Health-state utilities in long-term advanced melanoma survivors comparable with the general population.

BACKGROUND: Checkpoint inhibitors have been shown to substantially improve the survival of patients with advanced melanoma. With this growing group of survivors treated with immunotherapies, assessing their health-state utilities is essential and can be used for the calculation of quality-adjusted life years and for cost-effectiveness analyses. Therefore, we evaluated the health-state utilities in long-term advanced melanoma survivors. METHODS: Health-state utilities were evaluated in a cohort of advanced melanoma survivors 24-36 months (N = 37) and 36-plus months (N = 47) post-ipilimumab monotherapy. In addition, the health-state utilities of the 24-36 months survivor group were assessed longitudinally, and utilities of the combined survival groups (N = 84) were compared with a matched control population (N = 168). The EQ-5D was used to generate health-state utility values, and quality-of-life questionnaires were used to establish correlations and influencing factors of utility scores. RESULTS: Health-state utility scores were similar between the 24-36 months'- and the 36-plus months' survival group (0.81 vs 0.86; p = .22). In survivors, lower utility scores were associated with symptoms of depression (ß = - .82, p = .022) and fatigue burden (ß = - .29, p = .007). Utility scores did not significantly change after 24-36 months of survival, and the utilities of survivors were comparable to the matched control population (0.84 vs 0.87; p = .07). DISCUSSION: Our results show that long-term advanced melanoma survivors treated with ipilimumab monotherapy experience relatively stable and high health-state utility scores.

Health-related quality of life of long-term advanced melanoma survivors treated with anti-CTLA-4 immune checkpoint inhibition compared to matched controls.

BACKGROUND: Checkpoint inhibitors have changed overall survival for patients with advanced melanoma. However, there is a lack of data on health-related quality of life (HRQoL) of long-term advanced melanoma survivors, years after treatment. Therefore, we evaluated HRQoL in long-term advanced melanoma survivors and compared the study outcomes with matched controls without cancer. MATERIAL AND METHODS: Ipilimumab-treated advanced melanoma survivors without evidence of disease and without subsequent systemic therapy for a minimum of two years following last administration of ipilimumab were eligible for this study. The European Organization for Research and Treatment of Cancer quality of life questionnaire Core 30 (EORTC QLQ-C30), the Multidimensional Fatigue Inventory (MFI), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M) were administered. Controls were individually matched for age, gender, and educational status. Outcomes of survivors and controls were compared using generalized estimating equations, and differences were interpreted as clinically relevant according to published guidelines. RESULTS: A total of 89 survivors and 265 controls were analyzed in this study. After a median follow-up of 39 (range, 17-121) months, survivors scored significantly lower on physical (83.7 vs. 89.8, difference (diff) = -5.80, p=.005), role (83.5 vs. 90, diff = -5.97, p=.02), cognitive (83.7 vs. 91.9, diff = -8.05, p=.001), and social functioning (86.5 vs. 95.1, diff = -8.49, p= <.001) and had a higher symptom burden of fatigue (23.0 vs. 15.5, diff = 7.48, p=.004), dyspnea (13.3 vs. 6.7, diff = 6.47 p=.02), diarrhea (7.9 vs. 4.0, diff = 3.78, p=.04), and financial impact (10.5 vs. 2.5, diff = 8.07, p=.001) than matched controls. Group differences were indicated as clinically relevant. DISCUSSION: Compared to matched controls, long-term advanced melanoma survivors had overall worse functioning scores, more physical symptoms, and financial difficulties. These data may contribute to the development of appropriate survivorship care.

Updating methods improved the performance of a clinical prediction model in new patients.

OBJECTIVE: Ideally, clinical prediction models are generalizable to other patient groups. Unfortunately, they perform regularly worse when validated in new patients and are then often redeveloped. While the original prediction model usually has been developed on a large data set, redevelopment then often occurs on the smaller validation set. Recently, methods to update existing prediction models with the data of new patients have been proposed. We used an existing model that preoperatively predicts the risk of severe postoperative pain (SPP) to compare five updating methods. STUDY DESIGN AND SETTING: The model was tested and updated with a set of 752 new patients (274 [36] with SPP). We studied the discrimination (ability to distinguish between patients with and without SPP) and calibration (agreement between the predicted risks and observed frequencies of SPP) of the five updated models in 283 other patients (100 [35%] with SPP). RESULTS: Simple recalibration methods improved the calibration to a similar extent as revision methods that made more extensive adjustments to the original model. Discrimination could not be improved by any of the methods. CONCLUSION: When the performance is poor in new patients, updating methods can be applied to adjust the model, rather than to develop a new model.

A multi-center comparison of diagnostic methods for the biochemical evaluation of suspected mitochondrial disorders.

A multicenter comparison of mitochondrial respiratory chain and complex V enzyme activity tests was performed. The average reproducibility of the enzyme assays is 16% in human muscle samples. In a blinded diagnostic accuracy test in patient fibroblasts and SURF1 knock-out mouse muscle, each lab made the correct diagnosis except for two complex I results. We recommend that enzyme activities be evaluated based on ratios, e.g. with complex IV or citrate synthase activity. In spite of large variations in observed enzyme activities, we show that inter-laboratory comparison of patient sample test results is possible by using normalization against a control sample.

Systematic review: diagnostic accuracy of clinical decision rules for venous thromboembolism in elderly.

BACKGROUND: Physicians committed to the care of elderly patients, are challenged with the diagnosis of venous thromboembolism (VTE: deep venous thrombosis and pulmonary embolism) due to a higher incidence, co-morbidities masking signs and symptoms and burdening referrals. Clinical decision rules (CDRs) have been developed and implemented for VTE. Yet, until now, no study has evaluated the existing evidence of the diagnostic accuracy of CDRs for VTE in elderly. PURPOSE: To assess the effect of increasing age on diagnostic accuracy of CDRs for VTE in elderly. DATA SOURCES: A computerized systematic search was performed in Medline and Embase from 1950 to 2010. After checking reference lists and field experts, all key journals were hand searched. STUDY SELECTION: After review of 1538 eligible citations, nine articles were included and critically appraised on methodological quality by two reviewers using the QUADAS criteria. DATA EXTRACTION: Data on age subgroups, type of CDRs, sensitivity, specificity, safety, efficiency and the prevalence of deep venous thrombosis (DVT) and pulmonary embolism (PE) were extracted. DATA SYNTHESIS: Although sensitivity and safety of the CDRs for VTE in elderly remained high, the specificity and efficiency decreased substantially in older age groups. LIMITATIONS: A limited number of studies met our inclusion criteria. Possible referral bias due to inclusion of relatively high risk elderly patients. CONCLUSIONS: This diagnostic review demonstrates an increase of prevalence of PE with age and a strong decrease of specificity and efficiency for CDRs of VTE in older patients. Moreover, due to referral bias the decrease in specificity in the elderly may even be underestimated. Although the safety of CDRs for VTE is high, adapting these rules for elderly is much needed to make them more efficient for aged patients.

Excluding venous thromboembolism using point of care D-dimer tests in outpatients: a diagnostic meta-analysis.

OBJECTIVE: To review the evidence on the diagnostic accuracy of the currently available point of care D-dimer tests for excluding venous thromboembolism. DESIGN: Systematic review of research on the accuracy of point of care D-dimer tests, using bivariate regression to examine sources of variation and to estimate sensitivity and specificity. DATA SOURCES: Studies on the diagnostic accuracy of point of care D-dimer tests published between January 1995 and September 2008 and available in either Medline or Embase. Review methods The analysis included studies that compared point of care D-dimer tests with predefined reference criteria for venous thromboembolism, enrolled consecutive outpatients, and allowed for construction of a 2x2 table. RESULTS: 23 studies (total number of patients 13 959, range in mean age 38-65 years, range of venous thromboembolism prevalence 4-51%) were included in the meta-analysis. The studies reported two qualitative point of care D-dimer tests (SimpliRED D-dimer (n=12) and Clearview Simplify D-dimer (n=7)) and two quantitative point of care D-dimer tests (Cardiac D-dimer (n=4) and Triage D-dimer (n=2)). Overall sensitivity ranged from 0.85 (95% confidence interval 0.78 to 0.90) to 0.96 (0.91 to 0.98) and overall specificity from 0.48 (0.33 to 0.62) to 0.74 (0.69 to 0.78). The two quantitative tests Cardiac D-dimer and Triage D-dimer scored most favourably. CONCLUSIONS: In outpatients suspected of venous thromboembolism, point of care D-dimer tests can contribute important information and guide patient management, notably in low risk patients (that is, those patients with a low score on a clinical decision rule).

Validation, updating and impact of clinical prediction rules: a review.

OBJECTIVE: To provide an overview of the research steps that need to follow the development of diagnostic or prognostic prediction rules. These steps include validity assessment, updating (if necessary), and impact assessment of clinical prediction rules. STUDY DESIGN AND SETTING: Narrative review covering methodological and empirical prediction studies from primary and secondary care. RESULTS: In general, three types of validation of previously developed prediction rules can be distinguished: temporal, geographical, and domain validations. In case of poor validation, the validation data can be used to update or adjust the previously developed prediction rule to the new circumstances. These update methods differ in extensiveness, with the easiest method a change in model intercept to the outcome occurrence at hand. Prediction rules -- with or without updating -- showing good performance in (various) validation studies may subsequently be subjected to an impact study, to demonstrate whether they change physicians' decisions, improve clinically relevant process parameters, patient outcome, or reduce costs. Finally, whether a prediction rule is implemented successfully in clinical practice depends on several potential barriers to the use of the rule. CONCLUSION: The development of a diagnostic or prognostic prediction rule is just a first step. We reviewed important aspects of the subsequent steps in prediction research.

Multiple imputation to correct for partial verification bias revisited.

Partial verification refers to the situation where a subset of patients is not verified by the reference (gold) standard and is excluded from the analysis. If partial verification is present, the observed (naive) measures of accuracy such as sensitivity and specificity are most likely to be biased. Recently, Harel and Zhou showed that partial verification can be considered as a missing data problem and that multiple imputation (MI) methods can be used to correct for this bias. They claim that even in simple situations where the verification is random within strata of the index test results, the so-called Begg and Greenes (B&G) correction method underestimates sensitivity and overestimates specificity as compared with the MI method. However, we were able to demonstrate that the B&G method produces similar results as MI, and that the claimed difference has been caused by a computational error. Additional research is needed to better understand which correction methods should be preferred in more complex scenarios of missing reference test outcome in diagnostic research.