Publications

BACKGROUND: The proportion of proposed new treatments that are 'successful' is of ethical, scientific, and public importance. We investigated how often new, experimental treatments evaluated in randomized controlled trials (RCTs) are superior to established treatments.

OBJECTIVES: Our main question was: "On average how often are new treatments more effective, equally effective or less effective than established treatments?" Additionally, we wanted to explain the observed results, i.e. whether the observed distribution of outcomes is consistent with the 'uncertainty requirement' for enrollment in RCTs. We also investigated the effect of choice of comparator (active versus no treatment/placebo) on the observed results.

SEARCH METHODS: We searched the Cochrane Methodology Register (CMR) 2010, Issue 1 in The Cochrane Library (searched 31 March 2010); MEDLINE Ovid 1950 to March Week 2 2010 (searched 24 March 2010); and EMBASE Ovid 1980 to 2010 Week 11 (searched 24 March 2010).

SELECTION CRITERIA: Cohorts of studies were eligible for the analysis if they met all of the following criteria: (i) consecutive series of RCTs, (ii) registered at or before study onset, and (iii) compared new against established treatments in humans.

DATA COLLECTION AND ANALYSIS: RCTs from four cohorts of RCTs met all inclusion criteria and provided data from 743 RCTs involving 297,744 patients. All four cohorts consisted of publicly funded trials. Two cohorts involved evaluations of new treatments in cancer, one in neurological disorders, and one for mixed types of diseases. We employed kernel density estimation, meta-analysis and meta-regression to assess the probability of new treatments being superior to established treatments in their effect on primary outcomes and overall survival.

MAIN RESULTS: The distribution of effects seen was generally symmetrical in the size of difference between new versus established treatments. Meta-analytic pooling indicated that, on average, new treatments were slightly more favorable both in terms of their effect on reducing the primary outcomes (hazard ratio (HR)/odds ratio (OR) 0.91, 99% confidence interval (CI) 0.88 to 0.95) and improving overall survival (HR 0.95, 99% CI 0.92 to 0.98). No heterogeneity was observed in the analysis based on primary outcomes or overall survival (I(2) = 0%). Kernel density analysis was consistent with the meta-analysis, but showed a fairly symmetrical distribution of new versus established treatments indicating unpredictability in the results. This was consistent with the interpretation that new treatments are only slightly superior to established treatments when tested in RCTs. Additionally, meta-regression demonstrated that results have remained stable over time and that the success rate of new treatments has not changed over the last half century of clinical trials. The results were not significantly affected by the choice of comparator (active versus placebo/no therapy).

AUTHORS' CONCLUSIONS: Society can expect that slightly more than half of new experimental treatments will prove to be better than established treatments when tested in RCTs, but few will be substantially better. This is an important finding for patients (as they contemplate participation in RCTs), researchers (as they plan design of the new trials), and funders (as they assess the 'return on investment'). Although we provide the current best evidence on the question of expected 'success rate' of new versus established treatments consistent with a priori theoretical predictions reflective of 'uncertainty or equipoise hypothesis', it should be noted that our sample represents less than 1% of all available randomized trials; therefore, one should exercise the appropriate caution in interpretation of our findings. In addition, our conclusion applies to publicly funded trials only, as we did not include studies funded by commercial sponsors in our analysis.

OBJECTIVES: To assess whether the reported methodological quality of randomized controlled trials (RCTs) reflects the actual methodological quality and to evaluate the association of effect size (ES) and sample size with methodological quality.

STUDY DESIGN AND SETTING: Systematic review. This is a retrospective analysis of all consecutive phase III RCTs published by eight National Cancer Institute Cooperative Groups up to 2006. Data were extracted from protocols (actual quality) and publications (reported quality) for each study.

RESULTS: Four hundred twenty-nine RCTs met the inclusion criteria. Overall reporting of methodological quality was poor and did not reflect the actual high methodological quality of RCTs. The results showed no association between sample size and actual methodological quality of a trial. Poor reporting of allocation concealment and blinding exaggerated the ES by 6% (ratio of hazard ratio [RHR]: 0.94; 95% confidence interval [CI]: 0.88, 0.99) and 24% (RHR: 1.24; 95% CI: 1.05, 1.43), respectively. However, actual quality assessment showed no association between ES and methodological quality.

CONCLUSION: The largest study to date shows that poor quality of reporting does not reflect the actual high methodological quality. Assessment of the impact of quality on the ES based on reported quality can produce misleading results.

Centrosomes are central regulators of mitosis that are often amplified in cancer cells. Centrosomal protein of 63kDa (CEP63) is a centrosomal protein that has an effective role in mitotic spindle assembly and cell cycle regulation. Genetic alterations in CEP63 coding gene has been widely studied for inducing aneuploidy and solid tumors in humans. The nonsynonymous single nucleotide polymorphisms (nsSNPs) are a genetic variant resulting in amino acid substitution and are reported in a wide range of human diseases. Here we report one new SNP (rs112926188) in a CEP63 coding region that can potentially disrupt the structure and basic functionality of a CEP63 protein. We used extensive functional and structural level analyses of an available SNP in a CEP63 coding gene. Furthermore the disease-association analysis was carried out to examine the possible pathogenic variant among the available dataset. To understand atomic arrangement in 3D space, native and pathogenic mutant structures were modeled. Molecular dynamics simulations were performed to understand structural consequences of prioritized deleterious mutation. Our analysis showed that rs112926188 allele substituting proline at the 61st residue position (L61P) produced more flexibility in 3D space. Moreover the flexible nature of mutant L61P was validated by a hydrogen bond network. This nature of mutant L61P CEP63 may restrict the recruitment of essential centrosomal proteins to their respective location and may play an active role in inducing aneuploidy.

The importance of randomized controlled trials (RCTs) versus observational studies has been debated for several years. However, the question is not whether RCTs are better than observational study designs. RCTs certainly provide the most unbiased answers in scenarios where it is logistically and ethically feasible to conduct both RCTs and observational studies. That is, study design is not a choice but a function of matching the research question to provide the most unbiased answers. The basic concept that underpins every clinical research project is the requirement of a clearly defined research question domain. Broadly, the clinical research question domain relates to prognosis, diagnostic accuracy, treatment or adverse events. While RCTs provide the most unbiased answers on questions related to the efficacy of treatments, other designs are better suited to answer questions related to prognosis or diagnostic accuracy of tests. In this paper, we illustrate the significance of matching study design to the research question domain while using clinical scenarios as an example. Although there are several other question domains that also concern the practice of medicine, we are only focusing on study designs concerning the issue of prognosis and diagnostic accuracy in this paper.

Individuals carrying deleterious germline mutations placing them at increased risk for hereditary cancer syndromes (high-risk consumers) often have a great deal of fear and concern over transmitting mutations to their offspring, particularly conditions which are autosomal dominant. Preimplantation genetic diagnosis (PGD) is a procedure that can detect certain germline cancer predisposing mutations present in embryos. The objective of this review was to assess high-risk consumers' knowledge and perceptions of PGD for hereditary cancers. A systematic literature review was conducted through PubMed, Wiley Interscience, PsychInfo, and Cochrane Library databases to identify all articles assessing consumer knowledge and attitudes of PGD for hereditary cancer syndromes. We assessed heterogeneity and the robustness of findings through additional analyses according to study location, hereditary cancer type, and sample size. Thirteen articles remained eligible after the application of specific criteria. Results show a general low level of knowledge about PGD for hereditary cancers, moderate rates of acceptability among high-risk groups, and high levels of need for information about PGD. Individuals in specific risk groups such as those with a personal or family history of hereditary breast and ovarian cancer (HBOC) syndrome or familial adenomatous polyposis (FAP) may benefit from educational information from healthcare professionals about the use of PGD.

BACKGROUND: Bisphosphonates are specific inhibitors of osteoclastic activity and used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010.

OBJECTIVES: To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus nonamino bisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression-free survival (PFS), and decreases skeletal-related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw and hypocalcemia.

SEARCH METHODS: We searched MEDLINE, LILACS, EMBASE (December 2009 to October 2011) and the Cochrane Controlled Trials Register (all years, latest Issue September 2011) to identify all randomized trials in MM up to October 2011 using a combination of text and MeSH terms. We also handsearched relevant meeting proceedings (December 2009 to October 2011).

SELECTION CRITERIA: Any randomized controlled trial (RCT) assessing the role of bisphosphonates and observational studies or case reports examining bisphosphonate-related osteonecrosis of the jaw in patients with MM were eligible for inclusion.

DATA COLLECTION AND ANALYSIS: Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) under a random-effects model. Statistical heterogeneity was explored using metaregression.

MAIN RESULTS: In this update, we included 2 studies (2464 patients) that were not part of our last Cochrane review published in 2010. In this review we included 16 RCTs comparing bisphosphonates with either placebo or no treatment and 4 RCTs with a different bisphosphonate as a comparator. The 20 included RCTs enrolled 6692 patients. Overall methodological quality of reporting was moderate. Thirty per cent (6/20) of trials reported the method of generating the randomization sequence. Forty per cent (8/20) of trials had adequate allocation concealment. Withdrawals and dropouts were described in 60% (12/20) of trials. Pooled results showed no direct effect of bisphosphonates on OS compared with placebo or no treatment (HR 0.96, 95% CI 0.82 to 1.13; P = 0.64). However, there was a statistically significant heterogeneity among the included RCTs (I(2) = 55%, P = 0.01) for OS. To explain this heterogeneity we performed a metaregression assessing the relationship between bisphosphonate potency and improvement in OS, which found indicating an OS benefit with zoledronate (P = 0.058). This provided a further rationale for performing network meta-analyses of the various types of bisphosphonates that were not compared head to head in RCTs. Results from network meta-analyses showed superior OS with zoledronate compared with etidronate (HR 0.43, 95% CI 0.16 to 0.86) and placebo (HR 0.61, 95% CI 0.28 to 0.98). However, there was no difference between zoledronate and other bisphosphonates. Pooled analysis did not demonstrate a beneficial effect of bisphosphonates compared with placebo or no treatment in improving PFS (HR 0.70, 95% CI 0.41 to 1.19; P = 0.18) There was no heterogeneity among trials reporting PFS estimates (I(2) = 35%, P = 0.20).Pooled analysis demonstrated a beneficial effect of bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; I(2) = 7%), skeletal-related events (SRE) (RR 0.80, 95% CI 0.72 to 0.89; I(2) = 2%) and amelioration of pain (RR 0.75, 95% CI 0.60 to 0.95; I(2) = 63%). The network meta-analysis did not show any difference in the incidence of osteonecrosis of the jaw (5 RCTs, 3198 patients) between bisphosphonates. Rates of osteonecrosis of the jaw in observational studies (9 studies, 1400 patients) ranged from 0% to 51%. The pooled results (6 RCTs, 1689 patients) showed no statistically significant increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.60; P = 0.11).The pooled results (3 RCTs, 1002 patients) showed no statistically significant increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74). The network meta-analysis did not show any differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used.

AUTHORS' CONCLUSIONS: Use of bisphosphonates in patients with MM reduces pathological vertebral fractures, SREs and pain. Assuming a baseline risk of 20% to 50% for vertebral fracture without treatment, between 8 and 20 MM patients should be treated to prevent vertebral fracture(s) in one patient. Assuming a baseline risk of 31% to 76% for pain amelioration without treatment, between 5 and 13 MM patients should be treated to reduce pain in one patient. With a baseline risk of 35% to 86% for SREs without treatment, between 6 and 15 MM patients should be treated to prevent SRE(s) in one patient. Overall, there were no significant adverse effects associated with the administration of bisphosphonates identified in the included RCTs. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or nonaminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate appears to be superior to placebo and etidronate in improving OS.

BACKGROUND: The proportion of proposed new treatments that are 'successful' is of ethical, scientific, and public importance. We investigated how often new, experimental treatments evaluated in randomized controlled trials (RCTs) are superior to established treatments.

OBJECTIVES: Our main question was: "On average how often are new treatments more effective, equally effective or less effective than established treatments?" Additionally, we wanted to explain the observed results, i.e. whether the observed distribution of outcomes is consistent with the 'uncertainty requirement' for enrollment in RCTs. We also investigated the effect of choice of comparator (active versus no treatment/placebo) on the observed results.

SEARCH METHODS: We searched the Cochrane Methodology Register (CMR) 2010, Issue 1 in The Cochrane Library (searched 31 March 2010); MEDLINE Ovid 1950 to March Week 2 2010 (searched 24 March 2010); and EMBASE Ovid 1980 to 2010 Week 11 (searched 24 March 2010).

SELECTION CRITERIA: Cohorts of studies were eligible for the analysis if they met all of the following criteria: (i) consecutive series of RCTs, (ii) registered at or before study onset, and (iii) compared new against established treatments in humans.

DATA COLLECTION AND ANALYSIS: RCTs from four cohorts of RCTs met all inclusion criteria and provided data from 743 RCTs involving 297,744 patients. All four cohorts consisted of publicly funded trials. Two cohorts involved evaluations of new treatments in cancer, one in neurological disorders, and one for mixed types of diseases. We employed kernel density estimation, meta-analysis and meta-regression to assess the probability of new treatments being superior to established treatments in their effect on primary outcomes and overall survival.

MAIN RESULTS: The distribution of effects seen was generally symmetrical in the size of difference between new versus established treatments. Meta-analytic pooling indicated that, on average, new treatments were slightly more favorable both in terms of their effect on reducing the primary outcomes (hazard ratio (HR)/odds ratio (OR) 0.91, 99% confidence interval (CI) 0.88 to 0.95) and improving overall survival (HR 0.95, 99% CI 0.92 to 0.98). No heterogeneity was observed in the analysis based on primary outcomes or overall survival (I(2) = 0%). Kernel density analysis was consistent with the meta-analysis, but showed a fairly symmetrical distribution of new versus established treatments indicating unpredictability in the results. This was consistent with the interpretation that new treatments are only slightly superior to established treatments when tested in RCTs. Additionally, meta-regression demonstrated that results have remained stable over time and that the success rate of new treatments has not changed over the last half century of clinical trials. The results were not significantly affected by the choice of comparator (active versus placebo/no therapy).

AUTHORS' CONCLUSIONS: Society can expect that slightly more than half of new experimental treatments will prove to be better than established treatments when tested in RCTs, but few will be substantially better. This is an important finding for patients (as they contemplate participation in RCTs), researchers (as they plan design of the new trials), and funders (as they assess the 'return on investment'). Although we provide the current best evidence on the question of expected 'success rate' of new versus established treatments consistent with a priori theoretical predictions reflective of 'uncertainty or equipoise hypothesis', it should be noted that our sample represents less than 1% of all available randomized trials; therefore, one should exercise the appropriate caution in interpretation of our findings. In addition, our conclusion applies to publicly funded trials only, as we did not include studies funded by commercial sponsors in our analysis.

This paper presents a Rough Set Theory (RST) based classification model to identify hospice candidates within a group of terminally ill patients. Hospice care considerations are particularly valuable for terminally ill patients since they enable patients and their families to initiate end-of-life discussions and choose the most desired management strategy for the remainder of their lives. Unlike traditional data mining methodologies, our approach seeks to identify subgroups of patients possessing common characteristics that distinguish them from other subgroups in the dataset. Thus, heterogeneity in the data set is captured before the classification model is built. Object related reducts are used to obtain the minimum set of attributes that describe each subgroup existing in the dataset. As a result, a collection of decision rules is derived for classifying new patients based on the subgroup to which they belong. Results show improvements in the classification accuracy compared to a traditional RST methodology, in which patient diversity is not considered. We envision our work as a part of a comprehensive decision support system designed to facilitate end-of-life care decisions. Retrospective data from 9105 patients is used to demonstrate the design and implementation details of the classification model.

BACKGROUND: Dual processing theory of human cognition postulates that reasoning and decision-making can be described as a function of both an intuitive, experiential, affective system (system I) and/or an analytical, deliberative (system II) processing system. To date no formal descriptive model of medical decision-making based on dual processing theory has been developed. Here we postulate such a model and apply it to a common clinical situation: whether treatment should be administered to the patient who may or may not have a disease.

METHODS: We developed a mathematical model in which we linked a recently proposed descriptive psychological model of cognition with the threshold model of medical decision-making and show how this approach can be used to better understand decision-making at the bedside and explain the widespread variation in treatments observed in clinical practice.

RESULTS: We show that physician's beliefs about whether to treat at higher (lower) probability levels compared to the prescriptive therapeutic thresholds obtained via system II processing is moderated by system I and the ratio of benefit and harms as evaluated by both system I and II. Under some conditions, the system I decision maker's threshold may dramatically drop below the expected utility threshold derived by system II. This can explain the overtreatment often seen in the contemporary practice. The opposite can also occur as in the situations where empirical evidence is considered unreliable, or when cognitive processes of decision-makers are biased through recent experience: the threshold will increase relative to the normative threshold value derived via system II using expected utility threshold. This inclination for the higher diagnostic certainty may, in turn, explain undertreatment that is also documented in the current medical practice.

CONCLUSIONS: We have developed the first dual processing model of medical decision-making that has potential to enrich the current medical decision-making field, which is still to the large extent dominated by expected utility theory. The model also provides a platform for reconciling two groups of competing dual processing theories (parallel competitive with default-interventionalist theories).

BACKGROUND: Intention-to-treat (ITT) is the standard data analysis method which includes all patients regardless of receiving treatment. Although the aim of ITT analysis is to prevent bias due to prognostic dissimilarity, it is also a counter-intuitive type of analysis as it counts patients who did not receive treatment, and may lead to "bias toward the null." As treated (AT) method analyzes patients according to the treatment actually received rather than intended, but is affected by the selection bias. Both ITT and AT analyses can produce biased estimates of treatment effect, so instrumental variable (IV) analysis has been proposed as a technique to control for bias when using AT data. Our objective is to correct for bias in non-experimental data from previously published individual patient data meta-analysis by applying IV methods

METHODS: Center prescribing preference was used as an IV to assess the effects of methotrexate (MTX) in preventing debilitating complications of chronic graft-versus-host-disease (cGVHD) in patients who received peripheral blood stem cell (PBSCT) or bone marrow transplant (BMT) in nine randomized controlled trials (1107 patients). IV methods are applied using 2-stage logistic, 2-stage probit and generalized method of moments models.

RESULTS: ITT analysis showed a statistically significant detrimental effect with the use of day 11 MTX, resulting in cGVHD odds ratio (OR) of 1.34 (95% CI 1.02-1.76). AT results showed no difference in the odds of cGVHD with the use of MTX [OR 1.31 (95%CI 0.99-1.73)]. IV analysis further corrected the results toward no difference in the odds of cGVHD between PBSCT vs. BMT, allowing for a possibility of beneficial effects of MTX in preventing cGVHD in PBSCT recipients (OR 1.14; 95%CI 0.83-1.56).

CONCLUSION: All instrumental variable models produce similar results. IV estimates correct for bias and do not exclude the possibility that MTX may be beneficial, contradicting the ITT analysis.