Aug 13, 2013 Crossover How to Extend The Trial!! Unsubscribe from Billy Angus? How to Clean Your Mac 2019 - Duration: 16:59. Cox 1,257,674 views. Apr 13, 2012 Many clinical trials have a crossover design. Certain considerations that are relevant to the crossover design, but play no role in standard parallel-group trials, must receive adequate attention in trial planning and data analysis for the results to be of scientific value. In the simplest and most.
Why try CrossOver Mac
before you buy?
Unlike an emulator that requires a full copy of the Window OS, CrossOver translates the commands your Windows application wants to use to the macOS and back. This translation system means you don't need to spend hours setting up Windows OS first, you can just install your Windows application directly into CrossOver and run it.
But it's a big process to try and recreate all the Windows OS commands, and CrossOver isn't complete yet. Many Windows applications work great, but some might have reduced functionality, or possibly not run at all. That's why we encourage everyone to try their favorite Windows applications first in our 14-day, completely functional trial of CrossOver and see for before purchasing.
We also maintain a large Compatibility Center database of user reports, documenting how various Windows applications run in CrossOver. If your program runs under CrossOver you're good to go with the easiest, least expensive, and friendliest Windows compatibility software out there. And even if it doesn't, you've only spent a few minutes to potentially save yourself several hundred dollars and all the hassles that come with Windows.
So before you go plunking down your hard-earned money for an emulator AND a copy of Windows AND spend an entire afternoon setting it all up, give us a try!
Associated Data
Abstract
Objective
Although crossover trials enjoy wide use, standards for analysis and reporting have not been established. We reviewed methodological aspects and quality of reporting in a representative sample of published crossover trials.
Methods
We searched MEDLINE for December 2000 and identified all randomized crossover trials. We abstracted data independently, in duplicate, on 14 design criteria, 13 analysis criteria, and 14 criteria assessing the data presentation.
Results
We identified 526 randomized controlled trials, of which 116 were crossover trials. Trials were drug efficacy (48%), pharmacokinetic (28%), and nonpharmacologic (30%). The median sample size was 15 (interquartile range 8–38). Most (72%) trials used 2 treatments and had 2 periods (64%). Few trials reported allocation concealment (17%) or sequence generation (7%). Only 20% of trials reported a sample size calculation and only 31% of these considered pairing of data in the calculation. Carry-over issues were addressed in 29% of trial's methods. Most trials reported and defended a washout period (70%). Almost all trials (93%) tested for treatment effects using paired data and also presented details on by-group results (95%). Only 29% presented CIs or SE so that data could be entered into a meta-analysis.
Conclusion
Reports of crossover trials frequently omit important methodological issues in design, analysis, and presentation. Guidelines for the conduct and reporting of crossover trials might improve the conduct and reporting of studies using this important trial design.
Introduction
Because they reduce bias associated with imbalance in known and unknown confounding variables, randomized clinical trials (RCTs) represent the 'gold standard' for evaluating therapeutic effectiveness.[] Unlike the parallel group trial, crossover trials provide each participant with two or more sequential treatments in a random order usually separated by a washout period []. Within a trial, each participant is able to act as his or her own control and permits between and within group comparisons [,].
For the study of new and developmental drugs, crossover studies are extremely popular [,], particularly when the new treatment may only be a slight modification to the standard. In this case, there is likely to be a positive correlation in the responses to the new and old treatments making the crossover design ideal []. Crossover studies are most appropriate in studies where the effects of the treatment(s) are short-lived and reversible and are best suited to trials related to symptomatic but chronic conditions or diseases [,]. It is generally agreed that the crossover design should not be used when the condition of interest is unstable and may change regardless of interventions []. In spite of criticism [], however, the crossover design appears to be used commonly in inappropriate circumstances [,].
Despite their popularity, little is known about the quality or prevalence of randomized crossover trials. We aimed to review key methodological issues in the reporting of these trials in a representative sample of published trials.
Methods
Study cohort
Our study is nested within a larger analysis of RCTs [] where we used an extended version of the Cochrane search strategy (phase 1) to identify all randomized trials published in December 2000 and indexed on PubMed by July 2002 []. A randomized trial was defined as a prospective study assessing health-care interventions in human participants who were randomly allocated to study groups. Abstracts were initially screened to exclude obvious non-trials, and complete primary reports in the languages AWC could read (English and French) were reviewed for all remaining studies.
We defined randomized crossover trials as studies where an individual receives two or more interventions through randomization to one of a set of prespecified sequences of treatments. Appendix 1 displays common characteristics and features of crossover trials. We included crossover trials of any intervention in any health condition. We excluded studies examining primarily cost-effectiveness or diagnostic test properties, as well as studies employing re-randomization which involves randomization of study participants into the second stage of a clinical trial [].
Dec 29, 2018 Seventeenth edition of my tutorial series on DJay Pro 2 for Mac by Algoriddim! Learn how to configure a DJ controller, edit the configuration for a natively supported DJ controller, or Midi Map in. Sharing MIDI mappings. Select 'Edit Configurations.' From the 'MIDI Configuration' menu at the top of the MIDI configuration window. Select the configuration you want to share from the list. Select 'Show in Finder' from the 'Options' menu. How can I use an external mixer with djay Pro? Connect the external device to your Computer. Make sure the correct driver is installed and djay Pro can access the device after start up. Access the djay Pro settings click on the burger menu button at the top left of the application window. To start mapping a new MIDI device, follow these steps: Launch djay Pro and wait for it to be fully loaded. Plug your MIDI controller into your computer via a spare USB port and turn it on. If this is the first time using the controller, you will see a. Next, the device MIDI Configuration window. How to setup midi settings in djay pro download.
Data collection
Data extraction was conducted by two independent reviewers (PW and EM) using a standardized pre-piloted form. We classified trials by journal type, specialty, and intervention. We also recorded the trial design, study aim, number of groups (interventions, periods), number of data collection sites, funding sources, and sample size. If information about funding sources and number of study sites was unclear from the trial report, we requested clarification from the trialists. We assessed the reporting of several important methodological details. We recorded descriptions of sample size calculations and primary outcomes. With liberal definitions of adequacy [], the reporting of patient preference and methods of random sequence generation, and allocation concealment were recorded. We also noted the handling of non-compliers, carryover, period, and treatment effects. We calculated descriptive summary statistics both overall and stratified by study design. We entered the data into an electronic database such that duplicate entries existed for each study; when two entries did not match, we reached consensus through discussion and 3rd party arbitration (BR).
Data analysis
In order to assess inter-rater reliability on inclusion of articles, we calculated a kappa score which provides a measure of inter-rater agreement independent of chance []. We determined the proportion of crossover trials for each item reported using simple tabulations and calculated the exact confidence intervals around a proportion [13].
Results
Results of our literature search
In total, 519 randomized trials published in December 2000 were identified. Of these, 116 or 22% were identified as crossover studies. Of the 116 publications included, 2 reported 3 separate trials [,], and 7 reported two independent trials within their publication [-]. Therefore, we included a total of 127 randomized crossover trials. Agreement on the final cohort was excellent (K= 0.94).
Characteristics of the individual trials
In total, 30/127 (24%) trials measured drug pharmacokinetics, 36/127 (28%) were non-drug interventions while almost half, 61/127 (48%) were studies of drug efficacy. The number of periods ranged between 1 and 6, as six trials reported only on the first period. The median sample size was 15 (interquartile range: 8–38). Additional File 1 details the reporting characteristics of included studies stratified by study design (drug efficacy vs. pharmacokinetic vs. non-drug intervention). Of all 116 included publications, one was a letter to the editors [], one was a summary of previously conducted research [], and one did not contain an abstract []. Of the remaining trials, 77/113 (68%) used the term 'crossover' in their title or abstract while 36/113 (33%) did not.
Design of the individual trials
Several important study design characteristics were poorly reported (Additional File 1). For example, while 92/127 (72%) trials employed an AB/BA design (2 periods, 2 treatments), the study design was unclear in approximately a quarter of studies, 29/127 (23%). In almost three-quarters of included studies, carryover effects were not addressed in the methods section, 90/127 (71%), although 87/127 (70%) studies either used or explained the absence of a washout period. In 37/127 (30%) of studies it was unclear whether washout was considered. In the majority of studies, 114/127 (90%), it was not reported how groups were randomized, while allocation concealment was reported in less than a fifth of trials, 22/127 (17%). In total, sample size calculations before the study were provided in 26/127 (20%) studies. Of these, 8/26 (31%) reported using a paired data design and, 5/26 (19%, 95% CI: 9–38%) reported post-hoc power calculations in their results.
Analysis of the individual trials
One hundred and seventeen trials (117/127 (92%) adequately detailed the handling of attrition. Of these, 74/117 (63%) reported applying an intention-to-treat (ITT) approach, whereby all patients randomized are included in the analysis. Tests for carryover and period effects were described or used in 22/127 (17%) and 17/127 (13%) of all included studies respectively. While the test for treatment effect was adjusting for co-variates in 4/127 (3%) studies, 121/127 (95%) studies reported a paired analysis.
Almost all studies 109/127 (86%) did not provide details regarding patient flow. Only 15/127 (12%) studies adequately described this component in their study design, with only 3/127 (2%) trials providing the CONSORT patient flow diagram recommended for parallel group trials.
Patient preference regarding intervention was reported in 10/127 (92%) of the studies. Individual participant data were presented in 15/127 (12%) studies while results were displayed graphically in 25/127 (20%). A paired summary statistic was reported in 118/127 (93%) of studies. Although the CI or SE was reported in 38/127 (29%) studies, it was calculable in most of the remaining studies that had not reported it, 78/89 (88%). Finally, in 79/127 (62%) of the studies, the trialists based their analysis and conclusions on the differences between groups as opposed to differences within individuals (i.e. within groups) – the latter was reported in only 3/127 (2%) studies. Interestingly, in 45/127 (35%) studies, the authors interpreted their results based on both differences within and between groups.
Discussion
We found that important design issues are often under-reported in randomized crossover trials. Given their popularity – representing almost a quarter of trials published in December 2000 [] – few reported important methodological issues such as allocation concealment, issues of carryover effects, and within-participant effects. Transparency and interpretation can be improved by creating standard reporting guidelines for authors and journals reporting the cross-over trial design. As yet the CONSORT reporting guidelines [] have not been extended specifically for crossover trials.
There are several important strengths and limitations to be considered in our analysis. Strengths include our rigorous searching of PubMed during the study period, ensuring that adequate time had passed to allow all potential trials to be filed on the database. We extracted data in duplicate to reduce abstraction errors and resolved discrepancies by consensus. There are also limitations to consider. We searched only PubMed, the largest and most accessed database of medical articles. Other databases may have included additional articles. While every randomized trial published in December 2000 was read and appraised, it is possible that we missed some trials originally designed as crossover trials that were reported as parallel trials, reporting on only the first or second period of the trial. The methodological issues that we examined are a matter of debate. While evidence of bias exists for methodological issues such as blinding, sequence generation and allocation concealment [], such evidence is lacking for other details such as flow diagrams, patient preference, and importantly, carryover effects. It is possible that if we had identified other methodological issues, we would have found different results. However, we developed these criteria based on studies in which we have participated and widespread consensus on methodological criteria, as reported in the CONSORT Statements []. Our data abstraction focused on prespecified criteria. During peer-review, a reviewer noted the important issue of differing analysis issues according to whether the main outcome measure in a trial is continuous, categorical, ordinal or binary, issues we had not considered. Finally, our analysis is based on the assumption that the reporting of methods and results in a published article reflects what was actually done. It is possible that some authors did conduct the methodological item, but failed to report it [].
The crossover design has numerous advantages that investigators may wish to use for early stage trials. The particular strength of this design is that the interventions under investigation are evaluated within the same patients and so eliminates between-subject variability []. Further, this trial design permits opportunities of head-to-head trials and patients receiving multiple treatments can express preferences for or against particular treatments.
However, even when properly applied, crossover trials may have certain weaknesses. Patients may drop out after the first intervention period and thus not receive a second or third treatment. This makes within-subject comparison impossible [] and is particularly important if withdrawal is related to side-effects [,]. This further complicates the concept of intent-to-treat analysis as patients randomized may complete the first period, but randomization typically does not occur at the second period. Also, there may be a residual [] or carry-over of effect of treatments across study periods, which could potentially distort the results obtained during the second treatment or subsequent periods [,], although examples of this are few [30]. Thus, the observed treatment effects will depend upon the order in which they were received.
Some have argued against consistent testing for carryover effects of interventions across periods as carry-over effects are rare and statistical manipulation after the fact cannot address the impact of a carry-over effect.[30] Senn, in particular, has argued for a common sense approach to crossover trials, where no carry-over is assumed and thus, not tested for.[] He specifically argues that tests for carry-over are generally underpowered even with an appreciable carry-over effect. He recommends instead that the wash-out period between periods be sufficient to prevent carryover effects. This paper does not aim to solve this issue, but rather displays the incongruence across crossover trials on the issue of carry-over and other design issues.
Another major potential threat to the validity of the crossover design involves the use of inappropriate statistical analysis []. Given that subjects act as their own controls, the analyses could be based on paired data (using an unpaired test) [,] and the within-subject variability in outcomes could be considered in sample size calculations []. Essentially, the use of a paired design is much more efficient than a parallel group design when researchers expect a high correlation between patients' responses to the different treatments.
Conclusion
Crossover Mac Trial Limitations Free
We found large heterogeneity in the reporting of crossover trials, possibly reflecting a lack of standards within the field. There is a clear need for minimum standards for transparent reporting of crossover trials.
Abbreviations
RCTs: Randomized Clinical Trials; CONSORT: Consolidated Standards of Reporting Trials.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
AWC, AV, EM, DA, GG contributed to study concept.
AWC conducted the searches.
AWC, EM, PW conducted data abstraction.
AWC, EM, PW analyzed the data. Traktor pro effects download. Djay pro 2 log out of spotify.
AWC, EM, PW, DA, GG wrote initial drafts of the manuscript.
AWC, AV, EM, PW, DA, GG approved the final manuscript.
Appendix 1
Features used to assess reporting of methodological details in published crossover studies
Design
Carryover: concept recognized in the methods section, credibly was absent and washout was either used or explained absence.
Allocation: Randomization and concealment methods are described.
Sample size calculation: methods reported and explained (prospective versus retrospective, paired vs. unpaired analysis)
Analysis
Non-Compliers: clear if all participants are included, excluded, included under intention to treat (ITT) or not mentioned
Test for carryover effect: Yes formal, Yes informal, No, or unclear
Test for period effect: Yes formal, yes informal, no, not clear
Test for treatment effect: paired/unpaired, adjusted/unadjusted for period effect
Patient preference recorded: yes or no
Presentation
Patient flow: presented as a CONSORT style diagram or other method
Detail for primary outcome:
• Individual data presented: Yes versus no
Crossover Mac Trial Limitations Of Trial
Inference
• paired summary statistic: Yes, No but calculable, No
Slant of paper: authors base slant of paper on differences between groups, within in groups or a combination
Flow chart of included studies.
Supplementary Material
Additional file 1:Reporting characteristics of included crossover studies stratified by study setting (drug efficacy vs. pharmacokinetic vs. non-drug intervention)
Acknowledgements
The authors thank Ms. Beth Rachlis for study arbitration. No funding was received for this study. Free download serato skin for virtual dj mac.
References
- Mills EJ, Kelly S, Wu P, Guyatt GH. Epidemiology and reporting of randomized trials employing re-randomization of patient groups: a systematic survey. Contemp Clin Trials. 2007;28:268–75. doi: 10.1016/j.cct.2006.09.002. [PubMed] [CrossRef] [Google Scholar]
- Louis TA, Lavori PW, Bailar JC, Polansky M. Crossover and self-controlled designs in clinical research. NEJM. 1984;310:24–31. [PubMed] [Google Scholar]
- Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. Int J Epid. 2002;31:140–149. doi: 10.1093/ije/31.1.140. [PubMed] [CrossRef] [Google Scholar]
- Maclure M. The case-crossover design: a method for studying transient effects on the risk of acute events. Am J Epidemiol . 1991;133:144–153. [PubMed] [Google Scholar]
- Brown BW., Jr The crossover experiment for clinical trials. Biometrics. 1980;36:69–79. doi: 10.2307/2530496. [PubMed] [CrossRef] [Google Scholar]
- Cleophas TJ, de Vogel EM. Crossover studies are a better format for comparing equivalent treatments than parallel-group studies. Pharm World Sci. 1998;20:113–117. doi: 10.1023/A:1008626002664. [PubMed] [CrossRef] [Google Scholar]
- Cleophas TJ. A simple method for the estimation of interaction bias in crossover studies. J Clin Pharmacol. 1990;30:1036–1040. [PubMed] [Google Scholar]
- Daya S. Differences between crossover and parallel study designs-debate? Fertil Steril. 1999;71:771–773. doi: 10.1016/S0015-0282(98)00495-6. [PubMed] [CrossRef] [Google Scholar]
- Khan KS, Daya S, Collins JA, Walter SD. Empirical evidence of bias in infertility research: overestimation of treatment effect in crossover trials using pregnancy as the outcome measure. Fertil Steril. 1996;65:939–945. [PubMed] [Google Scholar]
- Chan AW, Altman DG. Epidemiology and reporting of randomized trials published in PubMed journals. Lancet. 2005;365:1159–1162. doi: 10.1016/S0140-6736(05)71879-1. [PubMed] [CrossRef] [Google Scholar]
- Robinson KA, Dickersin K. Development of a highly sensitive search strategy for the retrieval of reports of controlled trials using PubMed. Int J Epidemiol. 2002;31:150–53. doi: 10.1093/ije/31.1.150. [PubMed] [CrossRef] [Google Scholar]
- Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, Gøtzsche PC, Lang T, CONSORT GROUP (Consolidated Standards of Reporting Trials) The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med. 2001;134:663–94. [PubMed] [Google Scholar]
- Jaynes ET. ' Confidence Intervals vs. Bayesian Intervals'. In: Harper WL, Hooker CA, editor. Foundations of Probability Theory, Statistical Inference, and Statistical Theories of Science. D. Reidel, Dordrecht; 1976. p. 175. [Google Scholar]
- Schwartz JL, Bugianesi KJ, Ebel DL, De Smet M, Haesen R, Larson PJ, et al. The effect of rofecoxib on the pharmacodynamics and pharmacokinetics of warfarin. Clin Pharmacol Ther. 2000;68:626–636. doi: 10.1067/mcp.2000.112244. [PubMed] [CrossRef] [Google Scholar]
- Powers JL, Gooch WM, 3rd, Oddo LP. Comparison of the palatability of the oral suspension of cefdinir vs. amoxicillin/clavulanate potassium, cefprozil and azithromycin in pediatric patients. Pediatr Infect Dis J. 2000;19:S174–80. [PubMed] [Google Scholar]
- Koutsoumbi P, Epanomeritakis E, Tsiaoussis J, Athanasakis H, Chrysos E, Zoras O, Vassilakis JS, Xynos E. The effect of erythromycin on human esophageal motility is mediated by serotonin receptors. Amer J Gastroenterol. 2000;95:3388–3392. doi: 10.1111/j.1572-0241.2000.03278.x. [PubMed] [CrossRef] [Google Scholar]
- Turley E, McKeown A, Bonham MP, O'Connor JM, Chopra M, Harvey LJ, et al. Copper supplementation in humans does not affect the susceptibility of low density lipoprotein to in vitro induced oxidation (FOODCUE project) Free Rad Biol Med. 2000;29:1129–1134. doi: 10.1016/S0891-5849(00)00409-3. [PubMed] [CrossRef] [Google Scholar]
- Herrera D, Mayet L, Galindo MC, Jung H. Pharmacokinetics of a sustained-release dosage form of clomipramine. J Clin Pharmacol. 2000;40:1488–93. [PubMed] [Google Scholar]
- Kosoglou T, Salfi M, Lim JM, Batra VK, Cayen MN, Affrime MB. Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine. Br J Clin Pharmcol. 2000;50:581–9. doi: 10.1046/j.1365-2125.2000.00290.x.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
- Lepore M, Pampanelli S, Fanelli C, Porcellati F, Di Vincenzo A, Cordoni C, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continous subcutaneous infusion of insulin lispro. Diabetes. 2000;49:2142–2148. doi: 10.2337/diabetes.49.12.2142. [PubMed] [CrossRef] [Google Scholar]
- Nakaishi H, Matsumoto H, Tominaga S, Hirayama M. Effects of black current anthocyanoside intake on dark adaptation and VDT work-induced transient refractive alteration in healthy humans. Altern Med Rev. 2000;5:553–62. [PubMed] [Google Scholar]
- Marathe PH, Arnold ME, Meeker J, Greene DS, Barbhaiya RH. Pharmacokinetics and bioavailability of a metformin/glyburide tablet administered alone and with food. J Clin Pharmacol. 2000;40:1494–502. [PubMed] [Google Scholar]
- Marx CE, McIntosh E, Wilson WH, McEvoy JP. Mecamylamine increases cigarette smoking in psychiatric patients. J Clin Psychopharmacol . 2000;20:706–707. doi: 10.1097/00004714-200012000-00023. [PubMed] [CrossRef] [Google Scholar]
- Holt S, Suder A, Dronfield C, Holt C, Beasley R. Intranasal-agonist in allergic rhinitis. Allergy. 2000;55:1198. doi: 10.1034/j.1398-9995.2000.00830.x. [PubMed] [CrossRef] [Google Scholar]
- Fernhall B, Szymanksi LM, Gorman PA, Kamimori GH, Kessler CM. Both Atenolol and Propranol blunt the fibrinolytic response to exercise but not resting fibrinolytic potential. Am J Cardiol. 2000;86:1398–1400. doi: 10.1016/S0002-9149(00)01242-X. [PubMed] [CrossRef] [Google Scholar]
- Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273:408–12. doi: 10.1001/jama.273.5.408. [PubMed] [CrossRef] [Google Scholar]
- Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet. 2001;357:1191–4. doi: 10.1016/S0140-6736(00)04337-3. [PubMed] [CrossRef] [Google Scholar]
- Devereaux PJ, Choi PT, El-Dika S, Bhandari M, Montori VM, Schünemann HJ, et al. An observational study found that authors of randomized controlled trials frequently use concealment of randomization and blinding, despite the failure to report these methods. J Clin Epidemiol. 2004;57:1232–1236. doi: 10.1016/j.jclinepi.2004.03.017. [PubMed] [CrossRef] [Google Scholar]
- Wallenstein S, Fisher AC. The analysis of the two-period repeated measurements crossover design with application to clinical trials. Biometrics. 1977;33:261–269. doi: 10.2307/2529321. [PubMed] [CrossRef] [Google Scholar]
- Senn SJ, D'Angelo G, Potvin D. Carry-over in cross-over trials in bioequivalence: theoretical concerns and empirical evidence. Pharmaceutical Statistics. 2004;3:13–142. doi: 10.1002/pst.88. [CrossRef] [Google Scholar]
- Senn SJ. Cross-over trials, carry-over effects and the art of self-delusion. Stat Med. 1988;7:1099–101. doi: 10.1002/sim.4780071010. [PubMed] [CrossRef] [Google Scholar]
- Liu G, Liang KY. Sample size calculations for studies with correlated observations. Biometrics. 1997;53:937–947. doi: 10.2307/2533554. [PubMed] [CrossRef] [Google Scholar]
Crossover Mac Trial Limitations Free