Project description:To fairly compare the nestedness of ecological networks, a network's observed nestedness can be divided by its maximum nestedness. The authors show that a greedy algorithm does not find networks' maximum nestedness values. Simulated annealing achieved much better results, laying the foundation for future development of even more sophisticated algorithms.
Project description:The progress made over the past 50 years in disease-directed clinical trials has significantly increased cure rates for children and adolescents with cancer. The Children's Oncology Group (COG) is now conducting more studies that emphasize improving quality of life for young people with cancer. These types of clinical trials are classified as cancer control (CCL) studies by the National Cancer Institute and require different resources and approaches to facilitate adequate accrual and implementation at COG institutions. Several COG institutions that had previously experienced problems with low accruals to CCL trials have successfully implemented local nursing leadership for these types of studies. Successful models of nurses as institutional leaders and "champions" of CCL trials are described.
Project description:BackgroundPlatform trials allow adding new experimental treatments to an on-going trial. This feature is attractive to practitioners due to improved efficiency. Nevertheless, the operating characteristics of a trial that adds arms have not been well-studied. One controversy is whether just the concurrent control data (i.e. of patients who are recruited after a new arm is added) should be used in the analysis of the newly added treatment(s), or all control data (i.e. non-concurrent and concurrent).MethodsWe investigate the benefits and drawbacks of using non-concurrent control data within a two-stage setting. We perform simulation studies to explore the impact of a linear and a step trend on the inference of the trial. We compare several analysis approaches when one includes all the control data or only concurrent control data in the analysis of the newly added treatment.ResultsWhen there is a positive trend and all the control data are used, the marginal power of rejecting the corresponding hypothesis and the type one error rate can be higher than the nominal value. A model-based approach adjusting for a stage effect is equivalent to using concurrent control data; an adjustment with a linear term may not guarantee valid inference when there is a non-linear trend.ConclusionsIf strict error rate control is required then non-concurrent control data should not be used; otherwise it may be beneficial if the trend is sufficiently small. On the other hand, the root mean squared error of the estimated treatment effect can be improved through using non-concurrent control data.
Project description:Important considerations for exercise trials in cancer patients are contamination and differential drop-out among the control group members that might jeopardize the internal validity. This systematic review provides an overview of different control groups design characteristics of exercise-oncology trials and explores the association with contamination and drop-out rates.Randomized controlled exercise-oncology trials from two Cochrane reviews were included. Additionally, a computer-aided search using Medline (Pubmed), Embase and CINAHL was conducted after completion date of the Cochrane reviews. Eligible studies were classified according to three control group design characteristics: the exercise instruction given to controls before start of the study (exercise allowed or not); and the intervention the control group was offered during (any (e.g., education sessions or telephone contacts) or none) or after (any (e.g., cross-over or exercise instruction) or none) the intervention period. Contamination (yes or no) and excess drop-out rates (i.e., drop-out rate of the control group minus the drop-out rate exercise group) were described according to the three design characteristics of the control group and according to the combinations of these three characteristics; so we additionally made subgroups based on combinations of type and timing of instructions received.40 exercise-oncology trials were included based on pre-specified eligibility criteria. The lowest contamination (7.1% of studies) and low drop-out rates (excess drop-out rate -4.7±9.2) were found in control groups offered an intervention after the intervention period. When control groups were offered an intervention both during and after the intervention period, contamination (0%) and excess drop-out rates (-10.0±12.8%) were even lower.Control groups receiving an intervention during and after the study intervention period have lower contamination and drop-out rates. The present findings can be considered when designing future exercise-oncology trials.
Project description:The EORTC GastroIntestinal Tract Cancer Group and the EORTC HeadQuarters wish to set up a European screening platform for advanced colo-rectal cancer (CRC) patients. The goal of this screening platform is to provide quick access to new drugs to patients by offering a new structure for clinical trials.
Currently some of the most challenging clinical questions arise from the molecular sub-division of CRC that would theoretically allow to inhibit the specific, altered pathways in the patients.
A major problem for trials in this "personalized medicine" is that the low frequency of the different mutations requires a high effort for screening and identifying the patients.
The EORTC CRC screening platform will hopefully offer a feasible and efficient way to characterize the patients on the molecular basis of their tumors and allow to offer them rapid and preferential participation in clinical studies with new drugs targeted to their specific pathway alterations.
Project description:Investigating targeted therapies can be challenging due to diverse tumor mutations and slow patient accrual for clinical studies. The Signature Program is a series of 8 phase 2, agent-specific basket protocols using a rapid study start-up approach involving no predetermined study sites. Each protocol evaluated 1 agent (buparlisib, dovitinib, binimetinib, encorafenib, sonidegib, BGJ398, ceritinib, or ribociclib) in patients with solid or hematologic malignancies and an actionable mutation. The primary endpoint of each study was the clinical benefit rate (ie, complete or partial response, or stable disease) at 16 weeks. A total of 192 individual sites were opened in the United States, with a median start-up time of 3.6 weeks. The most common tumor types among the 595 treated patients were colorectal (9.2%), non-small cell lung adenocarcinoma (9.1%), and ovarian (8.4%). Frequent genetic alterations were in PIK3CA, RAS, p16, and PTEN. Overall, 30 partial or complete responses were observed with 6 compounds in 16 tumor types. The Signature Program presents a unique and successful approach for rapid signal finding across multiple tumors and allowed various agents to be evaluated in patients with rare alterations. Incorporating these program features in conventional studies could lead to improved trial efficiencies and patient outcomes.
Project description:Objectives: To identify similarities and differences in gene expression data in the MEK/ERK and PI3K pathways and to determine how histone modification affects these same pathways. Goal: To identify and functionally characterize novel targets of these signaling pathways in the context of chondrocyte differentiation. Keywords: Teatment, signaling, one-colour array, signaling pathway comparison
Project description:BACKGROUND:Master protocols, classified as basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies (e.g., multiple treatments or populations or that allow adding/removing arms during the trial), offering enhanced efficiency and a more ethical approach to trial evaluation. Despite the many advantages of these designs, they are infrequently used. METHODS:We conducted a landscape analysis of master protocols using a systematic literature search to determine what trials have been conducted and proposed for an overall goal of improving the literacy in this emerging concept. On July 8, 2019, English-language studies were identified from MEDLINE, EMBASE, and CENTRAL databases and hand searches of published reviews and registries. RESULTS:We identified 83 master protocols (49 basket, 18 umbrella, and 16 platform trials). The number of master protocols has increased rapidly over the last five years. Most have been conducted in the US (n = 44/83) and investigated experimental drugs (n = 82/83) in the field of oncology (n = 76/83). The majority of basket trials were exploratory (i.e., phase I/II; n = 47/49) and not randomized (n = 44/49), and more than half (n = 28/48) investigated only a single intervention. The median sample size of basket trials was 205 participants (interquartile range, Q3-Q1 [IQR]: 500-90 = 410), and the median study duration was 22.3 (IQR: 74.1-42.9 = 31.1) months. Similar to basket trials, most umbrella trials were exploratory (n = 16/18), but the use of randomization was more common (n = 8/18). The median sample size of umbrella trials was 346 participants (IQR: 565-252 = 313), and the median study duration was 60.9 (IQR: 81.3-46.9 = 34.4) months. The median number of interventions investigated in umbrella trials was 5 (IQR: 6-4 = 2). The majority of platform trials were randomized (n = 15/16), and phase III investigation (n = 7/15; one did not report information on phase) was more common in platform trials with four of them using seamless II/III design. The median sample size was 892 (IQR: 1835-255 = 1580), and the median study duration was 58.9 (IQR: 101.3-36.9 = 64.4) months. CONCLUSIONS:We anticipate that the number of master protocols will continue to increase at a rapid pace over the upcoming decades. More efforts to improve awareness and training are needed to apply these innovative trial design methods to fields outside of oncology.