Whose data set is it anyway? Sharing raw data from randomized trials

BACKGROUND: Sharing of raw research data is common in many areas of medical research, genomics being perhaps the most well-known example. In the clinical trial community investigators routinely refuse to share raw data from a randomized trial without giving a reason. DISCUSSION: Data sharing benefits numerous research-related activities: reproducing analyses; testing secondary hypotheses; developing and evaluating novel statistical methods; teaching; aiding design of future trials; meta-analysis; and, possibly, preventing error, fraud and selective reporting. Clinical trialists, however, sometimes appear overly concerned with being scooped and with misrepresentation of their work. Both possibilities can be avoided with simple measures such as inclusion of the original trialists as co-authors on any publication resulting from data sharing. Moreover, if we treat any data set as belonging to the patients who comprise it, rather than the investigators, such concerns fall away. CONCLUSION: Technological developments, particularly the Internet, have made data sharing generally a trivial logistical problem. Data sharing should come to be seen as an inherent part of conducting a randomized trial, similar to the way in which we consider ethical review and publication of study results. Journals and funding bodies should insist that trialists make raw data available, for example, by publishing data on the Web. If the clinical trial community continues to fail with respect to data sharing, we will only strengthen the public perception that we do clinical trials to benefit ourselves, not our patients

Asteroid mega-impacts and Precambrian banded iron formations: 2.63 Ga and 2.56 Ga impact ejecta/fallout at the base of BIF/argillite units, Hamersley Basin, Pilbara Craton, Western Australia

The temporal association between late Archaean to earliest Proterozoic asteroid impact ejecta/fallout units and overlying banded iron formations suggests that, in some instances, these impacts were closely followed by significant transformation in the nature of source terrains of the sediments. The Jeerinah Impact Layer (JIL) [B.M. Simonson, D. Davies, S.W. Hassler, Discovery of a layer of probable impact melt spherules in the late Archean Jeerinah Formation, Fortescue Group, Western Australia. Aust. J. Earth Sci. 47 (2000) 315-325; B.M. Simonson, S.W. Hassler, Revised correlations in the early Precambrian Hamersley Basin based on a horizon of resedimented impact spherules. Aust. J. Earth Sci. 44 (1997) 37-48; B.M. Simonson, B.P. Glass, Spherule layers - records of ancient impacts. Ann. Rev. Earth Planet. Sci. 32 (2004) 329-361; A.Y. Glikson, Early Precambrian asteroid impact-triggered tsunami: excavated seabed, debris flows, exotic boulders, and turbulence features associated with 3.47-2.47 Ga-old asteroid impact fallout units, Pilbara Craton, Western Australia. Astrobiology 4 (2001) 19-50; S.W. Hassler, B.M. Simonson, D.Y. Sumner, D. Murphy, Neoarchaean impact spherule layers in the Fortescue and Hamersley Groups, Western Australia: stratigraphic and depositional implications of re-correlation. Aust. J. Earth Sci. 52 (2005) 759-772; B. Rasmussen, C. Koeberl, Iridium anomalies and shocked quartz in a late Archean spherule layer from the Pilbara Craton: new evidence for a major asteroid impact at 2.63 Ga. Geology 32 (2004) 1029-1032; B. Rasmussen, T.S. Blake, I.R. Fletcher, U-Pb zircon age constraints on the Hamersley spherule beds: Evidence for a single 2.63 Ga Jeerinah-Carawine impact ejecta layer. Geology, 33 (2005) 725-728.] overlies an argillite-dominated unit (Jeerinah Formation, 2684 ± 6 Ma [A.F. Trendall, W. Compston, D.R. Nelson, J.R. deLaeter, V.C. Bennett, SHRIMP zircon ages constraining the depositional chronology of the Hamersley Group, Western Australia. Aust. J. Earth Sci. 51 (2004) 621-644.]) and lies directly below a thin volcanic tuff (2629 ± 5 Ma, [A.F. Trendall, W. Compston, D.R. Nelson, J.R. deLaeter, V.C. Bennett, SHRIMP zircon ages constraining the depositional chronology of the Hamersley Group, Western Australia. Aust. J. Earth Sci. 51 (2004) 621-644.]) and banded iron formation (BIF) (upper part of Marra Mamba Iron Formation, 2597 ± 5 Ma [A.F. Trendall, W. Compston, D.R. Nelson, J.R. deLaeter, V.C. Bennett, SHRIMP zircon ages constraining the depositional chronology of the Hamersley Group, Western Australia. Aust. J. Earth Sci. 51 (2004) 621-644.]). The Spherule Marker Bed (SMB) [B.M. Simonson, Geological evidence for an early Precambrian microtektite strewn field in the Hamersley Basin of Western Australia. Geol. Soc. Am. Bull. 104 (1992) 829-839; B.M. Simonson, S.W. Hassler, K.A. Schubel, Lithology and proposed revisions in stratigraphic nomenclature of the Wittenoom Formation (Dolomite) and overlying formations, Hamersley Group, Western Australia. Geol. Surv. W. Aust. Rep. 345 (1993) 65-79; S.W. Hassler, B.M. Simonson, D.Y. Sumner, D. Murphy, Neoarchaean impact spherule layers in the Fortescue and Hamersley Groups, Western Australia: stratigraphic and depositional implications of re-correlation. Aust. J. Earth Sci. 52 (2005) 759-772. [5]], which includes two impact cycles [A.Y. Glikson, Early Precambrian asteroid impact-triggered tsunami: excavated seabed, debris flows, exotic boulders, and turbulence features associated with 3.47-2.47 Ga-old asteroid impact fallout units, Pilbara Craton, Western Australia. Astrobiology 4 (2001) 19-50.], is located at the top of a carbonate/calcareous siltstone-dominated sequence (Bee Gorge Member, Wittenoom Formation, 2565 ± 9 Ma [A.F. Trendall, W. Compston, D.R. Nelson, J.R. deLaeter, V.C. Bennett, SHRIMP zircon ages constraining the depositional chronology of the Hamersley Group, Western Australia. Aust. J. Earth Sci. 51 (2004) 621-644.]) and below a carbonate-poor siltstone-chert-BIF sequence (Mount Sylvia Formation, Bruno's Band [BIF], Mount McRae Shale, 2504 ± 5 Ma [B. Rasmussen, T.S. Blake, I.R. Fletcher, U-Pb zircon age constraints on the Hamersley spherule beds: Evidence for a single 2.63 Ga Jeerinah-Carawine impact ejecta layer. Geology, 33 (2005) 725-728.]). No ferruginous sediments overlie impact layers hosted by stromatolitic carbonates (< 2.63 Ga microkrystite spherule-bearing Carawine mega-breccia, east Hamersley Basin; ∼ 2.6-2.65 Ga Monteville impact layer; 2567 Ma Reivilo Formation, west Griqualand Basin, Transvaal) - a lack possibly attributable to enclosed oxygenated high-pH reef environment. Barring a possible presence of undocumented hiatuses between the impact layers and directly overlying units, and within the accuracy limits of U-Pb zircon age data, it follows that the JIL and SMB mega-impacts were succeeded by enhanced supply of ferruginous and clastic materials. The location of 5 out of 8 Archaean to earliest Proterozoic impact fallout/ejecta units below iron-rich sediments [A.Y. Glikson, Asteroid impact ejecta units overlain by iron-rich sediments in 3.5-2.4 Ga terrains, Pilbara and Kaapvaal cratons: Accidental or cause-effect relationships? Earth Planet. Sci. Lett. 246 (2006) 149-160.], including 3.47 Ga, 3.26 Ga, 3.24 Ga, 2.63 Ga and 2.56 Ga units, unless accidental, suggests enrichment of sea water in soluble ferrous iron, possibly derived from impact-triggered mafic volcanic and hydrothermal activity. The scarcity of shocked quartz grains in the ejecta suggests impacts occurred in oceanic regions of the late Archaean Earth [A.Y. Glikson, Early Precambrian asteroid impact-triggered tsunami: excavated seabed, debris flows, exotic boulders, and turbulence features associated with 3.47-2.47 Ga-old asteroid impact fallout units, Pilbara Craton, Western Australia. Astrobiology 4 (2001) 19-50; A.Y. Glikson, Oceanic mega-impacts and crustal evolution, Geology 27 (1999) 341-387; B.M. Simonson, D. Davies, M. Wallace, S. Reeves, S.W. Hassler, Iridium anomaly but no shocked quartz from late Archean microkrystite layer: oceanic impact ejecta? Geology 26 (1998) 195-198.]. Should further examples of sedimentary facies changes associated with large impact events be identified, the impact factor will need to be taken into account in accounting for the crustal transformations during the transition from the end-Archaean to the earliest Proterozoic

Empirical Study of Data Sharing by Authors Publishing in PLoS Journals

Many journals now require authors share their data with other investigators, either by depositing the data in a public repository or making it freely available upon request. These policies are explicit, but remain largely untested. We sought to determine how well authors comply with such policies by requesting data from authors who had published in one of two journals with clear data sharing policies.We requested data from ten investigators who had published in either PLoS Medicine or PLoS Clinical Trials. All responses were carefully documented. In the event that we were refused data, we reminded authors of the journal's data sharing guidelines. If we did not receive a response to our initial request, a second request was made. Following the ten requests for raw data, three investigators did not respond, four authors responded and refused to share their data, two email addresses were no longer valid, and one author requested further details. A reminder of PLoS's explicit requirement that authors share data did not change the reply from the four authors who initially refused. Only one author sent an original data set.We received only one of ten raw data sets requested. This suggests that journal policies requiring data sharing do not lead to authors making their data sets available to independent investigators

Data and programming code from the studies on the learning curve for radical prostatectomy

Our group analyzed a multi-institutional data set to address the question of how the outcomes of surgery for prostate cancer are affected by surgeon-specific factors. The cohort consists of 9076 patients treated by open radical prostatectomy at one of four US academic institutions 1987 - 2003. The primary analyses focused on 7765 patients without neoadjuvant therapy. The most well-known finding is that of a surgical "learning curve", with rates of prostate cancer cure strongly dependent on surgeon experience. In this "data note", we provide the raw data set, as well as well-annotated programming code for the main analyses. Data include markers of cancer severity (stage, grade and prostate-specific antigen level), cancer outcome, and surgeon variables such as training and experience

Bias Due to Changes in Specified Outcomes during the Systematic Review Process

Background Adding, omitting or changing outcomes after a systematic review protocol is published can result in bias because it increases the potential for unacknowledged or post hoc revisions of the planned analyses. The main objective of this study was to look for discrepancies between primary outcomes listed in protocols and in the subsequent completed reviews published on the Cochrane Library. A secondary objective was to quantify the risk of bias in a set of meta-analyses where discrepancies between outcome specifications in protocols and reviews were found. Methods and Findings New reviews from three consecutive issues of the Cochrane Library were assessed. For each review, the primary outcome(s) listed in the review protocol and the review itself were identified and review authors were contacted to provide reasons for any discrepancies. Over a fifth (64/288, 22%) of protocol/review pairings were found to contain a discrepancy in at least one outcome measure, of which 48 (75%) were attributable to changes in the primary outcome measure. Where lead authors could recall a reason for the discrepancy in the primary outcome, there was found to be potential bias in nearly a third (8/28, 29%) of these reviews, with changes being made after knowledge of the results from individual trials. Only 4(6%) of the 64 reviews with an outcome discrepancy described the reason for the change in the review, with no acknowledgment of the change in any of the eight reviews containing potentially biased discrepancies. Outcomes that were promoted in the review were more likely to be significant than if there was no discrepancy (relative risk 1.66 95% CI (1.10, 2.49), p = 0.02). Conclusion In a review, making changes after seeing the results for included studies can lead to biased and misleading interpretation if the importance of the outcome (primary or secondary) is changed on the basis of those results. Our assessment showed that reasons for discrepancies with the protocol are not reported in the review, demonstrating an under-recognition of the problem. Complete transparency in the reporting of changes in outcome specification is vital; systematic reviewers should ensure that any legitimate changes to outcome specification are reported with reason in the review

Decision Curve Analysis for Personalized Treatment Choice between Multiple Options.

BACKGROUND Decision curve analysis can be used to determine whether a personalized model for treatment benefit would lead to better clinical decisions. Decision curve analysis methods have been described to estimate treatment benefit using data from a single randomized controlled trial. OBJECTIVES Our main objective is to extend the decision curve analysis methodology to the scenario in which several treatment options exist and evidence about their effects comes from a set of trials, synthesized using network meta-analysis (NMA). METHODS We describe the steps needed to estimate the net benefit of a prediction model using evidence from studies synthesized in an NMA. We show how to compare personalized versus one-size-fit-all treatment decision-making strategies, such as "treat none" or "treat all patients with a specific treatment" strategies. First, threshold values for each included treatment need to be defined (i.e., the minimum risk difference compared with control that renders a treatment worth taking). The net benefit per strategy can then be plotted for a plausible range of threshold values to reveal the most clinically useful strategy. We applied our methodology to an NMA prediction model for relapsing-remitting multiple sclerosis, which can be used to choose between natalizumab, dimethyl fumarate, glatiramer acetate, and placebo. RESULTS We illustrated the extended decision curve analysis methodology using several threshold value combinations for each available treatment. For the examined threshold values, the "treat patients according to the prediction model" strategy performs either better than or close to the one-size-fit-all treatment strategies. However, even small differences may be important in clinical decision making. As the advantage of the personalized model was not consistent across all thresholds, improving the existing model (by including, for example, predictors that will increase discrimination) is needed before advocating its clinical usefulness. CONCLUSIONS This novel extension of decision curve analysis can be applied to NMA-based prediction models to evaluate their use to aid treatment decision making. HIGHLIGHTS Decision curve analysis is extended into a (network) meta-analysis framework.Personalized models predicting treatment benefit are evaluated when several treatment options are available and evidence about their effects comes from a set of trials.Detailed steps to compare personalized versus one-size-fit-all treatment decision-making strategies are outlined.This extension of decision curve analysis can be applied to (network) meta-analysis-based prediction models to evaluate their use to aid treatment decision making

Acupuncture is a feasible treatment for post-thoracotomy pain: results of a prospective pilot trial

BACKGROUND: Thoracotomy is associated with severe pain that may persist for years. Acupuncture is a complementary therapy with a proven role in pain control. A randomized trial showed that acupuncture was effective in controlling pain after abdominal surgery, but the efficacy of this technique for the treatment of thoracotomy pain has not been established. We developed a novel technique for convenient application of acupuncture to patients undergoing thoracotomy, and in a Phase II trial evaluated the safety of this intervention and the feasibility of doing a randomized trial. METHODS: Adult patients scheduled for unilateral thoracotomy with preoperative epidural catheter placement received acupuncture immediately prior to surgery. Eighteen semi-permanent intradermal needles were inserted on either side of the spine, and four were inserted in the legs and auricles. Needles were removed after four weeks. Using a numerical rating scale, pain was measured on the first five postoperative days. After discharge, pain was assessed using the Brief Pain Inventory at 7, 30, 60 and 90 days. RESULTS: Thirty-six patients were treated with acupuncture. Of these, 25, 23, and 22 patients provided data at 30, 60, and 90 days, respectively. The intervention was well tolerated by patients with only one minor and transient adverse event of skin ulceration. CONCLUSION: The rate of data completion met our predefined criterion for determining a randomized trial to be feasible (at least 75% of patients tolerated the intervention and provided evaluable data). This novel intervention is acceptable to patients undergoing thoracotomy and does not interfere with standard preoperative care. There was no evidence of important adverse events. We are now testing the hypothesis that acupuncture significantly adds to standard perioperative pain management in a randomized trial

Message to complementary and alternative medicine: evidence is a better friend than power

BACKGROUND: Evidence-based medicine (EBM) is being embraced by an increasing number of practitioners and advocates of complementary and alternative medicine (CAM). A significant constituency within CAM, however, appears to have substantive doubts about EBM and some are expressly hostile. DISCUSSION: Many of the arguments raised against EBM within the CAM community are based on a caricature radically at odds with established, accepted and published principles of EBM practice. Contrary to what has sometimes been argued, EBM is not cookbook medicine that ignores individual needs. Neither does EBM mandate that only proven therapies should be used. Before EBM, decisions on health care tended to be based on tradition, power and influence. Such modes usually act to the disadvantage of marginal groups. CONCLUSION: By placing CAM on an equal footing with conventional medicine - what matters for both is evidence of effectiveness - EBM provides an opportunity for CAM to find an appropriate and just place in health care

Do we want more cancer patients on clinical trials If so, what are the barriers to greater accrual

It is often stated that only a small proportion of adult cancer patients participate in clinical trials. This is said to be a bad thing, with calls for more trials to include more patients. Here I argue that whether or not greater accrual to clinical trials would be a good thing depends on the trials we conduct. The vast majority of clinical trials in cancer are currently early phase trials, and most do not lead to further studies even if they have encouraging results. The key metric is thus not the number of patients on clinical trials, but the number on the sort of large, randomized, Phase III trials that can be used as a basis for clinical decisions. I also address two important barriers to greater clinical trial participation. The first barrier is financial: clinical research has long been the poor cousin of basic research, with perhaps no more than a nickel in the cancer research dollar going to clinical research. The second barrier is regulatory: clinical research has become so overburdened by regulation that it takes years to initiate a trial, and dedicated staff just to deal with the paperwork once the trial starts. This not only adds significantly to the costs of clinical research, but scares many young investigators away. It has been estimated that nearly half of all US-sponsored trials are being conducted abroad, and it is plausible that excessive regulation is at least partly responsible. That statistic should serve as a wake-up call to the US clinical research community to implement the recommendations of the now decade-old report of National Cancer Institute Clinical Trials Program Review Group, which largely center around simplifying trials and streamlining trial procedures

A panel of kallikrein markers can predict outcome of prostate biopsy following clinical work-up: an independent validation study from the European Randomized Study of Prostate Cancer screening, France

<p>Abstract</p> <p>Background</p> <p>We have previously shown that a panel of kallikrein markers - total prostate-specific antigen (PSA), free PSA, intact PSA and human kallikrein-related peptidase 2 (hK2) - can predict the outcome of prostate biopsy in men with elevated PSA. Here we investigate the properties of our panel in men subject to clinical work-up before biopsy.</p> <p>Methods</p> <p>We applied a previously published predictive model based on the kallikrein panel to 262 men undergoing prostate biopsy following an elevated PSA (≥ 3 ng/ml) and further clinical work-up during the European Randomized Study of Prostate Cancer screening, France. The predictive accuracy of the model was compared to a "base" model of PSA, age and digital rectal exam (DRE).</p> <p>Results</p> <p>83 (32%) men had prostate cancer on biopsy of whom 45 (54%) had high grade disease (Gleason score 7 or higher). Our model had significantly higher accuracy than the base model in predicting cancer (area-under-the-curve [AUC] improved from 0.63 to 0.78) or high-grade cancer (AUC increased from 0.77 to 0.87). Using a decision rule to biopsy those with a 20% or higher risk of cancer from the model would reduce the number of biopsies by nearly half. For every 1000 men with elevated PSA and clinical indication for biopsy, the model would recommend against biopsy in 61 men with cancer, the majority (≈80%) of whom would have low stage <it>and </it>low grade disease at diagnosis.</p> <p>Conclusions</p> <p>In this independent validation study, the model was highly predictive of prostate cancer in men for whom the decision to biopsy is based on both elevated PSA and clinical work-up. Use of this model would reduce a large number of biopsies while missing few cancers.</p