality of the platform by quantifying outcomes across smoking status (current, former, never smokers) and by estimating the effect of smoking cessation on resource use and survival, by comparing outcomes of hypothetical cohorts of smokers who quit at diagnosis and smokers that continued to smoke post diagnosis. The cumulative incidence of all-cause mortality was 37.9% (95% CI: 34.9, 41.4) for never smokers, 34.7% (95% CI: 32.1, 36.9) for current smokers, and 46.4% (95% CI: 43.6, 49.0) for former smokers, at 14 years. Over 14 years, smokers who did not quit at diagnosis had 16.3% (95% CI: 9.6, 38.4%) more COPD-related emergency department visits than smokers who quit at diagnosis. In summary, we combined methods from clinical and economic modeling to create a novel tool that policymakers and health economists can use to inform future COPD policy decisions and quantify the effect of modifying COPD risk factors on resource utilization and morality.

Hospital resources do not predict accuracy of secondary trauma triage: A population-based analysis.

BACKGROUND: The identification of patients who require transfer from non-trauma centers to trauma centers (secondary triage) is complicated by high rates of undertriage and overtriage. The objective of this study was to evaluate variations in secondary triage accuracy across non-trauma centers and identify factors associated with highly accurate secondary triage. METHODS: We performed a population-based study of injured patients who presented to non-trauma centers in a large regional trauma system. Patients were categorized as undertriaged, overtriaged, or appropriately triaged based on transfer status and presence of a severe injury (Injury Severity Score >15, death within 24 hours, or critical injury as defined by the American College of Surgeons). Mixed-effect models, adjusted for case mix and hospital resource, were used to compare triage accuracy across hospitals and identify factors associated with high-performing centers. RESULTS: Among 118,973 patients identified at 182 non-trauma centers, 37,528 (31.5%) had severe injuries. The majority (76.9%) of severely injured patients were not transferred to a trauma center (undertriaged), while 9.6% of nonseverely injured patients were transferred to a trauma center (overtriaged). Mixed-effect models demonstrated that at the average hospital severely injured patients were 3.76 times more likely to be transferred than nonseverely injured patients (diagnostic odds ratio, 3.76; 95% confidence interval, 3.20-4.31). Despite significant variation in triage accuracy across hospitals, adjusted analyses suggested that local resources bore no relationship to triage accuracy. CONCLUSION: Triage accuracy varies significantly across non-trauma centers, after adjusting for hospital resources. These findings suggest that other potentially modifiable factors play a key role in transfer decisions. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

Cost-effectiveness of Tisagenlecleucel vs Standard Care in High-risk Relapsed Pediatric Acute Lymphoblastic Leukemia in Canada.

Importance: Tisagenlecleucel, a chimeric antigen receptor T-cell therapy for relapsed or refractory pediatric acute lymphoblastic leukemia, has been approved for use in multiple jurisdictions. The public list price is US $475 000, or more than CaD $600 000. Assessing the cost-effectiveness of tisagenlecleucel is necessary to inform policy makers on the economic value of this treatment. Objective: To assess the value for money of tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible pediatric patients with acute lymphoblastic leukemia under unknown long-term effectiveness. Design, Setting, and Participants: A cost-utility analysis of tisagenlecleucel compared with current standard care using a Canadian population-based registry of pediatric patients with acute lymphoblastic leukemia was performed. Results from 3 pooled single-arm tisagenlecleucel clinical trials and a provincial pediatric cancer registry were combined to create treatment and control arms, respectively. The population-based control arm consisted of patients meeting clinical trial inclusion and exclusion criteria, starting at second relapse. Multistate and individual-level simulation modeling were combined to predict patient lifetime health trajectories by treatment strategy. Tisagenlecleucel efficacy was modeled across long-term cure rates, from 10% to 40%, to account for limited information on its long-term effectiveness. Uncertainty was tested with 1-way and probabilistic sensitivity analysis. Data were collected in September 2017, and analysis began in December 2017. Exposures: Tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible patients. Main Outcomes and Measures: Relative health care costs, survival gains, and quality-adjusted life-years (QALYs) between tisagenlecleucel and current standard care. Results: The treatment and control arms were modeled on 192 and 118 patients, respectively. The mean (SD) age of control individuals was 10 (4.25) years, and the mean (SD) age of the pooled clinical trial sample was 11 (6) years. The control individuals had 78 boys (66%), and the pooled clinical trial sample had 102 boys (53%). Treatment with tisagenlecleucel was associated with an additional 2.14 to 9.85 life years or 1.68 to 6.61 QALYs, compared with current care. The average additional cost of tisagenlecleucel was CaD $470 013 (US $357 031). Accounting for the total discounted cost over the patient lifetime resulted in an incremental cost of CaD $71 000 (US $53 933) to CaD $281 000 (US $213 453) per QALY gain. Conclusions and Relevance: To our knowledge, this study offers the first cost-effectiveness analysis of tisagenlecleucel compared with current standard care for pediatric patients with acute lymphoblastic leukemia using a constructed population-based control arm. At a willingness-to-pay threshold of $150 000/QALY, tisagenlecleucel had a 32% likelihood of being cost-effective. Tisagenlecleucel cost-effectiveness would fall below $50 000/QALY with a long-term cure rate of over 0.40 or a price discount of 49% at its currently known effectiveness.