Supporting the decision to perform molecular profiling for cancer patients based on routinely collected data through the use of machine learning.

BACKGROUND: Personalized medicine offers targeted therapy options for cancer treatment. However, the decision whether to include a patient into next-generation sequencing (NGS) testing is not standardized. This may result in some patients receiving unnecessary testing while others who could benefit from it are not tested. Typically, patients who have exhausted conventional treatment options are of interest for consideration in molecularly targeted therapy. To assist clinicians in decision-making, we developed a decision support tool using routine data from a precision oncology program. METHODS: We trained a machine learning model on clinical data to determine whether molecular profiling should be performed for a patient. To validate the model, the model's predictions were compared with decisions made by a molecular tumor board (MTB) using multiple patient case vignettes with their characteristics. RESULTS: The prediction model included 440 patients with molecular profiling and 13,587 patients without testing. High area under the curve (AUC) scores indicated the importance of engineered features in deciding on molecular profiling. Patient age, physical condition, tumor type, metastases, and previous therapies were the most important features. During the validation MTB experts made the same decision of recommending a patient for molecular profiling only in 10 out of 15 of their previous cases but there was agreement between the experts and the model in 9 out of 15 cases. CONCLUSION: Based on a historical cohort, our predictive model has the potential to assist clinicians in deciding whether to perform molecular profiling.

Hypertensive Heart Disease-The Imaging Perspective.

Hypertensive heart disease (HHD) develops in response to the chronic exposure of the left ventricle and left atrium to elevated systemic blood pressure. Left ventricular structural changes include hypertrophy and interstitial fibrosis that in turn lead to functional changes including diastolic dysfunction and impaired left atrial and LV mechanical function. Ultimately, these changes can lead to heart failure with a preserved (HFpEF) or reduced (HFrEF) ejection fraction. This review will outline the clinical evaluation of a patient with hypertension and/or suspected HHD, with a particular emphasis on the role and recent advances of multimodality imaging in both diagnosis and differential diagnosis.

Swapping data: A pragmatic approach for enabling academic-industrial partnerships.

Objectives: Academic institutions have access to comprehensive sets of real-world data. However, their potential for secondary use-for example, in medical outcomes research or health care quality management-is often limited due to data privacy concerns. External partners could help achieve this potential, yet documented frameworks for such cooperation are lacking. Therefore, this work presents a pragmatic approach for enabling academic-industrial data partnerships in a health care environment. Methods: We employ a value-swapping strategy to facilitate data sharing. Using tumor documentation and molecular pathology data, we define a data-altering process as well as rules for an organizational pipeline that includes the technical anonymization process. Results: The resulting dataset was fully anonymized while still retaining the critical properties of the original data to allow for external development and the training of analytical algorithms. Conclusion: Value swapping is a pragmatic, yet powerful method to balance data privacy and requirements for algorithm development; therefore, it is well suited to enable academic-industrial data partnerships.

The power of zero calcium in 82-Rubidium PET irrespective of sex and age.

BACKGROUND: Despite clinical suspicion, many non-invasive tests for coronary artery disease (CAD) are normal. Coronary artery calcification score (CACS) is a well-validated method to detect and risk stratify CAD. Patients with zero calcium score (ZCS) rarely have abnormal tests. Therefore, aims were to evaluate CACS as a gatekeeper to further functional downstream testing for CAD and estimate potential radiation and cost savings. METHODS: Consecutive patients with suspected CAD referred for PET were included (n = 2640). Prevalence and test characteristics of ZCS were calculated in different groups. Summed stress score ≥ 4 was considered abnormal and summed difference score ≥ 7 equivalent to ≥ 10% ischemia. To estimate potential radiation/cost reduction, PET scans were hypothetically omitted in ZCS patients. RESULTS: Mean age was 65 ± 11 years, 46% were female. 21% scans were abnormal and 26% of patients had ZCS. CACS was higher in abnormal PET (median 561 vs 27, P < 0.001). Abnormal PET was significantly less frequent in ZCS patients (2.6% vs 27.6%, P < 0.001). Sensitivity/negative predictive value (NPV) of ZCS to detect/exclude abnormal PET and ≥ 10% ischemia were 96.8% (95%-CI 95.0%-97.9%)/97.4% (95.9%-98.3%) and 98.9% (96.7%-99.6%)/99.6% (98.7%-99.9%), respectively. Radiation and cost reduction were estimated to be 23% and 22%, respectively. CONCLUSIONS: ZCS is frequent, and most often consistent with normal PET scans. ZCS offers an excellent NPV to exclude an abnormal PET and ≥ 10% ischemia across different gender and age groups. CACS is a suitable gatekeeper before advanced cardiac imaging, and potential radiation/cost savings are substantial. However, further studies including safety endpoints are needed.

Achievement of Low-Density Lipoprotein Cholesterol Targets in Cardiac Rehabilitation: Impact of the 2019 ESC/EAS Dyslipidaemia Guidelines.

In 2019 the European Society of Cardiology (ESC) lowered the target values for low-density lipoprotein cholesterol (LDL-C) from <1.8 mmol/L to <1.4 mmol/L for secondary prevention of cardiovascular disease (CVD). The aim of this study was to determine the clinical impact of the 2019 ESC/EAS dyslipidaemia guidelines on lipid-lowering therapies and achievement rates of LDL-C targets in a contemporary cohort of CAD patients participating in an ambulatory cardiac rehabilitation (CR) program.We conducted a retrospective analysis of prospectively collected data from the Swiss Secondary Prevention Registry (SwissPR) in patients with Coronary Artery Disease (CAD), who completed the ambulatory cardiovascular rehabilitation program (CR) of the University Hospital Basel, Switzerland from January 2017 to April 2021. To evaluate the impact of the guideline publication, the cohort was split into a pre-Guideline 2019 group (A) and a post-Guideline 2019 group (B). In total 1320 patients were screened leaving 875 patients for analysis. At discharge, more patients in group B were on maximal statin doses (20% vs. 9%, p < 0.0001) and on combination therapy with ezetimibe (51% vs. 17%, p < 0.0001) than in group A, which resulted in 53% of patients reaching the LDL-C target of <1.4 mmol/L in group B. Regression analysis revealed that dyslipidaemia and positive smoking history represent independent predictors for intensified lipid-lowering medication, whereas absolving CR after publication of the 2019 guidelines was the only significant predictor for reduced LDL-C at CR discharge. We found a significant difference in prescription rates of lipid-lowering medication, especially combination therapies and statin doses, after publication of the 2019 ESC/EAS dyslipidaemia guidelines resulting in an achievement rate of >50% of the LDL-C target <1.4 mmol/L in CAD patients participating in ambulatory CR.

Left ventricular ejection fraction, myocardial blood flow and hemodynamic variables in adenosine and regadenoson vasodilator 82-Rubidium PET.

AIMS: In most Rubidium-(Rb)-positron emission tomography (PET) studies, dipyridamole was used as vasodilator. The aim was to evaluate vasodilator PET left ventricular ejection fraction (LVEF), myocardial blood flow (MBF), hemodynamics, and the influence of adenosine and regadenoson on these variables. METHODS AND RESULTS: Consecutive patients (N = 2299) with prior coronary artery disease (CAD) or no prior CAD undergoing adenosine/regadenoson 82Rb-PET were studied and compared according to CAD status and normal/abnormal PET (summed stress score 0-3 vs. ≥4). Rest and stress LVEF differed significantly depending on CAD status and scan results. In patients with no prior CAD, rest/stress LVEF were 68% and 72%, in patients with prior CAD 60% and 63%. LVEF during stress increased 5 ± 6% in normal compared to 1 ± 8% in abnormal PET (P<0.001). Global rest myocardial blood flow(rMBF), stress MBF(sMBF) and myocardial flow reserve (sMBF/rMBF) were significantly higher in no prior CAD patients compared to prior CAD patients(1.3 ± 0.5, 3.3 ± 0.9, 2.6 ± 0.8 and 1.2 ± 0.4, 2.6 ± 0.8, 2.4 ± 0.8 ml/g/min, respectively, P<0.001) and in normal versus abnormal scans, irrespective of CAD status(no prior CAD: 1.4 ± 0.5, 3.5 ± 0.8, 2.8 ± 0.8 and 1.2 ± 0.8, 2.5 ± 0.8, 2.2 ± 0.7; prior CAD: 1.3 ± 0.4, 3.1 ± 0.8, 2.7 ± 0.8 and 1.1 ± 0.4, 2.3 ± 0.7, 2.2 ± 0.7 ml/g/min, respectively, P<0.001). LVEF and hemodynamic values were similar for adenosine and regadenoson stress. Stress LVEF ≥70% excluded relevant ischemia (≥10%) with a negative predictive value (NPV) of 94% (CI 92-95%). CONCLUSIONS: Rest/stress LVEF, LVEF reserve and MBF values are lower in abnormal compared to normal scans. Adenosine and regadenoson seem to have similar effect on stress LVEF, MBF and hemodynamics. A stress LVEF ≥70% has a high NPV to exclude relevant ischemia.

Big mitral annular calcification: a case report of a dynamic liquefaction necrosis as a potential source of embolism.

BACKGROUND: Mitral annular calcification (MAC) is a degenerative, mostly asymptomatic abnormality usually in elderly patients. Caseous MAC (cMAC) is a rare form with central liquefaction necrosis, which typically involves the posterior annulus of the mitral valve and can cause serious sequelae. However, optimal management of patients with cMAC is not clearly defined. CASE SUMMARY: In a 71-year-old female patient, MAC was incidentally detected. Tissue characterization with cardiac magnetic resonance (CMR) revealed a cMAC and a conservative approach was chosen. Six months after cMAC diagnosis, the patient developed an acute hemi-occlusion of a retinal artery with cholesterol embolism. At this time, CMR showed a liquefied cavity of the cMAC. Except for atherosclerotic plaques in the aorta and carotid arteries, further stroke work-up was negative. Therefore, the conservative approach was continued. During follow-up, the liquefied cavity regressed completely after another 6 months and the patient was free from further events (total follow-up 3 years since diagnosis of cMAC). DISCUSSION: A clear diagnosis and quantitative assessment of dynamic processes, such as cMAC, are made possible by performing CMR with multi-parametric tissue characterization. Dynamic changes in cMAC may have serious clinical implications, such as mitral regurgitation or systemic embolization. Among cardiac tumours, thrombus and abscess, cMAC should be included in the differential diagnosis of an intracardiac mass of the posterior mitral annulus in order to avoid further inappropriate diagnostic interventions.

The Economic Burden of Cystic Fibrosis in Germany from a Payer Perspective.

BACKGROUND: Cystic fibrosis (CF) is a genetic disorder that is most common in white children and young adults. Long-term survival has improved steadily and will likely increase with the recent introduction of neonatal screening and causative treatment. However, these advances have substantial economic consequences for healthcare systems and payers. OBJECTIVE: This study aims to determine the economic burden of CF and to elucidate the structure of costs and the distribution of resources for different subpopulations, treatment strategies and sites of care for CF in Germany. METHODS: We conducted an observational cohort study to evaluate the economic burden of CF and the costs of treatment within different CF substrata from a payer perspective. Using claims data from a large German sickness fund, we identify the causal effect of CF on costs, service utilisation, and premature mortality. We compare the outcomes of a CF and a control group using entropy balancing and regression techniques, conduct further analyses for the CF group to gain insight into the economic burden associated with different levels of disease severity, and analyse pharmaceutical expenditures by collecting all CF-related expenses on outpatient drug treatment from the sickness fund database. RESULTS: Direct medical costs caused by CF in Germany in 2016 average €17,551 per patient-year and appear to be mainly driven by the cost of outpatient drug prescriptions (€12,869). We estimate that the national burden of disease totals €159 million. Costs increase with disease severity and related complications. If all eligible CF patients in the German population were to receive CF mutation-specific drugs, the economic burden of disease would more than triple to €594 million. CONCLUSION: CF has a constant and wide-ranging economic impact on payers, with considerable differences in the distribution of costs and service utilisation between younger and older patients as well as mild vs. severe patients. Pharmaceutical expenses will increase in the future as causative treatment gains importance. We encourage the use of a control group approach for burden-of-disease studies to be able to identify causal effects and thus to obtain more precise estimates.

Economic Burden and Quality-of-Life Effects of Chronic Lymphocytic Leukemia: A Systematic Review of the Literature.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia in the Western hemisphere. The disease affects quality of life (QOL) and poses an economic burden on patients, payers, and society. The objective of this review was to quantify the economic burden and quality-of-life effects and identify the gaps that should be addressed by future research. METHODS: Free-text and subject heading searches in MEDLINE, EMBASE, the Cochrane Library, the University of York Centre for Reviews and Dissemination Database, and the Web of Science Core Collection database were conducted to identify observational and interventional studies reporting costs and/or quality-of-life effects published up to 2 October 2015. Studies were included irrespective of whether they were conducted prospectively or retrospectively. The focus population consisted of adult patients aged 18 years or older affected by any stage of CLL. Studies were included regardless of whether the underlying population was treated at baseline or not. Risk of bias was assessed using a quality checklist developed by the Effective Public Health Practice Project for (randomized) controlled trials, cohort studies, and cross-sectional studies. Economic evaluations were rated using a checklist developed by Stuhldreher et al. (Int J Eat Disord 45:476-91, 2012). RESULTS: From 2451 records identified, 27 studies were found to be eligible for inclusion. Studies were heterogeneous with respect to methodology, perspective, and data used. Annual direct costs per person ranged from US$4491 in Germany to US$43,913 in the USA. The share of costs attributable to drug treatment varied between 26.2 and 79 %. Indirect costs amounted to US$4208. Severity of disease was a predictor for quality of life, whereas differences by age and sex were mainly present in subdomains. Comparisons of treated and untreated populations resulted in an increase of quality of life in favor of treated populations in the long-term perspective. Differences between treatments were small. Consequently, cost effectiveness in decision-analytic models did not depend on whether quality of life or survival are used to describe the benefits of treatment. CONCLUSIONS: Although the quantity and the quality of health economic and quality-of-life evidence have substantially increased, there is still a need for studies that take a patient or societal perspective. Factors that influence costs and the quality of life of patients seem to be well-established, while longitudinal lifetime cost studies at the population level are still scarce.

Outcome of patients with cardiac resynchronisation defibrillator therapy and a follow-up of at least five years after implant.

QUESTIONS UNDER STUDY: Cardiac resynchronisation therapy with defibrillator backup (CRT-D) is an established therapeutic option in selected heart failure patients. Data on its pronounced long-term outcome are scarce. We evaluated the long-term outcome (>5 years) of patients with the main focus on device-associated events. METHODS: Out of a prospective CRT-D registry with 219 patients, all 49 patients (22%) who survived for at least 5 years were analysed. Baseline characteristics, device associated issues (battery longevity, lead problems, phrenic nerve stimulation, infections and pacing threshold levels), implantable cardioverter-defibrillator (ICD) therapies, mortality, changes in left ventricular ejection fraction (LVEF) and improvement in New York Heart Association (NYHA) class were considered. RESULTS: The mean ± standard deviation age of the patients was 63±10 years and follow-up was 84±18 months. Seventy-eight percent were male, 73% had nonischaemic cardiomyopathy and 80% a primary prevention indication. After initially surviving 5 years, 8 patients (16%) died during further follow-up. LVEF improved from 23%±7% to 35%±13% (p-value <0.0001) at last follow-up. 14 patients (29%) had appropriate ICD therapy, mainly for ventricular tachycardia. No first-ever arrhythmic event occurred beyond year 4.5. Device longevity was 54±13 months. Twenty-three technical problems occurred in 20 patients (40%), 14 of whom (61%) required surgery (7 lead defects, 4 dislodgments, 3 others). Dislodgements occurred early (after 2±2 months); defects were scattered (2-59 months) during follow-up. CONCLUSION: Selected patients who survive for at least 5 years experience sustained improvement in LVEF and NYHA- class and only few arrhythmic episodes. Technical problems occur in 40% of patients (60% requiring surgery), mainly shortly after implant and again after 4 to 5 years.

Performance of compliance and persistence measures in predicting clinical and economic outcomes using administrative data from German sickness funds.

STUDY OBJECTIVE: To compare the performance of various compliance and persistence measures in predicting schizophrenia-related hospitalization rates and inpatient costs. DESIGN: Retrospective, nonrandomized cohort study. DATA SOURCE: Prescription claims databases from three German sickness funds (public health insurance programs). PATIENTS: A total of 1484 patients who were hospitalized in 2003 for a schizophrenia-related episode and subsequently received long-term antipsychotic pharmacotherapy. MEASUREMENTS AND MAIN RESULTS: Data on age, sex, schizophrenia, prescription drugs, hospitalizations, and inpatient expenditures were collected for each patient from the three German sickness funds. Refill compliance measures based on single-interval availability and multiple-interval availability, as well as refill persistence, were calculated for each patient over 1 year. Ten measurement variables were compared with respect to their performance in predicting disease-related hospitalization and inpatient expenditure, using multivariate logistic regression and gamma regression, respectively. C-statistics were calculated to determine each measure's predictive performance. Likelihood ratio tests showed that inclusion of compliance and persistence measures significantly improved (p<0.05) outcomes prediction in 6 of 10 hospitalization models and in 3 of 10 inpatient cost models compared with a baseline model that included only age, sex, and disease severity covariates. Refill compliance as a continuous variable of drug persistence, including transfer of oversupplies into subsequent periods, performed best in predicting hospitalization (C = 0.669). Availability ratios, capped at 100%, were superior to default availability ratios in predicting hospitalization. Allowing for cross-period carryover improved the discriminatory performance of the persistence models. CONCLUSION: Refill persistence measures appear sufficiently flexible to account for hospitalizations common in schizophrenia and other psychiatric diseases. A continuous refill persistence measure should be used to assess compliance in psychiatric conditions when working with administrative data.

Predictors of acute respiratory failure after bone marrow transplantation in children.

OBJECTIVE: To determine factors associated with acute respiratory failure after bone marrow transplantation which can be identified before the onset of lung disease. DESIGN: Population-based, retrospective study. SETTING: A referral-based pediatric intensive care unit and bone marrow transplant center. PATIENTS: Thirty-nine patients with lung disease (abnormal chest radiograph or a need for supplemental oxygen) were identified from a group of 318 pediatric bone marrow transplant patients from 1978 to 1988. Thirty-four of 39 patients with complete data were further classified into patients with mild lung disease (recovery without needing endotracheal intubation, n = 16) and patients with acute respiratory failure (requirement for endotracheal intubation, n = 18). INTERVENTIONS: Regression analyses were performed to define risk factors for development of respiratory failure (multivariate logistic regression) and for a shortened interval between the identification of lung disease and respiratory failure (Cox proportional hazards analysis). MEASUREMENTS AND MAIN RESULTS: Ninety-three percent (15/16) of patients with mild lung disease survived. Conversely, only 9% (2/23) of patients with respiratory failure survived. Predictors of respiratory failure included graft vs. host disease (odds ratio 28.3, 95% confidence interval 1.9-421, p = .015), a prelung disease (baseline) circulating creatinine concentration of > 1.5 mg/dL (> 132.6 mumol/L) (odds ratio 28.4, 95% confidence interval 1.4-577, p = .029), and male gender (odds ratio 14.6, 95% confidence interval 1-210, p = .049). Predictors of a shortened time to onset of respiratory failure included baseline serum creatinine value of > 1.5 mg/dL (> 132.6 mumol/L) (hazard ratio 6.2, 95% confidence interval 1.5-26.5, p = .013) and baseline total bilirubin concentration > 1.4 mg/dL (> 23.9 mumol/L) (hazard ratio 4.5, 95% confidence interval 0.98-20.7, p = .053). The median time to onset of respiratory failure was 4 days in patients with baseline creatinine values > or = 1.5 mg/dL (> 132.6 mumol/L) and 5 days in patients with baseline bilirubin concentrations > or = 1.4 mg/dL (> 23.9 mumol/L) vs. > 26 days in patients with creatinine < 1.5 mg/dL (< 132.6 mumol/L) and > 29 days in patients with bilirubin < 1.4 mg/dL (< 23.9 mumol/L) (Kaplan-Meier analysis). CONCLUSIONS: Renal and liver dysfunction preceded clinical evidence of lung disease in bone marrow transplant patients who developed respiratory failure. Lung disease leading to respiratory failure and adult respiratory distress syndrome appears to develop as one component of the multiple organ failure syndrome in pediatric bone marrow transplant patients.