The added value of ordinal analysis in clinical trials: an example in traumatic brain injury

INTRODUCTION: In clinical trials, ordinal outcome measures are often dichotomized into two categories. In traumatic brain injury (TBI) the 5-point Glasgow outcome scale (GOS) is collapsed into unfavourable versus favourable outcome. Simulation studies have shown that exploiting the ordinal nature of the GOS increases chances of detecting treatment effects. The objective of this study is to quantify the benefits of ordinal analysis in the real-life situation of a large TBI trial. METHODS: We used data from the CRASH trial that investigated the efficacy of corticosteroids in TBI patients (n = 9,554). We applied two techniques for ordinal analysis: proportional odds analysis and the sliding dichotomy approach, where the GOS is dichotomized at different cut-offs according to baseline prognostic risk. These approaches were compared to dichotomous analysis. The information density in each analysis was indicated by a Wald statistic. All analyses were adjusted for baseline characteristics. RESULTS: Dichotomous analysis of the six-month GOS showed a non-significant treatment effect (OR = 1.09, 95% CI 0.98 to 1.21, P = 0.096). Ordinal analysis with proportional odds regression or sliding dichotomy showed highly statistically significant treatment effects (OR 1.15, 95% CI 1.06 to 1.25, P = 0.0007 and 1.19, 95% CI 1.08 to 1.30, P = 0.0002), with 2.05-fold and 2.56-fold higher information density compared to the dichotomous approach respectively. CONCLUSIONS: Analysis of the CRASH trial data confirmed that ordinal analysis of outcome substantially increases statistical power. We expect these results to hold for other fields of critical care medicine that use ordinal outcome measures and recommend that future trials adopt ordinal analyses. This will permit detection of smaller treatment effects

Reporting ethics committee approval and patient consent by study design in five general medical journals.

BACKGROUND: Authors are required to describe in their manuscripts ethical approval from an appropriate committee and how consent was obtained from participants when research involves human participants. OBJECTIVE: To assess the reporting of these protections for several study designs in general medical journals. DESIGN: A consecutive series of research papers published in the Annals of Internal Medicine, BMJ, JAMA, Lancet and The New England Journal of Medicine between February and May 2003 were reviewed for the reporting of ethical approval and patient consent. Ethical approval, name of approving committee, type of consent, data source and whether the study used data collected as part of a study reported elsewhere were recorded. Differences in failure to report approval and consent by study design, journal and vulnerable study population were evaluated using multivariable logistic regression. RESULTS: Ethical approval and consent were not mentioned in 31% and 47% of manuscripts, respectively. 88 (27%) papers failed to report both approval and consent. Failure to mention ethical approval or consent was significantly more likely in all study designs (except case-control and qualitative studies) than in randomised controlled trials (RCTs). Failure to mention approval was most common in the BMJ and was significantly more likely than in The New England Journal of Medicine. Failure to mention consent was most common in the BMJ and was significantly more likely than in all other journals. No significant differences in approval or consent were found when comparing studies of vulnerable and non-vulnerable participants. CONCLUSION: The reporting of ethical approval and consent in RCTs has improved, but journals are less good at reporting this information for other study designs. Journals should publish this information for all research on human participants

Management of imatinib-resistant CML patients

Imatinib has had marked impact on outcomes in chronic myelogenous leukemia (CML) patients for all stages of the disease and is endorsed by international treatment guidelines as the first line option. Although imatinib is highly effective and well tolerated, the development of resistance represents a clinical challenge. Since the most frequently identified mechanism of acquired imatinib resistance is bcr-abl kinase domain point mutations, periodic hematologic, cytogenetic, and molecular monitoring is critical throughout imatinib therapy. Once cytogenetic remission is achieved, residual disease can be monitored by bcr-abl transcript levels as assayed by reverse transcription polymerase chain reaction (RT-PCR). Detection of bcr-abl mutants prior to and during imatinib therapy can aid in risk stratification as well as in determining therapeutic strategies. Thus, mutation screening is indicated in patients lacking or losing hematologic response. Moreover, search for mutations should also be performed when a 3-log reduction of bcr-abl transcripts is not achieved or there is a reproducible increase of transcript levels. In patients harboring mutations which confer imatinib resistance, novel second line tyrosine kinase inhibitors have demonstrated encouraging efficacy with low toxicity. Only the T315I bcr-abl mutant has proved totally resistant to all clinically available bcr-abl inhibitors. Strategies to further increase the rates of complete molecular remissions represent the next frontier in the targeted therapy of CML patients

Outcomes of traumatic brain injury: the prognostic accuracy of various scores and models

Introduction. Traumatic Brain Injury (TBI) is a worldwide health problem, and is a pathology that causes significant mortality and disability in Latin America. Different scores and prognostic models have been developed in order to predict the neurological outcomes of patients. We aimed to test the prognostic accuracy of the Marshall CT classification system, the Rotterdam CT scoring system, and the IMPACT and CRASH models, in predicting 6-month mortality and 6-month unfavourable outcomes in a cohort of trauma patients with TBI in a university hospital in Colombia. Methods. We analysed 309 patients with significant TBI who were treated in a regional trauma centre in Colombia over a two year period. Bivariate and multivariate analyses were undertaken. The discriminatory power of each model, as well as its accuracy and precision, were assessed by logistic regression and AUC. Shapiro Wilks, chi2 and Wilcoxon test were used to compare the actual outcomes in the cohort against the predicted outcomes. Results. The median age was 32 years, and 77.67% were male. All four prognostic models showed good accuracy in predicting outcomes. The IMPACT model had the greatest accuracy in predicting an unfavourable outcome (AUC 0.864; 95% CI 0.819 - 0.909) and in predicting mortality (AUC 0.902; 95% CI 0.862 - 0.943) in patients with TBI. Conclusion. All four prognostic models are applicable to eligible TBI patients in Colombia. The IMPACT model was shown to be more accurate than the other prognostic models, and had a higher sensitivity in predicting 6-month mortality and 6-month unfavourable outcomes in patients with TBI in a university hospital in Colombia

Sepsis and septic shock in patients with malignancies : a Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique study

Objectives: Cancer affects up to 20% of critically ill patients, and sepsis is one of the leading reasons for ICU admission in this setting. Early signals suggested that survival might be increasing in this population. However, confirmation studies have been lacking. The goal of this study was to assess trends in survival rates over time in cancer patients admitted to the ICU for sepsis or septic shock over the last 2 decades. Data Source: Seven European ICUs. Study Selection: A hierarchical model taking into account the year of admission and the source dataset as random variables was used to identify risk factors for day 30 mortality. Data Extraction: Data from cancer patients admitted to ICUs for sepsis or septic shock were extracted from the Groupe de Recherche Respiratoire en Reanimation Onco-Hematologique database (1994-2015). Data Synthesis: Overall, 2,062 patients (62% men, median [interquartile range] age 59 yr [48-67 yr]) were included in the study. Underlying malignancies were solid tumors (n = 362; 17.6%) or hematologic malignancies (n = 1,700; 82.4%), including acute leukemia (n = 591; 28.7%), non-Hodgkin lymphoma (n = 461; 22.3%), and myeloma (n = 244; 11.8%). Two-hundred fifty patients (12%) underwent allogeneic hematopoietic stem cell transplantation and 640 (31.0%) were neutropenic at ICU admission. Day 30 mortality was 39.9% (823 deaths). The year of ICU admission was associated with significant decrease in day 30 mortality over time (odds ratio, 0.96; 95% CI, 0.93-0.98; p = 0.001). Mechanical ventilation (odds ratio, 3.25; 95% CI, 2.52-4.19; p < 0.01) and vasopressors use (odds ratio, 1.42; 95% CI, 1.10-1.83; p < 0.01) were independently associated with day 30 mortality, whereas underlying malignancy, allogeneic hematopoietic stem cell transplantation, and neutropenia were not. Conclusions: Survival in critically ill oncology and hematology patients with sepsis improved significantly over time. As outcomes improve, clinicians should consider updating admission policies and goals of care in this population

Master of Science

thesisTraumatic brain injury (TBI) cases are complex and inherently time sensitive. Clinicians often base treatment decisions upon their individual experiences, training, and many other factors. Prognostic calculators can help enhance the clinician's understanding of the patient's prognosis. Stand-alone, internet-based TBI prognostic calculators exist, including a website developed based on the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT-TBI) [1,2]. An electronic health record (EHR) integrated prognostic calculator that provides the expected probability of favorable and unfavorable outcomes for an individual patient could make treatment planning for TBI patients more efficient, accurate, and standardized, with the ultimate goal of improving patient outcomes. The IMPACT-TBI calculator was integrated with the Epic® EHR and made available to clinicians at the University of Utah Health system in Salt Lake City, Utah. The use of the tool was monitored and analyzed to support the providers and improve care. The calculator was used 346 times over 17 months. Trauma service providers were most likely to use the tool, and there was a significant increase in tool use after a demonstration was given to providers. An IMPACT-TBI prognostic calculator was successfully integrated with a major commercial EHR system. The integration provided insight into strategies for better integration and adoption of advanced clinical decision support tools in the future

Statistical analysis of the primary outcome in acute stroke trials

Common outcome scales in acute stroke trials are ordered categorical or pseudocontinuous in structure but most have been analyzed as binary measures. The use of fixed dichotomous analysis of ordered categorical outcomes after stroke (such as the modified Rankin Scale) is rarely the most statistically efficient approach and usually requires a larger sample size to demonstrate efficacy than other approaches. Preferred statistical approaches include sliding dichotomous, ordinal, or continuous analyses. Because there is no best approach that will work for all acute stroke trials, it is vital that studies are designed with a full understanding of the type of patients to be enrolled (in particular their case mix, which will be critically dependent on their age and severity), the potential mechanism by which the intervention works (ie, will it tend to move all patients somewhat, or some patients a lot, and is a common hazard present), a realistic assessment of the likely effect size, and therefore the necessary sample size, and an understanding of what the intervention will cost if implemented in clinical practice. If these approaches are followed, then the risk of missing useful treatment effects for acute stroke will diminish

Management of germ cell tumors in children: Approaches to cure

The introduction of cisplatinum chemotherapy and current advances in the surgical treatment have resulted in a dramatic improvement of the prognosis of children with malignant germ cell tumors (GCT). Cisplatinum chemotherapy generally results in sufficient systemic tumor control, but local relapses may still occur in patients who did not receive adequate local treatment. Therefore, the therapeutic consideration must take into account age, primary site of the tumor, and its histology. In gonadal tumors, there is a high chance of primary complete resection since these tumors tend to be encapsulated, and particularly testicular GCT are often detected at a low tumor stage. In contrast, a primary complete resection may be impossible in large nongonadal tumors such as sacrococcygeal or mediastinal GCT. In these tumors, a neoadjuvant or pre-operative chemotherapy after clinical diagnosis by imaging and evaluation of tumor markers significantly facilitates complete resection on delayed surgery. In addition, the impact of chemotherapy on local tumor control may be enhanced by locoregional hyperthermia. In most intracranial GCT complete resection is impossible and may be associated with significant morbidity. Nevertheless, biopsy is essential for diagnosis in nonsecreting tumors. In intracranial GCT, radiotherapy significantly contributes to local tumor control, and doses are stratified according to histology. These general considerations have been integrated into national and international cooperative treatment protocols. In most current protocols, treatment is stratified according to an initial risk assessment that includes the parameters age, site, histology, stage, completeness of resection and the tumor markers alpha(1)-fetoprotein (AFP) and human choriogonadotropin (beta-HCG). With such modern protocols overall cure rates above 80% can be achieved. Moreover, the previously high-risk groups may now expect a favorable prognosis with this risk-adapted treatment, whereas an increasing number of low-risk patients are treated expectantly or with significantly reduced chemotherapy. As current biologic studies reveal distinct genetic patterns in childhood GCT, it can be expected that further combined clinical and genetic studies will be valuable for risk assessment of childhood GCT

Utility of the SENIORS elderly heart failure risk model applied to the RICA registry of acute heart failure

Background: Heart failure (HF) is predominantly a disease of the elderly. Reliable risk stratification would help in the management of this population, but no model has been well evaluated in elderly HF patients in both acute and chronic settings and not being restricted by ejection fraction. To evaluate the utility of the SENIORS risk model, developed from a clinical trial of elderly patients with chronic HF, in an independent cohort (National Spanish Registry: RICA) of elderly acute HF patients. Methods: We applied the SENIORS risk model to 926 patients in RICA to estimate risk at one year of a) composite outcome of all-cause mortality or cardiovascular hospital admission and b) all-cause mortality. Results: In the RICA registry mean age was 78 years, mean ejection fraction 51% and 87% were in NYHA II and III. At one year death/CV hospitalization occurred in 31.9% and all-cause mortality in 19.5%. The risk model provided good separation of Kaplan Meier curves stratified by tertile for death/CV hospitalization and all-cause mortality. The observed versus expected rates of death/CV hospitalization in the lowest, middle and highest risk tertiles were (%) 34/24, 45/41 and 57/67, and for death 13/16, 32/38 and 44/70 respectively. C-statistic for all-cause mortality or CV hospitalization was 0.60 and for all-cause mortality 0.66. Conclusion: The SENIORS risk model was a reliable tool for relative risk stratification among acute heart failure patients in a “real world” registry, but predicted versus observed risk showed some variability. The model provides a useful basis for clinical risk prediction