Physician services and costs after disclosure of diagnostic sequencing results in the NYCKidSeq program.

PURPOSE: To better understand the effects of returning diagnostic sequencing results on clinical actions and economic outcomes for pediatric patients with suspected genetic disorders. METHODS: Longitudinal physician claims data after diagnostic sequencing were obtained for patients aged 0 to 21 years with neurologic, cardiac, and immunologic disorders with suspected genetic etiology. We assessed specialist consultation rates prompted by primary diagnostic results, as well as marginal effects on overall 18-month physician services and costs. RESULTS: We included data on 857 patients (median age: 9.6 years) with a median follow-up of 17.3 months after disclosure of diagnostic sequencing results. The likelihood of having ≥1 recommendation for specialist consultation in 155 patients with positive findings was high (72%) vs 23% in 443 patients with uncertain findings and 21% in 259 patients with negative findings (P < .001). Follow-through consultation occurred in 30%. Increases in 18-month physician services and costs following a positive finding diminished after multivariable adjustment. Also, no significant differences between those with uncertain and negative findings were demonstrated. CONCLUSION: Our study did not provide evidence for significant increases in downstream physician services and costs after returning positive or uncertain diagnostic sequencing findings. More large-scale longitudinal studies are needed to confirm these findings.

Physician and informal care use explained by the Pediatric Quality of Life Inventory (PedsQL) in children with suspected genetic disorders.

PURPOSE: To examine associations between Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales and PedsQL Infant Scales with formal health care resource utilization (HCRU) and informal caregiver burden. METHODS: We studied a pediatric cohort of 837 patients (median age: 8.4 years) with suspected genetic disorders enrolled January 2019 through July 2021 in the NYCKidSeq program for diagnostic sequencing. Using linked ~ nine-month longitudinal survey and physician claims data collected through May 2022, we modeled the association between baseline PedsQL scores and post-baseline HCRU (median follow-up: 21.1 months) and informal care. We also assessed the longitudinal change in PedsQL scores with physician services using linear mixed-effects models. RESULTS: Lower PedsQL total and physical health scores were independently associated with increases in 18-month physician services, encounters, and weekly informal care. Comparing low vs. median total scores, increases were 10.6 services (95% CI: 1.0-24.6), 3.3 encounters (95% CI: 0.5-6.8), and $668 (95% CI: $350-965), respectively. For the psychosocial domain, higher scores were associated with decreased informal care. Based on adjusted linear mixed-effects modeling, every additional ten physician services was associated with diminished improvement in longitudinal PedsQL total score trajectories by 1.1 point (95% confidence interval: 0.6-1.6) on average. Similar trends were observed in the physical and psychosocial domains. CONCLUSION: PedsQL scores were independently associated with higher utilization of physician services and informal care. Moreover, longitudinal trajectories of PedsQL scores became less favorable with increased physician services. Adding PedsQL survey instruments to conventional measures for improved risk stratification should be evaluated in further research.

The Pediatric Quality of Life Inventory (PedsQL) is widely used to measure health-related quality of life in pediatric patients; however, few studies have examined whether the PedsQL is indicative of longitudinal outcomes of morbidity and health care needs. This study captures associations between PedsQL scores with utilization of physician and informal care in children with suspected genetic disorders. We demonstrate that lower PedsQL total and physical health scores are independently associated with greater utilization of physician services and informal care. Moreover, longitudinal trajectories of PedsQL scores become less favorable with increased physician services. Results can inform future applications of PedsQL instruments.

US private payers' perspectives on insurance coverage for genome sequencing versus exome sequencing: A study by the Clinical Sequencing Evidence-Generating Research Consortium (CSER).

PURPOSE: There is limited payer coverage for genome sequencing (GS) relative to exome sequencing (ES) in the U.S. Our objective was to assess payers' considerations for coverage of GS versus coverage of ES and requirements payers have for coverage of GS. The study was conducted by the NIH-funded Clinical Sequencing Evidence-Generating Research Consortium (CSER). METHODS: We conducted semi-structured interviews with representatives of private payer organizations (payers, N = 12) on considerations and evidentiary and other needs for coverage of GS and ES. Data were analyzed using thematic analysis. RESULTS: We described four categories of findings and solutions: demonstrated merits of GS versus ES, enhanced methods for evidence generation, consistent laboratory processes/sequencing methods, and enhanced implementation/care delivery. Payers see advantages to GS vs. ES and are open to broader GS coverage but need more proof of these advantages to consider them in coverage decision-making. Next steps include establishing evidence of benefits in specific clinical scenarios, developing quality standards, ensuring transparency of laboratory methods, developing clinical centers of excellence, and incorporating the role of genetic professionals. CONCLUSION: By comparing coverage considerations for GS and ES, we identified a path forward for coverage of GS. Future research should explicitly address payers' conditions for coverage.

Cost-effectiveness frameworks for comparing genome and exome sequencing versus conventional diagnostic pathways: A scoping review and recommended methods.

PURPOSE: Methodological challenges have limited economic evaluations of genome sequencing (GS) and exome sequencing (ES). Our objective was to develop conceptual frameworks for model-based cost-effectiveness analyses (CEAs) of diagnostic GS/ES. METHODS: We conducted a scoping review of economic analyses to develop and iterate with experts a set of conceptual CEA frameworks for GS/ES for prenatal testing, early diagnosis in pediatrics, diagnosis of delayed-onset disorders in pediatrics, genetic testing in cancer, screening of newborns, and general population screening. RESULTS: Reflecting on 57 studies meeting inclusion criteria, we recommend the following considerations for each clinical scenario. For prenatal testing, performing comparative analyses of costs of ES strategies and postpartum care, as well as genetic diagnoses and pregnancy outcomes. For early diagnosis in pediatrics, modeling quality-adjusted life years (QALYs) and costs over ≥20 years for rapid turnaround GS/ES. For hereditary cancer syndrome testing, modeling cumulative costs and QALYs for the individual tested and first/second/third-degree relatives. For tumor profiling, not restricting to treatment uptake or response and including QALYs and costs of downstream outcomes. For screening, modeling lifetime costs and QALYs and considering consequences of low penetrance and GS/ES reanalysis. CONCLUSION: Our frameworks can guide the design of model-based CEAs and ultimately foster robust evidence for the economic value of GS/ES.

To ban or not to ban tanning bed use for minors: A cost-effectiveness analysis from multiple US perspectives for invasive melanoma.

BACKGROUND: Tanning bed use is common among US adolescents, but is associated with increased melanoma risk. The decision to ban tanning bed use by adolescents should be made in consideration of the potential health benefits and costs. METHODS: The US population aged 14 to 17 years was modeled by microsimulation, which compared ban versus no ban strategies. Lifetime quality-adjusted life years (QALYs) and costs were estimated from a health care sector perspective and two societal perspectives: with and without the costs of policy enforcement and the economic losses of the indoor-tanning bed industry. RESULTS: Full adherence to the ban prevented 15,102 melanoma cases and 3299 recurrences among 17.1 million minors, saving $61in formal and informal health care costs per minor and providing an increase of 0.0002 QALYs. Despite the intervention costs of the ban and the economic losses to the indoor-tanning industry, banning was still the dominant strategy, with a savings of $12 per minor and $205.4 million among 17.1 million minors. Findings were robust against varying inspection costs and ban compliance, but were sensitive to lower excess risk of melanoma with early exposure to tanning beds. CONCLUSIONS: A ban on tanning beds for minors potentially lowers costs and increases cost effectiveness. Even after accounting for the costs of implementing a ban, it may be considered cost effective. Even after accounting for the costs of implementing a ban and economic losses in the indoor-tanning industry, a tanning bed ban for US minors may be considered cost effective. A ban has the potential to reduce the number of melanoma cases while decreasing health care costs. LAY SUMMARY: Previous meta-analyses have linked tanning bed use with an increased risk of melanoma, particularly with initial use at a young age. Yet, it remains unclear whether a ban of adolescents would be cost effective. Overall, a ban has the potential to reduce the number of melanoma cases while promoting a decrease in health care costs. Even after accounting for the costs of implementing a ban and the economic losses incurred by the indoor-tanning industry, a ban would be cost effective.

Active Surveillance Strategies for Low-Grade Prostate Cancer: Comparative Benefits and Cost-effectiveness.

Background Active surveillance (AS) is the recommended treatment option for low-risk prostate cancer (PC). Surveillance varies in MRI, frequency of follow-up, and the Prostate Imaging Reporting and Data System (PI-RADS) score that would repeat biopsy. Purpose To compare the effectiveness and cost-effectiveness of AS strategies for low-risk PC with versus without MRI. Materials and Methods This study developed a mathematical model to evaluate the cost-effectiveness of surveillance strategies in a simulation of men with a diagnosis of low-risk PC. The following strategies were compared: watchful waiting, prostate-specific antigen (PSA) and annual biopsy without MRI, and PSA testing and MRI with varied PI-RADS thresholds for biopsy. MRI strategies differed regarding scheduling and use of PI-RADS score of at least 3, or a PI-RADS score of at least 4 to indicate the need for biopsy. Life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios were calculated by using microsimulation. Sensitivity analysis was used to assess the impact of varying parameter values on results. Results For the base case of 60-year-old men, all strategies incorporating prostate MRI extended QALYs and life-years compared with watchful waiting and non-MRI strategies. Annual MRI strategies yielded 16.19 QALYs, annual biopsy with no MRI yielded 16.14 QALYs, and watchful waiting yielded 15.94 QALYs. Annual MRI with PI-RADS score of at least 3 or of at least 4 as the biopsy threshold and annual MRI with biopsy even after MRI with negative findings offered similar QALYs and the same unadjusted life expectancy: 23.05 life-years. However, a PI-RADS score of at least 4 yielded 42% fewer lifetime biopsies. With a cost-effectiveness threshold of $100 000 per QALY, annual MRI with biopsy for lesions with PI-RADS scores of 4 or greater was most cost-effective (incremental cost-effectiveness ratio, $67 221 per QALY). Age, treatment type, risk of initial grade misclassification, and quality-of-life impact of procedural complications affected results. Conclusion The use of active surveillance (AS) with biopsy decisions guided by findings from annual MRI reduces the number of biopsies while preserving life expectancy and quality of life. Biopsy in lesions with PI-RADS scores of 4 or greater is likely the most cost-effective AS strategy for men with low-risk prostate cancer who are younger than 70 years. © RSNA, 2021 Online supplemental material is available for this article. An earlier incorrect version appeared online. This article was corrected on July 13, 2021.

Establishing the value of genomics in medicine: the IGNITE Pragmatic Trials Network.

PURPOSE: A critical gap in the adoption of genomic medicine into medical practice is the need for the rigorous evaluation of the utility of genomic medicine interventions. METHODS: The Implementing Genomics in Practice Pragmatic Trials Network (IGNITE PTN) was formed in 2018 to measure the clinical utility and cost-effectiveness of genomic medicine interventions, to assess approaches for real-world application of genomic medicine in diverse clinical settings, and to produce generalizable knowledge on clinical trials using genomic interventions. Five clinical sites and a coordinating center evaluated trial proposals and developed working groups to enable their implementation. RESULTS: Two pragmatic clinical trials (PCTs) have been initiated, one evaluating genetic risk APOL1 variants in African Americans in the management of their hypertension, and the other to evaluate the use of pharmacogenetic testing for medications to manage acute and chronic pain as well as depression. CONCLUSION: IGNITE PTN is a network that carries out PCTs in genomic medicine; it is focused on diversity and inclusion of underrepresented minority trial participants; it uses electronic health records and clinical decision support to deliver the interventions. IGNITE PTN will develop the evidence to support (or oppose) the adoption of genomic medicine interventions by patients, providers, and payers.

Developing an Institute for Health Care Delivery Science: successes, challenges, and solutions in the first five years.

Medical knowledge is increasing at an exponential rate. At the same time, unexplained variations in practice and patient outcomes and unacceptable rates of medical errors and inefficiencies in health care delivery have emerged. Our Institute for Health Care Delivery Science (I-HDS) began in 2014 as a novel platform to conduct multidisciplinary healthcare delivery research. We followed ten strategies to develop a successful institute with excellence in methodology and strong understanding of the value of team science. Our work was organized around five hubs: 1) Quality/Process Improvement and Systematic Review, 2) Comparative Effectiveness Research, Pragmatic Clinical Trials, and Predictive Analytics, 3) Health Economics and Decision Modeling, 4) Qualitative, Survey, and Mixed Methods, and 5) Training and Mentoring. In the first 5 years of the I-HDS, we have identified opportunities for change in clinical practice through research using our health system's electronic health record (EHR) data, and designed programs to educate clinicians in the value of research to improve patient care and recognize efficiencies in processes. Testing the value of several model interventions has guided prioritization of evidence-based quality improvements. Some of the changes in practice have already been embedded in the EHR workflow successfully. Development and sustainability of the I-HDS has been fostered by a mix of internal and external funding, including philanthropic foundations. Challenges remain due to the highly competitive funding environment and changes needed to adapt the EHR to healthcare delivery research. Further stakeholder engagement and culture change working with hospital leadership and I-HDS core and affiliate members continues.

Gadoxetate-enhanced abbreviated MRI is highly accurate for hepatocellular carcinoma screening.

OBJECTIVES: The primary objective was to compare the performance of 3 different abbreviated MRI (AMRI) sets extracted from a complete gadoxetate-enhanced MRI obtained for hepatocellular carcinoma (HCC) screening. Secondary objective was to perform a preliminary cost-effectiveness analysis, comparing each AMRI set to published ultrasound performance for HCC screening in the USA. METHODS: This retrospective study included 237 consecutive patients (M/F, 146/91; mean age, 58 years) with chronic liver disease who underwent a complete gadoxetate-enhanced MRI for HCC screening in 2017 in a single institution. Two radiologists independently reviewed 3 AMRI sets extracted from the complete exam: non-contrast (NC-AMRI: T2-weighted imaging (T2wi)+diffusion-weighted imaging (DWI)), dynamic-AMRI (Dyn-AMRI: T2wi+DWI+dynamic T1wi), and hepatobiliary phase AMRI (HBP-AMRI: T2wi+DWI+T1wi during the HBP). Each patient was classified as HCC-positive/HCC-negative based on the reference standard, which consisted in all available patient data. Diagnostic performance for HCC detection was compared between sets. Estimated set characteristics, including historical ultrasound data, were incorporated into a microsimulation model for cost-effectiveness analysis. RESULTS: The reference standard identified 13/237 patients with HCC (prevalence, 5.5%; mean size, 33.7 ± 30 mm). Pooled sensitivities were 61.5% for NC-AMRI (95% confidence intervals, 34.4-83%), 84.6% for Dyn-AMRI (60.8-95.1%), and 80.8% for HBP-AMRI (53.6-93.9%), without difference between sets (p range, 0.06-0.16). Pooled specificities were 95.5% (92.4-97.4%), 99.8% (98.4-100%), and 94.9% (91.6-96.9%), respectively, with a significant difference between Dyn-AMRI and the other sets (p < 0.01). All AMRI methods were effective compared with ultrasound, with life-year gain of 3-12 months against incremental costs of US$ < 12,000. CONCLUSIONS: NC-AMRI has limited sensitivity for HCC detection, while HBP-AMRI and Dyn-AMRI showed excellent sensitivity and specificity, the latter being slightly higher for Dyn-AMRI. Cost-effectiveness estimates showed that AMRI is effective compared with ultrasound. KEY POINTS: • Comparison of different abbreviated MRI (AMRI) sets reconstructed from a complete gadoxetate MRI demonstrated that non-contrast AMRI has low sensitivity (61.5%) compared with contrast-enhanced AMRI (80.8% for hepatobiliary phase AMRI and 84.6% for dynamic AMRI), with all sets having high specificity. • Non-contrast and hepatobiliary phase AMRI can be performed in less than 14 min (including set-up time), while dynamic AMRI can be performed in less than 17 min. • All AMRI sets were cost-effective for HCC screening in at-risk population in comparison with ultrasound.

Tumor downstaging as an intermediate endpoint to assess the activity of neoadjuvant systemic therapy in patients with muscle-invasive bladder cancer.

BACKGROUND: Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) has been associated with improved overall survival (OS). This study was aimed at evaluating the impact of pathologic downstaging (pDS; ie, a pT stage at least 1 stage lower than the pre-NAC cT stage) on the OS of patients with MIBC treated with NAC. METHODS: The Retrospective International Study of Cancers of the Urothelial Tract (RISC) and the National Cancer Database (NCDB) were queried for cT2-4N0M0 patients treated with NAC. A multivariable Cox model including either pDS or pCR was generated. A nested model was built to evaluate the added value of pDS (excluding patients achieving a pCR) to a model including pCR alone. C indices were computed to assess discrimination. NCDB was used for validation. The treatment effect of NAC versus cystectomy alone in achieving pDS was estimated through an inverse probability-weighted regression adjustment. RESULTS: Overall, 189 and 2010 patients from the RISC and NCDB cohorts, respectively, were included; pDS and pCR were achieved by 33% and 35% and by 20% and 15% in RISC and NCDB, respectively. In both data sets, pDS and pCR were associated with better OS and C indices. Adding pDS excluding pCR to the model with pCR fit the data better (likelihood ratio, P = .019 for RISC and P < .001 for NCDB), and it yielded better discrimination (incremental C index, 4.2 for RISC and 1.6 for NCDB). The treatment effect of NAC in achieving pDS was 2.07-fold (P < .001) in comparison with cystectomy alone. CONCLUSIONS: A decrease of at least 1 stage from the cT stage to the pT stage is associated with improved OS in patients with MIBC treated with NAC.

Pathological downstaging as a novel endpoint for the development of neoadjuvant chemotherapy for upper tract urothelial carcinoma.

OBJECTIVES: To evaluate whether pathological downstaging (pDS) was more informative in predicting overall survival (OS) than pathological complete response (pCR) in patients treated with neoadjuvant chemotherapy (NAC) for upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: The National Cancer Database was queried for patients with high-grade cN0M0 disease who had received NAC. pDS was defined as a decrease of at least one stage from cT to pT stage along with pN0, including pCR. A multivariable Cox model predicting OS was generated by fitting alternatively either pDS or pCR, and adjusted for potential confounders. The discrimination of the Cox models for predicting OS was evaluated using Harrell's C-index. The analyses were repeated in patients diagnosed as having cT2-4N0M0 disease. RESULTS: Among 264 patients meeting the inclusion criteria, 72 (27%) and 39 (15%) achieved pDS and pCR, respectively. On multivariable analysis, both pDS (hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.13, 0.45; P < 0.001) and pCR (HR 0.37, 95% CI 0.18, 0.79; P = 0.01) were associated with OS. The model including pDS achieved better discrimination with respect to the model including pCR: C-index 76.4 vs 72.7, respectively. In the 128 patients diagnosed with cT2-4 disease, both pDS (HR 0.19, 95% CI 0.09, 0.40; P < 0.001) and pCR (HR 0.31, 95% CI 0.11, 0.85; P = 0.023) were confirmed as predictors of OS. The model including pDS was confirmed to discriminate better than the model including pCR: C-index 75 vs 68.9, respectively. CONCLUSION: The study showed that pDS after NAC for UTUC was more informative than pCR when predicting OS. These findings, although requiring prospective validation, can aid in the design of clinical trials seeking to refine the use of chemotherapy and other systemic therapies in this setting.

Local radiation and phototherapy are the most cost-effective treatments for stage IA mycosis fungoides: A comparative decision analysis model in the United States.

BACKGROUND: Treatments for early-stage mycosis fungoides (MF) include topical steroids, topical nitrogen mustard, topical bexarotene, narrowband ultraviolet B (NBUVB), psoralen plus ultraviolet A (PUVA), and local radiation. The relative cost-effectiveness of each treatment given the differences in treatment failure, disease progression, and therapy escalation is not established. OBJECTIVE: To compare the cost-effectiveness (CE) of treatment options for stage IA MF. METHODS: A state-transition model was constructed with health states of stage IA to stage IV disease, no MF, and death. Treatment-specific remission and relapse rates were obtained from the literature. Lifetime costs were calculated by accounting for medications, office visits, laboratory monitoring, related procedures, work absences, and travel. RESULTS: The order of CE of the study treatments was determined to be as follows: local radiation, $225,399 for 15.40 life-years (LYs); NBUVB, $344,728 for 15.17 LYs; PUVA, $371,741 for 15.07 LYs; topical corticosteroids, $469,354 for 14.65 LYs; topical nitrogen mustard, $951,662 for 14.29 LYs; and topical bexarotene, 11,892,496 for 13.55 LYs. Sensitivity analyses confirmed the CE rankings. LIMITATIONS: We assumed a constant probability of response, relapse rates, and 3-month treatment intervals. CONCLUSIONS: Local radiation is the most cost-effective treatment for limited local disease, whereas phototherapy (NBUVB or PUVA) is cost-effective for generalized disease. Our findings can serve to inform future studies and recommendations regarding selection of therapy for stage IA MF.

Effectiveness of Transurethral Resection plus Systemic Chemotherapy as Definitive Treatment for Muscle Invasive Bladder Cancer in Population Level Data.

PURPOSE: We investigated the characteristics and outcomes of patients with muscle invasive bladder cancer treated with transurethral resection plus chemotherapy alone in a large observational cohort reflecting the continuum of practice settings in the United States. MATERIALS AND METHODS: In the National Cancer Database from 2004 to 2015 we identified 1,538 patients treated with transurethral resection plus multi-agent chemotherapy as definitive treatment of cT2-T4aN0M0 urothelial carcinoma of the bladder. For comparison purposes we included in study 17,866 patients treated with radical cystectomy with or without perioperative chemotherapy. Baseline characteristics were compared between the 2 groups by multivariable logistic regression. Treatment outcomes were assessed using Kaplan-Meier analysis and a Cox regression model. RESULTS: On multivariate analysis several variables, including patient demography (older age, African American race, prior malignancy and lack of insurance), tumor characteristics (higher cT stage) and facility type (nonacademic facilities and lower radical cystectomy volume) were associated with a higher probability of transurethral resection plus chemotherapy for muscle invasive bladder cancer compared to the standard of care. Two and 5-year survival rates in all patients treated with transurethral resection plus chemotherapy were 49.0% and 32.9%, and in patients with cT2 disease the rates were 52.6% and 36.2%, respectively. CONCLUSIONS: This large population level cohort of unselected patients shows that long-term survival can be achieved in a subset of patients treated with transurethral resection plus chemotherapy alone for muscle invasive bladder cancer. However, the best candidates for this approach remain to be defined. Ongoing clinical trials are now being launched to evaluate the ability of biomarkers to accurately select patients who could be treated with this bladder sparing strategy.

Cardiovascular Risk Assessment: A Systematic Review of Guidelines.

BACKGROUND: Many guidelines exist for screening and risk assessment for the primary prevention of cardiovascular disease in apparently healthy persons. PURPOSE: To systematically review current primary prevention guidelines on adult cardiovascular risk assessment and highlight the similarities and differences to aid clinician decision making. DATA SOURCES: Publications in MEDLINE and CINAHL between 3 May 2009 and 30 June 2016 were identified. On 30 June 2016, the Guidelines International Network International Guideline Library, National Guideline Clearinghouse, National Library for Health Guidelines Finder, Canadian Medical Association Clinical Practice Guidelines Infobase, and Web sites of organizations responsible for guideline development were searched. STUDY SELECTION: 2 reviewers screened titles and abstracts to identify guidelines from Western countries containing recommendations for cardiovascular risk assessment for healthy adults. DATA EXTRACTION: 2 reviewers independently assessed rigor of guideline development using the Appraisal of Guidelines for Research and Evaluation II instrument, and 1 extracted the recommendations. DATA SYNTHESIS: Of the 21 guidelines, 17 showed considerable rigor of development. These recommendations address assessment of total cardiovascular risk (5 guidelines), dysglycemia (7 guidelines), dyslipidemia (2 guidelines), and hypertension (3 guidelines). All but 1 recommendation advocates for screening, and most include prediction models integrating several relatively simple risk factors for either deciding on further screening or guiding subsequent management. No consensus on the strategy for screening, recommended target population, screening tests, or treatment thresholds exists. LIMITATION: Only guidelines developed by Western national or international medical organizations were included. CONCLUSION: Considerable discrepancies in cardiovascular screening guidelines still exist, with no consensus on optimum screening strategies or treatment threshold. PRIMARY FUNDING SOURCE: Barts Charity.

Evaluation of Short-Term Changes in Serum Creatinine Level as a Meaningful End Point in Randomized Clinical Trials.

Observational studies have shown that acute change in kidney function (specifically, AKI) is a strong risk factor for poor outcomes. Thus, the outcome of acute change in serum creatinine level, regardless of underlying biology or etiology, is frequently used in clinical trials as both efficacy and safety end points. We performed a meta-analysis of clinical trials to quantify the relationship between positive or negative short-term effects of interventions on change in serum creatinine level and more meaningful clinical outcomes. After a thorough literature search, we included 14 randomized trials of interventions that altered risk for an acute increase in serum creatinine level and had reported between-group differences in CKD and/or mortality rate ≥3 months after randomization. Seven trials assessed interventions that, compared with placebo, increased risk of acute elevation in serum creatinine level (pooled relative risk, 1.52; 95% confidence interval, 1.22 to 1.89), and seven trials assessed interventions that, compared with placebo, reduced risk of acute elevation in serum creatinine level (pooled relative risk, 0.57; 95% confidence interval, 0.44 to 0.74). However, pooled risks for CKD and mortality associated with interventions did not differ from those with placebo in either group. In conclusion, several interventions that affect risk of acute, mild to moderate, often temporary elevation in serum creatinine level in placebo-controlled randomized trials showed no appreciable effect on CKD or mortality months later, raising questions about the value of using small to moderate changes in serum creatinine level as end points in clinical trials.

The Benefits and Harms of Lung Cancer Screening in Individuals With Comorbidities.

Introduction: Individuals with a history of smoking and a high risk of lung cancer often have a high prevalence of smoking-related comorbidities. The presence of these comorbidities might alter the benefit-to-harm ratio of lung cancer screening by influencing the risk of complications, quality of life, and competing risks of death. Nevertheless, individuals with chronic diseases are underrepresented in screening clinical trials. In this study, we use microsimulation modeling to determine the impact of chronic diseases on lung cancer benefits and harms. Methods: We extended a validated lung cancer screening microsimulation model that comprehensively recapitulates an individual's lung cancer development, progression, detection, follow-up, treatment, and survival. We parameterized the model to reflect the impact of chronic diseases on complications from invasive testing, quality of life, and mortality in individuals in five-year age categories between the ages of 50 and 80 years. Outcomes included life-years (LY) gained per 100,000 in patients with chronic obstructive pulmonary disease, diabetes mellitus, heart disease, and history of stroke compared with screening-eligible individuals without comorbidities. Results: Among individuals between the ages of 50 and 54 years, we found that the presence of a comorbidity altered the LY gained from screening per 100,000 individuals depending on the comorbidity: 4296 LY with no comorbidities; 3462 LY, 3260 LY, 3031 LY, and 3257 LY with chronic obstructive pulmonary disease, heart disease, diabetes mellitus, and stroke, respectively. We observed greater reductions in LY gained in individuals with two comorbidities; we observed similar patterns for individuals between the ages of 55 and 59 years, 60 and 64 years, 65 and 69 years, 70 and 74 years, and 75 and 80 years. Conclusions: Comorbidities reduce LY gained from screening per 100,000 compared with no comorbidities, and our results can be used by clinicians when discussing the benefits and harms of screening in their patients with comorbidities.

Potential Mediators for Treatment Effects of Novel Diabetes Medications on Cardiovascular and Renal Outcomes: A Meta-Regression Analysis.

BACKGROUND: Prior research suggests clinical effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are mediated by changes in glycated hemoglobin, body weight, systolic blood pressure, hematocrit, and urine albumin-creatinine ratio. We aimed to confirm these findings using a meta-analytic approach. METHODS AND RESULTS: We updated a systematic review of 9 GLP-1RA and 13 SGLT2i trials and summarized longitudinal mediator data. We obtained hazard ratios (HRs) for cardiovascular, renal, and mortality outcomes. We performed linear mixed-effects modeling of LogHRs versus changes in potential mediators and investigated differences in meta-regression associations among drug classes using interaction terms. HRs generally became more protective with greater glycated hemoglobin reduction among GLP-1RA trials, with average HR improvements of 20% to 30%, reaching statistical significance for major adverse cardiovascular events (ΔHR, 23%; P=0.02). Among SGLT2i trials, associations with HRs were not significant and differed from GLP1-RA trials for major adverse cardiovascular events (Pinteraction=0.04). HRs for major adverse cardiovascular events, myocardial infarction, and stroke became less efficacious (ΔHR, -15% to -34%), with more weight loss for SGLT2i but not for GLP-1RA trials (ΔHR, 4%-7%; Pinteraction<0.05). Among 5 SGLT2i trials with available data, HRs for stroke became less efficacious with larger increases in hematocrit (ΔHR, 123%; P=0.09). No changes in HRs by systolic blood pressure (ΔHR, -11% to 9%) and urine albumin-creatinine ratio (ΔHR, -1% to 4%) were found for any outcome. CONCLUSIONS: We confirmed increased efficacy findings for major adverse cardiovascular events with reduction in glycated hemoglobin for GLP1-RAs. Further research is needed on the potential loss of cardiovascular benefits with increased weight loss and hematocrit for SGLT2i.