The statistical significance of randomized controlled trial results is frequently fragile: A case for a Fragility Index

Objectives

A P-value <0.05 is one metric used to evaluate the results of a randomized controlled trial (RCT). We wondered how often statistically significant results in RCTs may be lost with small changes in the numbers of outcomes.

Study Design and Setting

A review of RCTs in high-impact medical journals that reported a statistically significant result for at least one dichotomous or time-to-event outcome in the abstract. In the group with the smallest number of events, we changed the status of patients without an event to an event until the P-value exceeded 0.05. We labeled this number the Fragility Index; smaller numbers indicated a more fragile result.

Results

The 399 eligible trials had a median sample size of 682 patients (range: 15-112,604) and a median of 112 events (range: 8-5,142); 53% reported a P-value <0.01. The median Fragility Index was 8 (range: 0-109); 25% had a Fragility Index of 3 or less. In 53% of trials, the Fragility Index was less than the number of patients lost to follow-up.

Conclusion

The statistically significant results of many RCTs hinge on small numbers of events. The Fragility Index complements the P-value and helps identify less robust results. 

Optical Coherence Tomography for the Monitoring of Neovascular Age-Related Macular Degeneration: A Systematic Review

Topic

To compare the accuracy of optical coherence tomography (OCT) with alternative tests for monitoring neovascular age-related macular degeneration (nAMD) and detecting disease activity among eyes previously treated for this condition.

Traditionally, fundus fluorescein angiography (FFA) has been considered the reference standard to detect nAMD activity, but FFA is costly and invasive. Replacement of FFA by OCT can be justified if there is a substantial agreement between tests.

Systematic review and meta-analysis. The index test was OCT. The comparator tests were visual acuity, clinical evaluation (slit lamp), Amsler chart, color fundus photographs, infrared reflectance, red-free images and blue reflectance, fundus autofluorescence imaging, indocyanine green angiography (ICGA), preferential hyperacuity perimetry, and microperimetry. We searched the following databases: MEDLINE, MEDLINE In-Process, EMBASE, Biosis, Science Citation Index, the Cochrane Library, Database of Abstracts of Reviews of Effects, MEDION, and the Health Technology Assessment database. The last literature search was conducted in March 2013. We used the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) to assess risk of bias.

We included 8 studies involving more than 400 participants. Seven reported the performance of OCT (3 time-domain [TD] OCT, 3 spectral-domain [SD] OCT, 1 both types) and 1 reported the performance of ICGA in the detection of nAMD activity. We did not find studies directly comparing tests in the same population. The pooled sensitivity and specificity of TD OCT and SD OCT for detecting active nAMD was 85% (95% confidence interval [CI], 72%–93%) and 48% (95% CI, 30%–67%), respectively. One study reported ICGA with sensitivity of 75.9% and specificity of 88.0% for the detection of active nAMD. Half of the studies were considered to have a high risk of bias.

There is substantial disagreement between OCT and FFA findings in detecting active disease in patients with nAMD who are being monitored. Both methods may be needed to monitor patients comprehensively with nAMD.

From Beijing with love: The global dimension of Bertolucci’s The Last Emperor

Famous for being the first foreign feature film that obtained permission to shoot in the Forbidden City, The Last Emperor (1987) is also one of the most ambitious and expensive independent productions of its time, awarded four Golden Globes and nine Academy Awards, including Best Picture. In addition, The Last Emperor can be considered as one of the first attempts of cinematic collaboration between West and East, in a period of cultural and economic transformations witnessed by China. This article aims to offer an overview of the production history of The Last Emperor, focusing on the co-production collaborations and the outcomes of a western auteur’s gaze on Chinese history. Questions of Orientalism, travel narrative and critical reception are taken into account in order to engage with the transnational implications of Bertolucci’s film and the western fascination with China.

The host galaxy and late-time evolution of the superluminous supernova PTF12dam

Superluminous supernovae (SLSNe) of Type Ic have a tendency to occur in faint host galaxies which are likely to have low mass and low metallicity. PTF12dam is one of the closest and best-studied superluminous explosions that has a broad and slowly fading light curve similar to SN 2007bi. Here we present new photometry and spectroscopy for PTF12dam from 200-500 d (rest frame) after peak and a detailed analysis of the host galaxy (SDSS J142446.21+461348.6 at z = 0.107). Using deep templates and image subtraction we show that the light curve can be fit with a magnetar model if escape of high-energy gamma rays is taken into account. The full bolometric light curve from -53 to +399 d (with respect to peak) cannot be fit satisfactorily with the pair-instability models. An alternative model of interaction with a dense circumstellar material (CSM) produces a good fit to the data although this requires a very large mass (˜13 M⊙) of hydrogen-free CSM. The host galaxy is a compact dwarf (physical size ˜1.9 kpc) and with Mg = -19.33 ± 0.10, it is the brightest nearby SLSN Ic host discovered so far. The host is a low-mass system (2.8 × 108 M⊙) with a star formation rate (5.0 M⊙ yr-1), which implies a very high specific star formation rate (17.9 Gyr-1). The remarkably strong nebular emission provide detections of the [O III] λ4363 and [O II] λλ7320, 7330auroral lines and an accurate oxygen abundance of 12 + log (O/H) = 8.05 ± 0.09. We show here that they are at the extreme end of the metallicity distribution of dwarf galaxies and propose that low metallicity is a requirement to produce these rare and peculiar SNe.

Stability in a Network Economy: The Role of Institutions

We consider an economy in which agents are embedded in a network of potential value-generating relationships. Agents are assumed to be able to participate in three types of economic interactions: Autarkic self-provision; bilateral interaction; and multilateral collaboration through endogenously provided platforms.
We introduce two stability concepts and provide sufficient and necessary conditions on the network structure that guarantee existence, in cases of the absence of externalities, link-based externalities and crowding externalities. We show that institutional arrangements based on socioeconomic roles and leadership guarantee stability. In particular, the stability of more complex economic outcomes requires more strict and complex institutional rules to govern economic interactions. We investigate strict social hierarchies, tiered leadership structures and global market places.

Knowledge Transfer in Quadruple Helix Ecosystems: An Absorptive Capacity Perspective

Increased understanding of knowledge transfer (KT) from universities to the wider regional knowledge ecosystem offers opportunities for increased regional innovation and commercialisation. The aim of this article is to improve the understanding of the KT phenomena in an open innovation context where multiple diverse quadruple helix stakeholders are interacting. An absorptive capacity-based conceptual framework is proposed, using a priori constructs which portrays the multidimensional process of KT between universities and its constituent stakeholders in pursuit of open innovation and commercialisation. Given the lack of overarching theory in the field, an exploratory, inductive theory building methodology was adopted using semi-structured interviews, document analysis and longitudinal observation data over a three-year period. The findings identify five factors, namely human centric factors, organisational factors, knowledge characteristics, power relationships and network characteristics, which mediate both the ability of stakeholders to engage in KT and the effectiveness of knowledge acquisition, assimilation, transformation and exploitation. This research has implications for policy makers and practitioners by identifying the need to implement interventions to overcome the barriers to KT effectiveness between regional quadruple helix stakeholders within an open innovation ecosystem.

The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer

BACKGROUND: Lapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination.

PATIENTS AND METHODS: DNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; clinicaltrials.gov) and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher's exact test, Kaplan-Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate.

RESULTS: There were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92).

CONCLUSION: Our findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.

Entity Linking for Web Search Queries

We consider the problem of linking web search queries to entities from a knowledge base such as Wikipedia. Such linking enables converting a user’s web search session to a footprint in the knowledge base that could be used to enrich the user profile. Traditional methods for entity linking have been directed towards finding entity mentions in text documents such as news reports, each of which are possibly linked to multiple entities enabling the usage of measures like entity set coherence. Since web search queries are very small text fragments, such criteria that rely on existence of a multitude of mentions do not work too well on them. We propose a three-phase method for linking web search queries to wikipedia entities. The first phase does IR-style scoring of entities against the search query to narrow down to a subset of entities that are expanded using hyperlink information in the second phase to a larger set. Lastly, we use a graph traversal approach to identify the top entities to link the query to. Through an empirical evaluation on real-world web search queries, we illustrate that our methods significantly enhance the linking accuracy over state-of-the-art methods.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.

METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).

FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.

INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.

FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

A comparison of theoretical Mg VI emission line strengths with active-region observations from SERTS

R-matrix calculations of electron impact excitation rates in N-like Mg VI are used to derive theoretical electron-density-sensitive emission line ratios involving 2s²2p³ - 2s2p⁴ transitions in the 269-403 Å wavelength range. A comparison of these with observations of a solar active region, obtained during the 1989 flight of the Solar EUV Rocket Telescope and Spectrograph (SERTS), reveals good agreement between theory and observation for the 2s²2p^{3 4}S - 2s2p ^{4 4}p transitions at 399.28, 400.67, and 403.30 Å, and the 2s²2p^{3 2}p - 2s2p^{4 2}D lines at 387.77 and 387.97 Å. However, intensities for the other lines attributed to Mg VI in this spectrum by various authors do not match the present theoretical predictions. We argue that these discrepancies are not due to errors in the adopted atomic data, as previously suggested, but rather to observational uncertainties or mis-identifications. Some of the features previously identified as Mg VI lines in the SERTS spectrum, such as 291.36 and 293.15 Å, are judged to be noise, while others (including 349.16 Å) appear to be blended.