|
1
|
Gaskin DJ, Zare H, Ibe CA, Yang M, Jones W, Gaston M, Porter G, Woods DL, Balamani M, Jones N, Rose VA, Williams RA, Rohde C. The impact of the Prime Time Sister Circles® (PTSC) on blood pressure of low-income mid-life African American women in the United States. J Public Health Policy 2023; 44:616-633. [PMID: 37899483 PMCID: PMC10709469 DOI: 10.1057/s41271-023-00450-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2023] [Indexed: 10/31/2023]
Abstract
There is a pressing need to develop and evaluate culturally tailored, community-based interventions that address hypertension management among low-income African American women. We employed a randomized controlled trial to test the effectiveness of the Prime Time Sister Circles® Program in reducing blood pressure and body mass index among low-income African American women ages with hypertension. Study participants (N = 339) were African American women aged 40-75 years who were diagnosed with hypertension and received their primary care at government funded health centers in Washington, D.C. Compared to the usual care group, Prime Time Sister Circles® participation was associated with a reduction in systolic BP by - 2.45 (CI - 6.13, 1.23) mmHg, a reduction in diastolic BP by - 3.66 mmHg (CI - 6.32, - 0.99), and a change in BMI by - 0.26 (CI - 2.00, 1.48) from baseline to 15 months. The results suggest that culturally tailored community-based interventions can improve hypertension management in low-income women.
Collapse
Affiliation(s)
- Darrell J Gaskin
- Johns Hopkins Center for Health Disparities Solutions, Johns Hopkins University, Baltimore, MD, USA.
- Department of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, 624 North Broadway Ste 441, Baltimore, MD, 21205-1900, USA.
| | - Hossein Zare
- Johns Hopkins Center for Health Disparities Solutions, Johns Hopkins University, Baltimore, MD, USA
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Global Health Services and Administration, University of Maryland Global Campus, Adelphi, MD, USA
| | - Chidinma A Ibe
- Johns Hopkins Center for Health Disparities Solutions, Johns Hopkins University, Baltimore, MD, USA
- Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Manshu Yang
- Department of Psychology, University of Rhode Island, Kingston, RI, USA
| | - Wehmah Jones
- American Institutes for Research, Washington, DC, USA
| | - Marilyn Gaston
- The Gaston & Porter Health Improvement Center, Inc., Washington, DC, USA
| | - Gayle Porter
- The Gaston & Porter Health Improvement Center, Inc., Washington, DC, USA
| | - Denise L Woods
- The Gaston & Porter Health Improvement Center, Inc., Washington, DC, USA
| | | | - Nicole Jones
- Johns Hopkins Center for Health Disparities Solutions, Johns Hopkins University, Baltimore, MD, USA
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | | | - Richard Allen Williams
- David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA
| | - Charles Rohde
- Johns Hopkins Center for Health Disparities Solutions, Johns Hopkins University, Baltimore, MD, USA
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| |
Collapse
|
|
2
|
Fortinsky RH, Shugrue N, Robison JT, Gitlin LN. The Case for Conducting Pragmatic Dementia Care Trials in Medicaid Home and Community-Based Service Settings. J Am Med Dir Assoc 2023; 24:1918-1923. [PMID: 37918816 PMCID: PMC10795107 DOI: 10.1016/j.jamda.2023.09.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 07/10/2023] [Accepted: 09/18/2023] [Indexed: 11/04/2023]
Abstract
Medicaid-funded home and community-based services (HCBSs) reach large numbers of individuals living with dementia who would otherwise reside in nursing homes with Medicaid funding. Medicaid HCBSs also often augment care provided by family and other informal caregivers to individuals living with dementia. Although Medicaid-funded HCBSs are offered in most states in lieu of nursing home care, they have been largely overlooked as health care system partners for implementation and testing of evidence-based dementia care interventions using embedded pragmatic clinical trial (ePCT) designs. In this article, we make the case for the importance of Medicaid-funded HCBSs as dementia care ePCT partners because of the volume of vulnerable clients with dementia served and the potential positive impacts that evidence-based dementia care programs can have on clients and their informal caregivers. This article first characterizes the Medicaid HCBS setting in terms of populations served and organizational arrangements across states. We then characterize strengths and potential limitations presented by Medicaid HCBSs as settings within which to implement dementia care ePCTs, using as a conceptual framework the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS-2) tool and its domains. We draw on our experiences implementing the Care of Persons with Dementia in their Environments (COPE) program in a statewide Medicaid HCBS setting to highlight how these potential ePCT partners can help optimize pragmatic approaches to several PRECIS-2 domains. We found that partners are especially effective in implementing pragmatic ways to determine eligibility for evidence-based dementia care programs; assist with recruitment of eligible individuals; incorporate dementia care interventions into the range of existing HCBSs; and track outcomes relevant to persons living with dementia, caregivers, HCBS providers, and Medicaid insurance stakeholders. We conclude with recommendations for researchers, potential ePCT partners, and policymakers to help facilitate the growth of dementia care ePCTs in Medicaid HCBS settings across the United States.
Collapse
Affiliation(s)
| | - Noreen Shugrue
- UConn Center on Aging, University of Connecticut, Farmington, CT, USA
| | - Julie T Robison
- UConn Center on Aging, University of Connecticut, Farmington, CT, USA
| | - Laura N Gitlin
- College of Nursing and Health Professions, Drexel University, Philadelphia, PA, USA
| |
Collapse
|
|
3
|
Chalmers I, Matthews R, Glasziou P, Boutron I, Armitage P. Trial analysis by treatment allocated or by treatment received? Origins of 'the intention-to-treat principle' to reduce allocation bias: Part 2. J R Soc Med 2023; 116:386-394. [PMID: 37975723 PMCID: PMC10686203 DOI: 10.1177/01410768231203936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2023] Open
Affiliation(s)
- I Chalmers
- Centre for Evidence-Based Medicine, University of Oxford, OX2 6HX, UK
| | - R Matthews
- Department of Mathematics, Aston University, Birmingham, B4 7ET, UK
| | - P Glasziou
- Institute for Evidence Based Healthcare, Bond University, Queensland, QLD 4226, Australia
| | - I Boutron
- Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Centre for Research in Epidemiology and Statistics (CR ESS), F-75004 Paris, France
| | - P Armitage
- 2 Reading Road, Wallingford OX10 9DP, UK
| |
Collapse
|
|
4
|
Giudici F, Pistilli B, Vaz-Luis I, Karimi M, Delaloge S, Bachelot T, Michiels S, Bardet A. Insights adjusting for non-adherence in randomized clinical trials: a reanalysis of an adjuvant trial of tamoxifen duration in early breast cancer. Br J Cancer 2023; 129:1516-1523. [PMID: 37697030 PMCID: PMC10628101 DOI: 10.1038/s41416-023-02420-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 08/23/2023] [Accepted: 08/30/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND Several randomized clinical trials provide evidence of the survival benefit of extended adjuvant tamoxifen in women with estrogen receptor (ER)-positive early breast cancer (BC). However, non-adherence may lead to underestimate treatment effects using intention to treat (ITT) methods. We reanalyzed a randomized trial using contemporary statistical methods adjusting for non-adherence. METHODS The TAM01 study was a phase 3 trial including women with early BC, who had completed 2-3 years of adjuvant tamoxifen between 1986 and 1995. Participants were randomly assigned to continue tamoxifen up to 10 years or to discontinue the treatment at randomization. Invasive disease-free survival (iDFS) and overall survival (OS) were estimated using marginal structural models (MSM) and rank preserving structural failure time model (RPSFTM). RESULTS Of 3830 patients enrolled, 2485 were randomized to extended tamoxifen, and 1345 to treatment discontinuation. The 10-year non-adherence rate in the extended group was 27.2%. Among women with ER-positive BC (n = 2402), extended tamoxifen was associated with a 45% and 21% relative improvement in iDFS by MSM and RPSFTM, respectively (Hazard Ratio (HR), 0.55; 95% Confidence Interval (CI), 0.48-0.64 and HR, 0.79; 95%CI, 0.67-0.95, respectively), a considerable greater benefit than in the ITT analysis (HR, 0.90; 95%CI, 0.81-0.99). The OS reanalysis revealed a substantial benefit of extended tamoxifen (MSM: HR, 0.70; 95%CI, 0.59-0.83; RPSFTM: HR, 0.85; 95%CI, 0.67-1.04), compared to the ITT analyses (HR, 0.94; 95%CI, 0.84-1.07). CONCLUSION This analysis emphasizes both the importance of adherence to hormonotherapy in hormone-receptor positive early BC and the usefulness of more complex statistical analyses.
Collapse
Affiliation(s)
- Fabiola Giudici
- Bureau de Biostatistique et d'Epidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France
- Oncostat U1018, Inserm, Université Paris-Saclay, Equipe labellisée Ligue Contre le Cancer, 114 Rue Edouard Vaillant, Villejuif, France
| | - Barbara Pistilli
- Department of Cancer Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, Villejuif, France
| | - Ines Vaz-Luis
- Department of Cancer Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, Villejuif, France
- Breast Cancer Survivorship Group, INSERM Unit 981, Gustave Roussy Institute, 114 Rue Edouard Vaillant, Villejuif, France
| | - Maryam Karimi
- Bureau de Biostatistique et d'Epidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France
- Oncostat U1018, Inserm, Université Paris-Saclay, Equipe labellisée Ligue Contre le Cancer, 114 Rue Edouard Vaillant, Villejuif, France
| | - Suzette Delaloge
- Department of Cancer Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, Villejuif, France
| | - Thomas Bachelot
- Department of Medical Oncology, Centre Léon Bérard, 28 Rue Laënnec, Lyon, France
| | - Stefan Michiels
- Bureau de Biostatistique et d'Epidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
- Oncostat U1018, Inserm, Université Paris-Saclay, Equipe labellisée Ligue Contre le Cancer, 114 Rue Edouard Vaillant, Villejuif, France.
| | - Aurelie Bardet
- Bureau de Biostatistique et d'Epidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France
- Oncostat U1018, Inserm, Université Paris-Saclay, Equipe labellisée Ligue Contre le Cancer, 114 Rue Edouard Vaillant, Villejuif, France
| |
Collapse
|
|
5
|
Wong KP, Qin J. Effectiveness of Social Virtual Reality Training in Enhancing Social Interaction Skills in Children With Attention-Deficit/Hyperactivity Disorder: Protocol for a Three-Arm Pilot Randomized Controlled Trial. JMIR Res Protoc 2023; 12:e48208. [PMID: 37721790 PMCID: PMC10546265 DOI: 10.2196/48208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 08/23/2023] [Accepted: 08/28/2023] [Indexed: 09/19/2023] Open
Abstract
BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders among children. Children with ADHD have challenges in understanding social cues and behavioral problems when entering a social setting. Virtual reality (VR) has been applied to improve cognitive behaviors in children with ADHD. Previous studies have not adopted VR to improve social interaction competence and appropriateness in children with ADHD. VR offers a more effective alternative to therapeutic strategies for children with ADHD. OBJECTIVE This study aims to examine the feasibility and effectiveness of social VR training in enhancing social interaction skills compared to traditional social skills training in children with ADHD. We hypothesize that participants in the social VR training group are likely to perform better on social interaction skills than those in the traditional social skills training group. METHODS In this nonblinded, 3-arm randomized controlled trial (RCT), 90 participants with ADHD recruited from the community will be randomized 1:1:1 to the social VR intervention group, traditional social skills training group, or waitlist control group. The child psychiatrist will conduct assessments for each participant at baseline and after the intervention. The Social Skills Rating Scale-Parent will be used to assess the social interaction skills of the participants before and after the intervention. Participants in the social VR intervention group and traditional social skills training group will receive twelve 20-minute training sessions for 3 weeks. The participants in the waitlist control group will receive no training. The primary outcome measure is training acceptability and compliance. The secondary outcome measures are the child psychiatrist's assessment and the Social Skills Rating Scale-Parent before and after the intervention. Another outcome measure is the Behavior Rating Inventory of Executive Function and Attention. Differences in the scale scores will be examined using a t test and an F test. RESULTS This study is set to commence in the fourth quarter of 2023. It is anticipated that participants in the social VR intervention group will exhibit superior social interaction skills than those in the traditional social skills training group. CONCLUSIONS To our knowledge, this RCT is the first study examining the feasibility and effectiveness of a social VR-based intervention for enhancing the social interaction skills of children with ADHD in Hong Kong. The VR-based social skills training is expected to provide a safer and more effective environment for children with ADHD to learn than the traditional approach. This study can lead to a full-scale RCT. TRIAL REGISTRATION ClinicalTrials.gov NCT05778526; https://clinicaltrials.gov/study/NCT05778526. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) PRR1-10.2196/48208.
Collapse
Affiliation(s)
- Ka Po Wong
- Department of Applied Social Sciences, The Hong Kong Polytechnic University, Hong Kong, China (Hong Kong)
| | - Jing Qin
- Centre for Smart Health, School of Nursing, The Hong Kong Polytechnic University, Hong Kong, China (Hong Kong)
| |
Collapse
|
|
6
|
Buis D, van Werkhoven CH, van Agtmael MA, Bax HI, Berrevoets M, de Boer M, Bonten M, Bosmans JE, Branger J, Douiyeb S, Gelinck L, Jong E, Lammers A, Van der Meer J, Oosterheert JJ, Sieswerda E, Soetekouw R, Stalenhoef JE, Van der Vaart TW, Bij de Vaate EA, Verkaik NJ, Van Vonderen M, De Vries PJ, Prins JM, Sigaloff K. Safe shortening of antibiotic treatment duration for complicated Staphylococcus aureus bacteraemia (SAFE trial): protocol for a randomised, controlled, open-label, non-inferiority trial comparing 4 and 6 weeks of antibiotic treatment. BMJ Open 2023; 13:e068295. [PMID: 37085305 PMCID: PMC10124302 DOI: 10.1136/bmjopen-2022-068295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/23/2023] Open
Abstract
INTRODUCTION A major knowledge gap in the treatment of complicated Staphylococcus aureus bacteraemia (SAB) is the optimal duration of antibiotic therapy. Safe shortening of antibiotic therapy has the potential to reduce adverse drug events, length of hospital stay and costs. The objective of the SAFE trial is to evaluate whether 4 weeks of antibiotic therapy is non-inferior to 6 weeks in patients with complicated SAB. METHODS AND ANALYSIS The SAFE-trial is a multicentre, non-inferiority, open-label, parallel group, randomised controlled trial evaluating 4 versus 6 weeks of antibiotic therapy for complicated SAB. The study is performed in 15 university hospitals and general hospitals in the Netherlands. Eligible patients are adults with methicillin-susceptible SAB with evidence of deep-seated or metastatic infection and/or predictors of complicated SAB. Only patients with a satisfactory clinical response to initial antibiotic treatment are included. Patients with infected prosthetic material or an undrained abscess of 5 cm or more at day 14 of adequate antibiotic treatment are excluded. Primary outcome is success of therapy after 180 days, a combined endpoint of survival without evidence of microbiologically confirmed disease relapse. Assuming a primary endpoint occurrence of 90% in the 6 weeks group, a non-inferiority margin of 7.5% is used. Enrolment of 396 patients in total is required to demonstrate non-inferiority of shorter antibiotic therapy with a power of 80%. Currently, 152 patients are enrolled in the study. ETHICS AND DISSEMINATION This is the first randomised controlled trial evaluating duration of antibiotic therapy for complicated SAB. Non-inferiority of 4 weeks of treatment would allow shortening of treatment duration in selected patients with complicated SAB. This study is approved by the Medical Ethics Committee VUmc (Amsterdam, the Netherlands) and registered under NL8347 (the Netherlands Trial Register). Results of the study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER NL8347 (the Netherlands Trial Register).
Collapse
Affiliation(s)
- Dtp Buis
- Department of Internal Medicine, Division of Infectious Diseases, Amsterdam Institute for Infection and Immunity, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
| | - C H van Werkhoven
- Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands
| | - M A van Agtmael
- Department of Internal Medicine, Division of Infectious Diseases, Amsterdam Institute for Infection and Immunity, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
| | - H I Bax
- Department of Internal Medicine, Section of Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands
- Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands
| | - M Berrevoets
- Department of Internal Medicine, Elisabeth twee-steden Hospital, Tilburg, The Netherlands
| | - Mgj de Boer
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - Mjm Bonten
- Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands
| | - J E Bosmans
- Department of Health Sciences, Faculty of Science, Amsterdam Public Health research institute, VU University Amsterdam, Amsterdam, The Netherlands
| | - J Branger
- Department of Internal Medicine, Flevohospital, Almere, The Netherlands
| | - S Douiyeb
- Department of Internal Medicine, Division of Infectious Diseases, Amsterdam Institute for Infection and Immunity, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
| | - Lbs Gelinck
- Department of Internal Medicine, Haaglanden Medisch Centrum, Den Haag, The Netherlands
| | - E Jong
- Department of Internal Medicine, Meander Medisch Centrum, Amersfoort, The Netherlands
| | - Ajj Lammers
- Department of Internal medicine & Infectious Diseases, Isala Zwolle, Zwolle, The Netherlands
| | - Jtm Van der Meer
- Department of Internal Medicine, Division of Infectious Diseases, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands
| | - J J Oosterheert
- Department of Internal Medicine, Infectious Diseases, UMC Utrecht, Utrecht, The Netherlands
| | - E Sieswerda
- Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands
- Department of Medical Microbiology, UMC Utrecht, Utrecht, The Netherlands
| | - R Soetekouw
- Department of Internal Medicine, Spaarne Gasthuis, Haarlem/Hoofddorp, The Netherlands
| | - J E Stalenhoef
- Department of Internal Medicine, OLVG, Amsterdam, The Netherlands
| | - T W Van der Vaart
- Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands
- Department of Internal Medicine, Division of Infectious Diseases, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands
| | - E A Bij de Vaate
- Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - N J Verkaik
- Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands
| | | | - P J De Vries
- Department of Internal Medicine, Tergooi Hospital, Hilversum, The Netherlands
| | - J M Prins
- Department of Internal Medicine, Division of Infectious Diseases, Amsterdam Institute for Infection and Immunity, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
| | - Kce Sigaloff
- Department of Internal Medicine, Division of Infectious Diseases, Amsterdam Institute for Infection and Immunity, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
| |
Collapse
|
|
7
|
Shakiba M, Nazemipour M, Mansournia N, Mansournia MA. Protective effect of intensive glucose lowering therapy on all-cause mortality, adjusted for treatment switching using G-estimation method, the ACCORD trial. Sci Rep 2023; 13:5833. [PMID: 37037931 PMCID: PMC10086045 DOI: 10.1038/s41598-023-32855-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 04/03/2023] [Indexed: 04/12/2023] Open
Abstract
Previous analysis of the action to control cardiovascular risk in diabetes showed an increased risk of mortality among patients receiving intensive glucose lowering therapy using conventional regression method with intention to treat approach. This method is biased when time-varying confounder is affected by the previous treatment. We used 15 follow-up visits of ACCORD trial to compare the effect of time-varying intensive vs. standard treatment of glucose lowering drugs on cardiovascular and mortality outcomes in diabetic patients. The treatment effect was estimated using G-estimation and compared with accelerated failure time model using two modeling strategies. The first model adjusted for baseline confounders and the second adjusted for both baseline and time-varying confounders. While the hazard ratio of all-cause mortality for intensive compared to standard therapy in AFT model adjusted for baseline confounders was 1.17 (95% CI 1.01-1.36), the result of time-dependent AFT model was compatible with both protective and risk effects. However, the hazard ratio estimated by G-estimation was 0.64 (95% CI 0.39-0.92). The results of this study revealed a protective effect of intensive therapy on all-cause mortality compared with standard therapy in ACCORD trial.
Collapse
Affiliation(s)
- Maryam Shakiba
- Cardiovascular Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
- Department of Biostatistics and Epidemiology, School of Health, Guilan University of Medical Sciences, Rasht, Iran
| | - Maryam Nazemipour
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, PO Box: 14155-6446, Tehran, Iran
| | - Nasrin Mansournia
- Department of Endocrinology, AJA University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Mansournia
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, PO Box: 14155-6446, Tehran, Iran.
| |
Collapse
|
|
8
|
Erlendsdottir M, Crawford FW. Randomized controlled trials of biomarker targets. Clin Trials 2023; 20:47-58. [PMID: 36373783 PMCID: PMC9974557 DOI: 10.1177/17407745221131820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Randomized controlled trials are used to estimate the causal effect of a treatment on a health outcome of interest in a patient population. Often the specified treatment in a randomized controlled trial is a medical intervention-such as a drug or procedure-experienced directly by the patient. Sometimes the "treatment" in a randomized controlled trial is a target-such as a goal biomarker measurement-that the patient's physician attempts to reach using available medications or procedures. Large randomized controlled trials of biomarker targets are common in clinical research, and trials have been conducted to compare targets in the management of hypertension, diabetes, anemia, and acute respiratory distress syndrome. However, different randomized controlled trials intended to evaluate the same biomarker targets have produced conflicting recommendations, and meta-analyses that aggregate results of trials of biomarker targets have been inconclusive. METHODS We use causal reasoning to explain why randomized controlled trials of biomarker targets can arrive at conflicting or misleading conclusions. We describe four key threats to the validity of trials of targets: (1) intention-to-treat analysis can be misleading when a direct effect of target assignment on the outcome exists due to lack of blinding; (2) incomparability in results across trials of targets; (3) time-varying adaptive treatment strategies; and (4) Goodhart's law, "when a measure becomes a target, it ceases to be a good measure." RESULTS We illustrate these findings using evidence from 15 randomized controlled trials of blood pressure targets for management of hypertension. Randomized trials of blood pressure targets exhibit substantial variation in the trial patient populations and antihypertensives used to achieve the blood pressure targets assigned in the trials. The trials did not compare or account for time-varying treatment strategies used to reach the randomized targets. Possible "off-target" effects of antihypertensive medications needed to reach lower blood pressure targets may explain the absence of a clear benefit from intensive blood pressure control. DISCUSSION Researchers should critically assess meta-analyses of trials of targets for variation in the types, distributions, and off-target effects of therapies studied. Trial investigators should release detailed information about the biomarker targets compared in new randomized trials, as well as confounders, treatments delivered, and outcomes. New randomized controlled trials should experimentally compare treatment algorithms incorporating biomarkers, rather than targets alone. Causal inference methodology that adjusts for time-varying confounding should be used to compare time-varying treatment strategies in observational settings.
Collapse
Affiliation(s)
| | - Forrest W. Crawford
- Department of Biostatistics, Yale School of Public Health,Department of Statistics & Data Science, Yale University,Department of Ecology & Evolutionary Biology, Yale University,Yale School of Management
| |
Collapse
|
|
9
|
Rogers JA, Maas H, Pitarch AP. An introduction to causal inference for pharmacometricians. CPT Pharmacometrics Syst Pharmacol 2022; 12:27-40. [PMID: 36385744 PMCID: PMC9835139 DOI: 10.1002/psp4.12894] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 11/18/2022] Open
Abstract
As formal causal inference begins to play a greater role in disciplines that intersect with pharmacometrics, such as biostatistics, epidemiology, and artificial intelligence/machine learning, pharmacometricians may increasingly benefit from a basic fluency in foundational causal inference concepts. This tutorial seeks to orient pharmacometricians to three such fundamental concepts: potential outcomes, g-formula, and directed acyclic graphs (DAGs).
Collapse
Affiliation(s)
| | - Hugo Maas
- Boehringer Ingelheim Pharma GmbH & Co. KGIngelheim am RheinGermany
| | | |
Collapse
|
|
10
|
Statistical methods for handling compliance in randomized controlled trials of device interventions: a systematic review. J Clin Epidemiol 2022; 152:226-237. [PMID: 36183902 DOI: 10.1016/j.jclinepi.2022.09.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 09/20/2022] [Accepted: 09/27/2022] [Indexed: 01/25/2023]
Abstract
OBJECTIVES We aimed to review the extent to which analysis of randomized controlled trials (RCTs) of device interventions includes methods to handle compliance to the study intervention as described in the protocol. STUDY DESIGN AND SETTING We conducted a systematic review of the statistical methods used to handle compliance to a device intervention when estimating the effect of the device compared to another intervention in RCTs. We searched Embase, MEDLINE, PsychInfo, and the Cochrane Central Register of Controlled Trials. We sought to evaluate what methods were used and how using these methods impacted the estimate of the effect size. RESULTS One hundred fifty eight RCTs were identified for inclusion, of which only 21 (13%) described using a method to account for compliance to the device intervention, consisting of alternative analysis populations such as per-protocol, modified intention-to-treat, or as-treated, alongside a primary intention-to-treat analysis. No causal inference methods were used. Fourteen (9%) studies included compliance as a factor in the analysis and investigated its effect on outcomes. CONCLUSION Although some studies consider methods to handle compliance, causal inference methods have not been well adopted in the analysis of device trials. An increased awareness of the applications of statistical methods to adjust for compliance is needed.
Collapse
|
|
11
|
Choi SJ, Kim DI, Yoon SH, Choi CM, Yoo JE. Randomized, single-blind, placebo-controlled trial on Hominis placenta extract pharmacopuncture for hot flashes in peri- and post-menopausal women. Integr Med Res 2022; 11:100891. [PMID: 36338608 PMCID: PMC9634366 DOI: 10.1016/j.imr.2022.100891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 09/29/2022] [Accepted: 10/06/2022] [Indexed: 11/05/2022] Open
Abstract
Background Hominis placenta pharmacopuncture is widely used for climacteric symptoms. This study examined the efficacy and safety of pharmacopuncture with PLC (the extract of Hominis placenta) on hot flashes for perimenopausal and postmenopausal women. Methods This study was a randomized placebo-controlled single-blind trial, which recruited 128 perimenopausal and postmenopausal women, randomly assigned to receive pharmacopuncture with PLC or normal saline (NS) for eight weeks. The primary outcome was the mean changes in the hot flash score (HFS) and the secondary outcomes were the mean changes in the Menopause Rating Scale (MRS), follicle-stimulating hormone (FSH) levels, and estradiol (E2) levels from baseline to eight weeks. Missing values were imputed using the last-observation-carried-forward method. Results After treatment (week 9), the HFS decreased significantly in both groups (p = 0.000). The residual HFS was 47.09 ± 41.39% and 56.45 ± 44.92 % in the PLC and control groups, respectively (p = 0.262). One month after the treatment (week 13), the score of the PLC group was reduced, but the score increased in the control group (p = 0.077). There were no statistically significant differences in the mean changes in MRS, FSH, and E2 between the two groups. No serious adverse events related to this trial were noted. Conclusion In this study, Hominis placenta extract pharmacopuncture did not differ significantly from NS in reducing the hot flash score. While this therapy appears safe, the potential for long-term effect of PLC extract needs to be examined in a large randomized controlled trial with appropriate controls.
Collapse
Affiliation(s)
- Su-Ji Choi
- Department of Korean Obstetrics & Gynecology, College of Korean Medicine, Dong-Guk University, Korean Medicine Hospital, Goyang, Republic of Korea
| | - Dong-Il Kim
- Department of Korean Obstetrics & Gynecology, College of Korean Medicine, Dong-Guk University, Korean Medicine Hospital, Goyang, Republic of Korea,Corresponding author at: Department of Korean Obstetrics & Gynecology, College of Korean Medicine, Dong-Guk University, Korean Medicine Hospital, 27 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do 10326, Republic of Korea.
| | - Sang Ho Yoon
- Department of Obstetrics and Gynecology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea
| | - Chang-Min Choi
- Department of Korean Gynecology, College of Korean Medicine, Wonkwang University, Iksan, Republic of Korea
| | - Jeong-Eun Yoo
- Laon Korean Medicine Clinic, Daejeon, Republic of Korea
| |
Collapse
|
|
12
|
Heindel P, Dieffenbach BV, Freeman NL, McGinigle KL, Menard MT. Central concepts for randomized controlled trials and other emerging trial designs. Semin Vasc Surg 2022; 35:424-430. [DOI: 10.1053/j.semvascsurg.2022.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/11/2022] [Accepted: 10/11/2022] [Indexed: 11/11/2022]
|
|
13
|
Zuber V, Grinberg NF, Gill D, Manipur I, Slob EAW, Patel A, Wallace C, Burgess S. Combining evidence from Mendelian randomization and colocalization: Review and comparison of approaches. Am J Hum Genet 2022; 109:767-782. [PMID: 35452592 PMCID: PMC7612737 DOI: 10.1016/j.ajhg.2022.04.001] [Citation(s) in RCA: 212] [Impact Index Per Article: 70.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Mendelian randomization and colocalization are two statistical approaches that can be applied to summarized data from genome-wide association studies (GWASs) to understand relationships between traits and diseases. However, despite similarities in scope, they are different in their objectives, implementation, and interpretation, in part because they were developed to serve different scientific communities. Mendelian randomization assesses whether genetic predictors of an exposure are associated with the outcome and interprets an association as evidence that the exposure has a causal effect on the outcome, whereas colocalization assesses whether two traits are affected by the same or distinct causal variants. When considering genetic variants in a single genetic region, both approaches can be performed. While a positive colocalization finding typically implies a non-zero Mendelian randomization estimate, the reverse is not generally true: there are several scenarios which would lead to a non-zero Mendelian randomization estimate but lack evidence for colocalization. These include the existence of distinct but correlated causal variants for the exposure and outcome, which would violate the Mendelian randomization assumptions, and a lack of strong associations with the outcome. As colocalization was developed in the GWAS tradition, typically evidence for colocalization is concluded only when there is strong evidence for associations with both traits. In contrast, a non-zero estimate from Mendelian randomization can be obtained despite only nominally significant genetic associations with the outcome at the locus. In this review, we discuss how the two approaches can provide complementary information on potential therapeutic targets.
Collapse
Affiliation(s)
- Verena Zuber
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK; MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK; UK Dementia Research Institute at Imperial College, Imperial College London, London, UK
| | | | - Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK; Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George's, University of London, London, UK; Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George's University Hospitals NHS Foundation Trust, London, UK; Genetics Department, Novo Nordisk Research Centre Oxford, Oxford, UK
| | - Ichcha Manipur
- Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK; Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Eric A W Slob
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
| | - Ashish Patel
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
| | - Chris Wallace
- Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK; Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK; MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
| | - Stephen Burgess
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
| |
Collapse
|
|
14
|
Guo L, Qian Y, Xie H. Assessing complier average causal effects from longitudinal trials with multiple endpoints and treatment noncompliance: An application to a study of Arthritis Health Journal. Stat Med 2022; 41:2448-2465. [PMID: 35274333 DOI: 10.1002/sim.9364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 01/24/2022] [Accepted: 02/09/2022] [Indexed: 11/06/2022]
Abstract
Treatment noncompliance often occurs in longitudinal randomized controlled trials (RCTs) on human subjects, and can greatly complicate treatment effect assessment. The complier average causal effect (CACE) informs the intervention efficacy for the subpopulation who would comply regardless of assigned treatment and has been considered as patient-oriented treatment effects of interest in the presence of noncompliance. Real-world RCTs evaluating multifaceted interventions often employ multiple study endpoints to measure treatment success. In such trials, limited sample sizes, low compliance rates, and small to moderate effect sizes on individual endpoints can significantly reduce the power to detect CACE when these correlated endpoints are analyzed separately. To overcome the challenge, we develop a multivariate longitudinal potential outcome model with stratification on latent compliance types to efficiently assess multivariate CACEs (MCACE) by combining information across multiple endpoints and visits. Evaluation using simulation data shows a significant increase in the estimation efficiency with the MCACE model, including up to 50% reduction in standard errors (SEs) of CACE estimates and 1-fold increase in the power to detect CACE. Finally, we apply the proposed MCACE model to an RCT on Arthritis Health Journal online tool. Results show that the MCACE analysis detects significant and beneficial intervention effects on two of the six endpoints while estimating CACEs for these endpoints separately fail to detect treatment effect on any endpoint.
Collapse
Affiliation(s)
- Lulu Guo
- Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, British Columbia, Canada.,Arthritis Research Canada, Vancouver, British Columbia, Canada
| | - Yi Qian
- Sauder School of Business, University of British Columbia, Vancouver, British Columbia, Canada
| | - Hui Xie
- Arthritis Research Canada, Vancouver, British Columbia, Canada.,Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.,Division of Epidemiology and Biostatistics, School of Public Health, The University of Illinois, Chicago, Illinois, USA
| |
Collapse
|
|
15
|
Zhou T, Zhou J, Hodges JS, Lin L, Chen Y, Cole SR, Chu H. Estimating the Complier Average Causal Effect in a Meta-Analysis of Randomized Clinical Trials With Binary Outcomes Accounting for Noncompliance: A Generalized Linear Latent and Mixed Model Approach. Am J Epidemiol 2022; 191:220-229. [PMID: 34564720 DOI: 10.1093/aje/kwab238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 08/30/2021] [Accepted: 09/22/2021] [Indexed: 11/14/2022] Open
Abstract
Noncompliance, a common problem in randomized clinical trials (RCTs), can bias estimation of the effect of treatment receipt using a standard intention-to-treat analysis. The complier average causal effect (CACE) measures the effect of an intervention in the latent subpopulation that would comply with their assigned treatment. Although several methods have been developed to estimate the CACE in analyzing a single RCT, methods for estimating the CACE in a meta-analysis of RCTs with noncompliance await further development. This article reviews the assumptions needed to estimate the CACE in a single RCT and proposes a frequentist alternative for estimating the CACE in a meta-analysis, using a generalized linear latent and mixed model with SAS software (SAS Institute, Inc.). The method accounts for between-study heterogeneity using random effects. We implement the methods and describe an illustrative example of a meta-analysis of 10 RCTs evaluating the effect of receiving epidural analgesia in labor on cesarean delivery, where noncompliance varies dramatically between studies. Simulation studies are used to evaluate the performance of the proposed method.
Collapse
|
|
16
|
Bounding the Implications of Noncompliance in Randomized Controlled Trials in Orthopaedics: An Example in Arthroscopic Surgery. J Am Acad Orthop Surg 2022; 30:e25-e33. [PMID: 34125734 DOI: 10.5435/jaaos-d-20-00919] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 04/28/2021] [Indexed: 02/01/2023] Open
Abstract
INTRODUCTION Randomized controlled trials (RCTs) are not impervious to bias especially when there are substantial numbers of patients who cross over from the treatment assigned by randomization to another treatment group, leading to loss of confidence in study results. The goals of this study were to (1) quantify the effects of crossovers on RCTs, (2) describe the specific effects of crossovers on RCTs for arthroscopic meniscectomy for osteoarthritis of the knee (APM/OAK), and (3) assess the confidence in APM/OAK in which there have been substantial numbers of patients crossing over to another treatment group than that assigned. METHODS Studies were included that were RCTs of APM/OAK with intention-to-treat (ITT) analysis and illustrated the problem of crossovers on confidence in the analysis. Studies were excluded if they consisted of APM for conditions other than OAK or had unavailability of data needed for the analysis. For eligible RCTs, the ITT effect was calculated; bounds for the average treatment effect (ATE) and the complier ATE were assessed by estimating confidence intervals for the bound through robust Bayesian analysis. RESULTS The eligible studies had different comparators and, therefore, were analyzed individually. Data were not pooled. The most extreme point estimates (with 95% confidence interval) for ITT ranged from -0.01 to 0.04 (-0.16 to 0.16); for ATE with no assumptions, 0.38 (-0.58 to 0.43) to 0.62 (0.56 to 0.70); for ATE with minimum assumptions, -0.50 (-0.22 to 0.10) to 0.61 (0.53 to 0.57); and for complier ATE, -0.01 to 0.07 (-0.22 to 0.24). DISCUSSION These data suggest large bounds, crossing the threshold of "no effect," which indicates a high degree of uncertainty and low confidence in the RCTs studied. The results demonstrate that when there are crossovers, ITT analyses do not estimate the ATE and confidence in the results of these RCTs is low. DATA AVAILABILITY All analyzed data are provided in the article. LEVEL OF EVIDENCE Level I (therapeutic study = RCT).
Collapse
|
|
17
|
Rewley J, Guszcza J, Dierst-Davies R, Steier D, Szwartz G, Patel M. Loss Aversion Explains Physical Activity Changes in a Behavioral Gamification Trial. Games Health J 2021; 10:430-436. [PMID: 34860130 DOI: 10.1089/g4h.2021.0130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Introduction: Loss aversion when using gamification is incompletely understood. The aim of this study was therefore to examine how participants alter their behavior vis-a-vis meeting a daily step goal based on the prospect of losing or gaining a gamification level. Methods: We enrolled 602 participants across four arms who were given pedometers. In the three experimental arms, participants began at the medium level and were allocated 70 points each week, losing 10 points each day they did not meet their step goal. Having at least 40 points at the end of the week resulted in a level increase, otherwise they lost a level. We fit a generalized estimating equation, clustered on participants, modeling step goal attainment on day 7. Our primary predictor was a categorical variable simultaneously indicating what level the participants began the week in and whether they had more than, less than, or exactly 40 points after 6 days. Results: Participants at risk of losing the highest level were 18.40% (confidence interval [95% CI]: 18.26-19.90) more likely to meet their step goal than those who had secured the highest level. Participants who could potentially move from the low to the medium level were 10.61% (95% CI: 9.98-11.24) more likely to meet their step goal than those in the Control group. Those in the Medium group were similarly more likely to achieve their step goal on day 7 (10.00%, 95% CI: 9.15-10.85) than those who had already secured an increase to the high level. Discussion: We find that participants in this trial generally exhibit loss aversion so long as the loss relates to something that was earned rather than endowed. This knowledge can be incorporated in future interventions using gamification by requiring participants to earn all levels as they progress. ClinicalTrials.gov identifier: NCT03311230.
Collapse
Affiliation(s)
- Jeffrey Rewley
- Center for Health Equity Research and Promotion, Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA.,Leonard Davis Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - James Guszcza
- Deloitte Touche Tohmatsu Limited, New York, New York, USA
| | | | - David Steier
- Heinz College, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA
| | | | - Mitesh Patel
- Center for Health Equity Research and Promotion, Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA.,Leonard Davis Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Health Care Management, The Wharton School, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
18
|
Renneberg B, Schulze J, Böhme S, West SG, Schüz B. Effectiveness and equity evaluation of an insurance-wide telephone-counseling program for self-management of chronic diseases: The Health Coach Study. Appl Psychol Health Well Being 2021; 14:606-625. [PMID: 34796658 DOI: 10.1111/aphw.12322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 11/05/2021] [Indexed: 11/30/2022]
Abstract
Trajectories of chronic illnesses depend on patient socioeconomic status (SES). This study examines main and equity effects (age, gender, education, region of residence) of a brief telephone self-management intervention on self-rated health and depressive symptoms of health insurance clients with chronic illnesses. Randomized invitation design (n = 2628) with predominantly male (82%) older individuals (modal age = 65-74) with one or more chronic illnesses. Primary outcomes: Self-rated health and depressive symptoms. Intervention: Brief CBT-based telephone counseling. Propensity score matching was used to equate intervention and control groups (n = 1314 pairs). Change score models were used to analyze changes in health-related outcome measures. The intervention resulted in improvements in self-rated health (d = .37) and fewer depressive symptoms (d = .17) over 4 and 6 months. There were comparable effects across education and regions, but younger and female participants profited more from the intervention compared with older and male participants. A brief telephone-based intervention led to improved self-rated health and well-being in a large sample of participants with chronic health conditions. This effect was observed over and above regular medical care. The intervention was equitable with respect to education and region, but not age and gender.
Collapse
Affiliation(s)
- Babette Renneberg
- Department of Clinical Psychology and Psychotherapy, Freie Universität Berlin, Berlin, Germany
| | - Julian Schulze
- Division of Psychological Assessment, Differential and Personality Psychology, Freie Universität Berlin, Berlin, Germany
| | - Sylvia Böhme
- Department of Clinical Psychology and Psychotherapy, Freie Universität Berlin, Berlin, Germany
| | - Stephen G West
- Psychology Department, Arizona State University, Tempe, Arizona, USA
| | - Benjamin Schüz
- Institute for Public Health and Nursing Research, University of Bremen, Bremen, Germany
| |
Collapse
|
|
19
|
Improved emotion regulation in depression following cognitive remediation: A randomized controlled trial. Behav Res Ther 2021; 147:103991. [PMID: 34740101 DOI: 10.1016/j.brat.2021.103991] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 08/23/2021] [Accepted: 10/25/2021] [Indexed: 01/18/2023]
Abstract
OBJECTIVE Executive functions (EFs) play a key role in emotion regulation and, related to this, depression. Cognitive remediation (CR) targeting EFs, such as Goal Management Training (GMT) and computerized cognitive training (CCT), may reduce maladaptive emotion regulation. However, the clinical potential of GMT in the context of depression and emotion regulation remains to be tested. Hence, the primary aim of the present study was to compare effects of GMT with CCT on symptoms of emotion dysregulation. METHOD The paper reports the effects of a preregistered randomized controlled trial. Sixty-three participants (18-60yrs) with active or remitted depression and EF complaints were randomized to nine sessions of GMT (n = 35) or CCT (n = 28). All were assessed at baseline, post-intervention, and at 6-month follow-up. The Ruminative Response Scale and the Difficulties in Emotion Regulation Scale were employed to assess emotion regulation. RESULTS Both groups improved following the intervention on emotion regulation domains after controlling for intention-to-treat, including brooding rumination and on items reflecting non-accepting reactions to distress. Relative to CCT, the GMT-group demonstrated increased clarity of emotional responses in the per protocol analysis. CONCLUSIONS Our findings demonstrate the potential of GMT and CCT in reducing maladaptive emotion regulation in depression.
Collapse
|
|
20
|
Kiefer C, Mayer A. Accounting for Latent Covariates in Average Effects from Count Regressions. MULTIVARIATE BEHAVIORAL RESEARCH 2021; 56:579-594. [PMID: 32329366 DOI: 10.1080/00273171.2020.1751027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
The effectiveness of a treatment on a count outcome can be assessed using a negative binomial regression, where treatment effects are defined as the difference between the expected outcome under treatment and under control. These treatment effects can to date only be estimated if all covariates are manifest (observed) variables. However, some covariates are latent variables that are measured by multiple fallible indicators. In such cases, it is important to control for measurement error of covariates in order to avoid attenuation bias and to get unbiased treatment effect estimates. In this paper, we propose a new approach to compute average and conditional treatment effects in regression models with a logarithmic link function involving multiple latent and manifest covariates. We extend the previously presented moment-based approach in several aspects: Building on a multigroup SEM framework for count variables instead of the generalized linear model, we allow for latent covariates and multiple covariates. We provide an illustrative example to explain the application and estimation in structural equation modeling software.
Collapse
Affiliation(s)
| | - Axel Mayer
- Institute of Psychology, RWTH Aachen University
| |
Collapse
|
|
21
|
Azarpazhooh MR, Bogiatzi C, Spence JD. Stroke Prevention: Little-Known and Neglected Aspects. Cerebrovasc Dis 2021; 50:622-635. [PMID: 34044404 DOI: 10.1159/000515829] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 03/10/2021] [Indexed: 11/19/2022] Open
Abstract
Combining available therapies has the potential to reduce the risk of stroke by 80% or more. A comprehensive review of all aspects of stroke prevention would be very lengthy; in this narrative review, we focus on some aspects of stroke prevention that are little-known and/or neglected. These include the following: (1) implementation of a Mediterranean diet; (2) B vitamins to lower homocysteine; (3) coordinated approaches to smoking cessation; (4) intensive lipid-lowering therapy; (5) lipid lowering in the elderly; (6) physiologically individualized therapy for hypertension based on renin/aldosterone phenotyping; (7) avoiding excessive blood pressure reduction in patients with stiff arteries; (8) treatment of insulin resistance with pioglitazone in stroke patients with prediabetes and diabetes; (9) impaired activation of clopidogrel in patients with variants of CYP2C19; (10) aspirin pseudoresistance due to enteric coating; (11) rationale for anticoagulation in patients with embolic stroke of unknown source; (12) pharmacologic properties of direct-acting oral anticoagulants that should be considered when choosing among them; (13) the identification of which patients with asymptomatic carotid stenosis are at a high enough risk to benefit from carotid endarterectomy or stenting; and (14) the importance of age in choosing between endarterectomy and stenting. Stroke prevention could be improved by better recognition of these issues and by implementation of the principles derived from them.
Collapse
Affiliation(s)
- M Reza Azarpazhooh
- Division of Neurology and Department of Epidemiology & Biostatistics, Western University, London, Ontario, Canada
| | - Chrysi Bogiatzi
- Department of Neurology, McMaster University, Hamilton, Ontario, Canada
| | - J David Spence
- Stroke Prevention & Atherosclerosis Research Center, Robarts Research Institute, Western University, London, Ontario, Canada
| |
Collapse
|
|
22
|
Akacha M, Bartels C, Bornkamp B, Bretz F, Coello N, Dumortier T, Looby M, Sander O, Schmidli H, Steimer JL, Vong C. Estimands-What they are and why they are important for pharmacometricians. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2021; 10:279-282. [PMID: 33951755 PMCID: PMC8090974 DOI: 10.1002/psp4.12617] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 02/02/2021] [Accepted: 02/09/2021] [Indexed: 11/08/2022]
Affiliation(s)
- Mouna Akacha
- Clinical Development and Analytics, Novartis Pharma AG, Basel, Switzerland
| | - Christian Bartels
- Clinical Development and Analytics, Novartis Pharma AG, Basel, Switzerland
| | - Björn Bornkamp
- Clinical Development and Analytics, Novartis Pharma AG, Basel, Switzerland
| | - Frank Bretz
- Clinical Development and Analytics, Novartis Pharma AG, Basel, Switzerland
| | - Neva Coello
- Clinical Development and Analytics, Novartis Pharma AG, Basel, Switzerland
| | - Thomas Dumortier
- Clinical Development and Analytics, Novartis Pharma AG, Basel, Switzerland
| | - Michael Looby
- Clinical Development and Analytics, Novartis Pharma AG, Basel, Switzerland
| | - Oliver Sander
- Clinical Development and Analytics, Novartis Pharma AG, Basel, Switzerland
| | - Heinz Schmidli
- Clinical Development and Analytics, Novartis Pharma AG, Basel, Switzerland
| | - Jean-Louis Steimer
- Clinical Development and Analytics, Novartis Pharma AG, Basel, Switzerland
| | - Camille Vong
- Clinical Development and Analytics, Novartis Pharma AG, Basel, Switzerland
| |
Collapse
|
|
23
|
Temporal Factors and Missed Doses of Tuberculosis Treatment. A Causal Associations Approach to Analyses of Digital Adherence Data. Ann Am Thorac Soc 2021; 17:438-449. [PMID: 31860328 PMCID: PMC7175980 DOI: 10.1513/annalsats.201905-394oc] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Rationale: Tuberculosis treatment lasts for 6 months or more. Treatment adherence is critical; regimen length, among other factors, makes this challenging. Globally, analyses mapping common types of nonadherence are lacking. For example, is there a greater challenge resulting from early treatment cessation (discontinuation) or intermittent missed doses (suboptimal dosing implementation)? This is essential knowledge for the development of effective interventions and more “forgiving” regimens, as well as to direct national tuberculosis programs. Objectives: To granularly describe how patients take their tuberculosis medication and the temporal factors associated with missed doses. Methods: The present study included patients with pulmonary tuberculosis enrolled in the control arm of a pragmatic, cluster-randomized trial in China of electronic reminders to improve treatment adherence. Treatment was the standard 6-month course (180 d), dosed every other day (90 doses). Medication monitor boxes recorded adherence (box opening) without prompting reminders. Patterns of adherence were visualized and described. Mixed-effects logistic regression models examined the temporal factors associated with per-dose suboptimal dosing implementation, adjusting for clustering within a participant. Cox regression models were used to examine the association between early suboptimal dosing implementation and permanent discontinuation. Results: Across 780 patients, 16,794 (23.9%) of 70,200 doses were missed, 9,487 of which were from suboptimal dosing implementation (56.5%). By 60 days, 5.1% of participants had discontinued, and 14.4% had discontinued by 120 days. Most participants (95.9%) missed at least one dose. The majority of gaps were of a single dose (71.4%), although 22.6% of participants had at least one gap of 2 weeks or more. In adjusted models, the initiation–continuation phase transition (odds ratio, 3.07 [95% confidence interval, 2.68–3.51]) and national holidays (1.52 [1.39–1.65]) were associated with increased odds of suboptimal dosing implementation. Early-stage suboptimal dosing implementation was associated with increased discontinuation rates. Conclusions: Digital tools provide an unprecedented step change in describing and addressing nonadherence. In our setting, nonadherence was common; patients displayed a complex range of patterns. Dividing nonadherence into suboptimal dosing implementation and discontinuation, we found that both increased over time. Discontinuation was associated with early suboptimal dosing implementation. These apparent causal associations between temporal factors and nonadherence present opportunities for targeted interventions. Clinical trial registered with the ISRCTN Registry (ISRCTN46846388).
Collapse
|
|
24
|
Webster-Clark M, Stürmer T, Wang T, Man K, Marinac-Dabic D, Rothman KJ, Ellis AR, Gokhale M, Lunt M, Girman C, Glynn RJ. Using propensity scores to estimate effects of treatment initiation decisions: State of the science. Stat Med 2020; 40:1718-1735. [PMID: 33377193 DOI: 10.1002/sim.8866] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 12/11/2020] [Accepted: 12/14/2020] [Indexed: 02/02/2023]
Abstract
Confounding can cause substantial bias in nonexperimental studies that aim to estimate causal effects. Propensity score methods allow researchers to reduce bias from measured confounding by summarizing the distributions of many measured confounders in a single score based on the probability of receiving treatment. This score can then be used to mitigate imbalances in the distributions of these measured confounders between those who received the treatment of interest and those in the comparator population, resulting in less biased treatment effect estimates. This methodology was formalized by Rosenbaum and Rubin in 1983 and, since then, has been used increasingly often across a wide variety of scientific disciplines. In this review article, we provide an overview of propensity scores in the context of real-world evidence generation with a focus on their use in the setting of single treatment decisions, that is, choosing between two therapeutic options. We describe five aspects of propensity score analysis: alignment with the potential outcomes framework, implications for study design, estimation procedures, implementation options, and reporting. We add context to these concepts by highlighting how the types of comparator used, the implementation method, and balance assessment techniques have changed over time. Finally, we discuss evolving applications of propensity scores.
Collapse
Affiliation(s)
| | - Til Stürmer
- Department of Epidemiology, UNC Chapel Hill, Chapel Hill, North Carolina, USA
| | - Tiansheng Wang
- Department of Epidemiology, UNC Chapel Hill, Chapel Hill, North Carolina, USA
| | - Kenneth Man
- Research Department of Practice and Policy, UCL School of Pharmacy, London, UK.,Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, University of Hong Kong, Hong Kong
| | - Danica Marinac-Dabic
- Office of Clinical Evidence and Analysis, FDA Center for Devices and Radiological Health, Silver Springs, Maryland, USA
| | - Kenneth J Rothman
- RTI Health Solutions, Raleigh, North Carolina, USA.,Department of Epidemiology, Boston University, Boston, Massachusetts, USA
| | - Alan R Ellis
- Department of Social Work, NC State University, Raleigh, North Carolina, USA
| | - Mugdha Gokhale
- Department of Epidemiology, UNC Chapel Hill, Chapel Hill, North Carolina, USA.,Pharmacoepidemiology, Center for Observational & Real-World Evidence, Merck, West Point, Pennsylvania, USA
| | - Mark Lunt
- The Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester, UK
| | - Cynthia Girman
- Department of Epidemiology, UNC Chapel Hill, Chapel Hill, North Carolina, USA.,CERobs Consulting, LLC, Chapel Hill, North Carolina, USA
| | - Robert J Glynn
- Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
25
|
Hernandez M, Lee JJ, Yeap BY, Ye R, Foote RL, Busse P, Patel SH, Dagan R, Snider J, Mohammed N, Lin A, Blanchard P, Cantor SB, Teferra MY, Hutcheson K, Yepes P, Mohan R, Liao Z, DeLaney TF, Frank SJ. The Reality of Randomized Controlled Trials for Assessing the Benefit of Proton Therapy: Critically Examining the Intent-to-Treat Principle in the Presence of Insurance Denial. Adv Radiat Oncol 2020; 6:100635. [PMID: 33732960 PMCID: PMC7940795 DOI: 10.1016/j.adro.2020.100635] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 11/04/2020] [Accepted: 11/17/2020] [Indexed: 11/29/2022] Open
Abstract
Purpose This study hypothesized that insurance denial would lead to bias and loss of statistical power when evaluating the results from an intent-to-treat (ITT), per-protocol, and as-treated analyses using a simulated randomized clinical trial comparing proton therapy to intensity modulated radiation therapy where patients incurred increasing rates of insurance denial. Methods and Materials Simulations used a binary endpoint to assess differences between treatment arms after applying ITT, per-protocol, and as-treated analyses. Two scenarios were developed: 1 with clinical success independent of age and another assuming dependence on age. Insurance denial was assumed possible for patients <65 years. All scenarios considered an age distribution with mean ± standard deviation: 55 ± 15 years, rates of insurance denial ranging from 0%-40%, and a sample of N = 300 patients (150 per arm). Clinical success rates were defined as 70% for proton therapy and 50% for intensity modulated radiation therapy. The average treatment effect, bias, and power were compared after applying 5000 simulations. Results Increasing rates of insurance denial demonstrated inherent weaknesses among all 3 analytical approaches. With clinical success independent of age, a per-protocol analysis demonstrated the least bias and loss of power. When clinical success was dependent on age, the per-protocol and ITT analyses resulted in a similar trend with respect to bias and loss of power, with both outperforming the as-treated analysis. Conclusions Insurance denial leads to misclassification bias in the ITT analysis, a missing data problem in the per-protocol analysis, and covariate imbalance between treatment arms in the as-treated analysis. Moreover, insurance denial forces the critical appraisal of patient features (eg, age) affected by the denial and potentially influencing clinical success. In the presence of insurance denial, our study suggests cautious reporting of ITT and as-treated analyses, and placing primary emphasis on the results of the per-protocol analysis.
Collapse
Affiliation(s)
- Mike Hernandez
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - J Jack Lee
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Beow Y Yeap
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Rong Ye
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Robert L Foote
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - Paul Busse
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Samir H Patel
- Department of Radiation Oncology, Mayo Clinic, Phoenix, Arizona
| | - Roi Dagan
- Department of Radiation Oncology, University of Florida Health, Gainesville, Florida
| | - James Snider
- Department of Radiation Oncology, University of Maryland Medical System, Baltimore, Maryland
| | - Nasiruddin Mohammed
- Department of Radiation Oncology, Northwestern Medicine, Warrenville, Illinois
| | - Alexander Lin
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Pierre Blanchard
- Department of Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif, France.,Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Scott B Cantor
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Menna Y Teferra
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kate Hutcheson
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Pablo Yepes
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Physics and Astronomy, Rice University, Houston, Texas
| | - Radhe Mohan
- Department of Physics and Astronomy, Rice University, Houston, Texas
| | - Zhongxing Liao
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Thomas F DeLaney
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Steven J Frank
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| |
Collapse
|
|
26
|
Spiegelman D, Lovato LC, Khudyakov P, Wilkens TL, Adebamowo CA, Adebamowo SN, Appel LJ, Beulens JWJ, Coughlin JW, Dragsted LO, Edenberg HJ, Eriksen JN, Estruch R, Grobbee DE, Gulayin PE, Irazola V, Krystal JH, Lazo M, Murray MM, Rimm EB, Schrieks IC, Williamson JD, Mukamal KJ. The Moderate Alcohol and Cardiovascular Health Trial (MACH15): Design and methods for a randomized trial of moderate alcohol consumption and cardiometabolic risk. Eur J Prev Cardiol 2020; 27:1967-1982. [PMID: 32250171 PMCID: PMC7541556 DOI: 10.1177/2047487320912376] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Observational studies have documented lower risks of coronary heart disease and diabetes among moderate alcohol consumers relative to abstainers, but only a randomized clinical trial can provide conclusive evidence for or against these associations. AIM The purpose of this study was to describe the rationale and design of the Moderate Alcohol and Cardiovascular Health Trial, aimed to assess the cardiometabolic effects of one alcoholic drink daily over an average of six years among adults 50 years or older. METHODS This multicenter, parallel-arm randomized trial was designed to compare the effects of one standard serving (∼11-15 g) daily of a preferred alcoholic beverage to abstention. The trial aimed to enroll 7800 people at high risk of cardiovascular disease. The primary composite endpoint comprised time to the first occurrence of non-fatal myocardial infarction, non-fatal ischemic stroke, hospitalized angina, coronary/carotid revascularization, or total mortality. The trial was designed to provide >80% power to detect a 15% reduction in the risk of the primary outcome. Secondary outcomes included diabetes. Adverse effects of special interest included injuries, congestive heart failure, alcohol use disorders, and cancer. RESULTS We describe the design, governance, masking issues, and data handling. In three months of field center activity until termination by the funder, the trial randomized 32 participants, successfully screened another 70, and identified ∼400 additional interested individuals. CONCLUSIONS We describe a feasible design for a long-term randomized trial of moderate alcohol consumption. Such a study will provide the highest level of evidence for the effects of moderate alcohol consumption on cardiovascular disease and diabetes, and will directly inform clinical and public health guidelines.
Collapse
Affiliation(s)
| | | | | | | | - Clement A Adebamowo
- Department of Epidemiology and Public Health, Greenebaum Comprehensive Cancer Center, University of Maryland, School of Medicine, USA
| | - Sally N Adebamowo
- Department of Epidemiology and Public Health, Greenebaum Comprehensive Cancer Center, University of Maryland, School of Medicine, USA
| | - Lawrence J Appel
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins ProHealth Clinical Research Center, USA
| | - Joline WJ Beulens
- Amsterdam UMC – location VUmc, Amsterdam Cardiovascular Sciences Research Institute, Netherlands
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Netherlands
| | - Janelle W Coughlin
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins ProHealth Clinical Research Center, USA
| | | | | | | | - Ramon Estruch
- CIBER de Fisiopatología de la Obesidad y la Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
- Department of Internal Medicine, Hospital Clínic, IDIBAPS August Pi i Sunyer Biomedical Research Institute, University of Barcelona, Spain
| | | | - Pablo E Gulayin
- Institute for Clinical Effectiveness and Health Policy, Argentina
| | - Vilma Irazola
- Institute for Clinical Effectiveness and Health Policy, Argentina
| | | | - Mariana Lazo
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins ProHealth Clinical Research Center, USA
| | - Margaret M Murray
- National Institute on Alcohol Abuse and Alcoholism, U.S. National Institutes of Health, USA
| | - Eric B Rimm
- Harvard TH Chan School of Public Health, USA
- Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, USA
| | | | | | | |
Collapse
|
|
27
|
Chen J, Xiao H, Chen Y, Sun H, Chen S, Zheng J. Effect of reminiscence therapy based on positive psychology theory (RTBPPT) on the positive feelings of the spousal caregivers of elderly patients with advanced cancer in China. Eur J Cancer Care (Engl) 2020; 29:e13324. [PMID: 32885518 DOI: 10.1111/ecc.13324] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 05/21/2020] [Accepted: 08/07/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Elderly patients with advanced cancer often experience various symptoms and need a great amount of care. However, their spousal caregivers are prone to negative emotions because of old age, poor health and the heavy burden of care. OBJECTIVE To examine the effect of a reminiscence therapy (RT) intervention on the spousal caregivers of elderly patients with advanced cancer. METHODS This study was a randomised controlled trial. Fifty-six spousal caregivers were randomly assigned to the control group (N = 29) receiving usual care and the experimental group (N = 27) receiving the RT intervention. The caregivers' caregiving burden, positive feelings towards caregiving and hope were measured before and immediately after the intervention. RESULTS The experimental group showed a significant reduction in the burden of spousal care compared to the control group (p < .01). The experimental group also had higher levels of positive feelings and hope than did the control group (p < .01). CONCLUSION RT is an effective approach to reducing the care burden of spouses of elderly patients with advanced cancer and enhancing the spouses' positive feelings and hope.
Collapse
Affiliation(s)
- Jingjing Chen
- School of Nursing, Fujian Medical University, Fuzhou, China
| | - Huimin Xiao
- School of Nursing, Fujian Medical University, Fuzhou, China
| | - Ying Chen
- School of Nursing, Fujian Medical University, Fuzhou, China
| | - Haiyan Sun
- Department of Oncology, The Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Shaohua Chen
- School of Nursing, Capital Medical University, Beijing, China
| | - Jianjing Zheng
- Department of Oncology, Fujian Provincial Hospital, Fuzhou, China
| |
Collapse
|
|
28
|
Allore HG, Goldfeld KS, Gutman R, Li F, Monin JK, Taljaard M, Travison TG. Statistical Considerations for Embedded Pragmatic Clinical Trials in People Living with Dementia. J Am Geriatr Soc 2020; 68 Suppl 2:S68-S73. [PMID: 32589276 PMCID: PMC7396162 DOI: 10.1111/jgs.16616] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 04/09/2020] [Accepted: 04/10/2020] [Indexed: 12/17/2022]
Abstract
There is overwhelming need for nonpharmacological interventions to improve the health and well-being of people living with dementia (PLWD). The National Institute on Aging Imbedded Pragmatic Alzheimer's Disease (AD) and AD-Related Dementias Clinical Trials (IMPACT) Collaboratory supports clinical trials of such interventions embedded in healthcare systems. The embedded pragmatic clinical trial (ePCT) is ideally suited to testing the effectiveness of complex interventions in vulnerable populations at the point of care. These trials, however, are complex to conduct and interpret, and face challenges in efficiency (i.e., statistical power) and reproducibility. In addition, trials conducted among PLWD present specific statistical challenges, including difficulty in outcomes ascertainment from PLWD, necessitating reliance on reports by caregivers, and heterogeneity in measurements across different settings or populations. These and other challenges undercut the reliability of measurement, the feasibility of capturing outcomes using pragmatic designs, and the ability to validly estimate interventions' effectiveness in real-world settings. To address these challenges, the IMPACT Collaboratory has convened a Design and Statistics Core, the goals of which are: to support the design and conduct of ePCTs directed toward PLWD and their caregivers; to develop guidance for conducting embedded trials in this population; and to educate quantitative and clinical scientists in the design, conduct, and analysis of these trials. In this article, we discuss some of the contemporary methodological challenges in this area and develop a set of research priorities the Design and Statistics Core will undertake to meet these goals. J Am Geriatr Soc 68:S68-S73, 2020.
Collapse
Affiliation(s)
- Heather G. Allore
- Department of Biostatistics, School of Public Health, Yale University, New Haven, Connecticut
- Section of Geriatrics, Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut
| | - Keith S. Goldfeld
- Division of Biostatistics, Department of Population Health, NYU Grossman School of Medicine, New York, New York
| | - Roee Gutman
- Department of Biostatistics, Brown University School of Public Health, Providence, Rhode Island
| | - Fan Li
- Department of Biostatistics, School of Public Health, Yale University, New Haven, Connecticut
| | - Joan K. Monin
- Department of Social and Behavioral Sciences, School of Public Health, Yale University, New Haven, Connecticut
| | - Monica Taljaard
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Thomas G. Travison
- Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
- Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts
| |
Collapse
|
|
29
|
Chis Ster AM, Cornelius V, Cro S. Current approaches to handling rescue medication in asthma and eczema randomized controlled trials are inadequate: a systematic review. J Clin Epidemiol 2020; 125:148-157. [PMID: 32504781 PMCID: PMC7482905 DOI: 10.1016/j.jclinepi.2020.05.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 05/05/2020] [Accepted: 05/28/2020] [Indexed: 01/10/2023]
Abstract
Objectives The objective of this study was to examine how rescue medication is defined, reported, and accounted for in randomized controlled trials (RCTs) in eczema and asthma populations. Study Design and Setting This is a systematic review of phase II/III RCTs evaluating monoclonal antibodies for treating chronic eczema or asthma. A search of EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials was conducted to identify eligible RCTs. Results Sixty published RCTs were identified, of which 60 (100%) allowed use of rescue medication but only 28 (47%) reported its use. Twenty-seven (45%) articles summarized rescue use by arm, with an average of 25% (95% CI (17%, 36%)) greater use in the placebo arm. Nine (15%) trials undertook an analysis that adjusted the primary treatment effect estimate for rescue medication use, but 8 of these used a suboptimal approach using single imputation, including 4 which used “last observation carried forward” after setting postrescue data to missing. Conclusion Rescue medication use in eczema and asthma trials evaluating monoclonal antibodies is often permitted, but not routinely reported. There is evidence of imbalance in rescue use between arms, but few articles attempted to estimate a rescue-adjusted treatment effect. In trials that did, the methods used were suboptimal which could introduce bias.
Collapse
Affiliation(s)
- Anca Maria Chis Ster
- Imperial College London, Imperial College Clinical Trials Unit, 1st Floor Stadium House, 68 Wood Lane, London W12 7RH, UK
| | - Victoria Cornelius
- Imperial College London, Imperial College Clinical Trials Unit, 1st Floor Stadium House, 68 Wood Lane, London W12 7RH, UK
| | - Suzie Cro
- Imperial College London, Imperial College Clinical Trials Unit, 1st Floor Stadium House, 68 Wood Lane, London W12 7RH, UK.
| |
Collapse
|
|
30
|
Affiliation(s)
- Joseph R. Dettori
- Spectrum Research, Inc, Steilacoom, WA, USA,Joseph R. Dettori, Spectrum Research, Inc, PO Box
88998, Steilacoom, WA 98388, USA.
| | | |
Collapse
|
|
31
|
Graham AL, Papandonatos GD, Cha S, Erar B, Amato MS. Improving Adherence to Smoking Cessation Treatment: Smoking Outcomes in a Web-based Randomized Trial. Ann Behav Med 2019; 52:331-341. [PMID: 29878062 DOI: 10.1093/abm/kax023] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Background Partial adherence in Internet smoking cessation interventions presents treatment and evaluation challenges. Increasing adherence may improve outcomes. Purpose To present smoking outcomes from an Internet randomized trial of two strategies to encourage adherence to tobacco dependence treatment components: (i) a social network (SN) strategy to integrate smokers into an online community and (ii) free nicotine replacement therapy (NRT). In addition to intent-to-treat analyses, we used novel statistical methods to distinguish the impact of treatment assignment from treatment utilization. Methods A total of 5,290 current smokers on a cessation website (WEB) were randomized to WEB, WEB + SN, WEB + NRT, or WEB + SN + NRT. The main outcome was 30-day point prevalence abstinence at 3 and 9 months post-randomization. Adherence measures included self-reported medication use (meds), and website metrics of skills training (sk) and community use (comm). Inverse Probability of Retention Weighting and Inverse Probability of Treatment Weighting jointly addressed dropout and treatment selection. Propensity weights were used to calculate Average Treatment effects on the Treated. Results Treatment assignment analyses showed no effects on abstinence for either adherence strategy. Abstinence rates were 25.7%-32.2% among participants that used all three treatment components (sk+comm +meds).Treatment utilization analyses revealed that among such participants, sk+comm+meds yielded large percentage point increases in 3-month abstinence rates over sk alone across arms: WEB = 20.6 (95% CI = 10.8, 30.4), WEB + SN = 19.2 (95% CI = 11.1, 27.3), WEB + NRT = 13.1 (95% CI = 4.1, 22.0), and WEB + SN + NRT = 20.0 (95% CI = 12.2, 27.7). Conclusions Novel propensity weighting approaches can serve as a model for establishing efficacy of Internet interventions and yield important insights about mechanisms. Clinical Trials.gov NCT01544153.
Collapse
Affiliation(s)
- Amanda L Graham
- Schroeder Institute for Tobacco Research and Policy Studies, Truth Initiative, Washington, DC, USA.,Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center/Cancer Prevention and Control Program, Washington, DC, USA
| | - George D Papandonatos
- Department of Biostatistics, Brown University School of Public Health, Providence, RI, USA
| | - Sarah Cha
- Schroeder Institute for Tobacco Research and Policy Studies, Truth Initiative, Washington, DC, USA
| | - Bahar Erar
- Department of Biostatistics, Brown University School of Public Health, Providence, RI, USA
| | - Michael S Amato
- Schroeder Institute for Tobacco Research and Policy Studies, Truth Initiative, Washington, DC, USA
| |
Collapse
|
|
32
|
Briceno D, Mohanty P, Di Biase L, Romero J, Rocca DGD, Trivedi C, Mohanty S, Natale A. CABANA trial: "beauty is in the eye of the beholder". J Interv Card Electrophysiol 2019; 57:1-3. [PMID: 31493123 DOI: 10.1007/s10840-019-00604-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 07/29/2019] [Indexed: 10/26/2022]
Abstract
The CABANA trial reported that catheter ablation, when compared with drug therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest in patients with atrial fibrillation. Despite multiple limitations in study design, the CABANA trial still confirmed that catheter ablation of atrial fibrillation led to clinically important and significant improvements in quality of life at 12 months without increasing the risk of complications.
Collapse
Affiliation(s)
- David Briceno
- Montefiore-Einstein Center for Heart and Vascular Care, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th St. Bronx, New York, NY, 10467, USA
| | - Prasant Mohanty
- Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, TX, 78705, USA
| | - Luigi Di Biase
- Montefiore-Einstein Center for Heart and Vascular Care, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th St. Bronx, New York, NY, 10467, USA. .,Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, TX, 78705, USA.
| | - Jorge Romero
- Montefiore-Einstein Center for Heart and Vascular Care, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th St. Bronx, New York, NY, 10467, USA
| | | | - Chintan Trivedi
- Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, TX, 78705, USA
| | - Sanghamitra Mohanty
- Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, TX, 78705, USA
| | - Andrea Natale
- Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, TX, 78705, USA
| |
Collapse
|
|
33
|
Ng SK, Byrnes J, Scuffham P. Identifying compliant participants through data matching improved estimation of intervention efficacy: randomized trials with opt-in/opt-out strategies. J Clin Epidemiol 2019; 115:125-132. [PMID: 31351121 DOI: 10.1016/j.jclinepi.2019.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 07/02/2019] [Accepted: 07/17/2019] [Indexed: 11/20/2022]
Abstract
OBJECTIVES We propose a data-matching approach to estimate intervention efficacy for randomized controlled trials (RCTs) when there is noncompliance to the allocated treatment with induced selection bias. STUDY DESIGN AND SETTING We considered a large RCT to compare health care costs and hospital length of stay 12 months after randomization. Participants allocated to the intervention group were eligible to receive health-coaching and disease-management services. An opt-out approach was adopted for recruitment. Control-group participants received usual care but were allowed to opt-in to receive the intervention. Using "nearest-neighbor"-matched data, we identified compliant participants in both arms to estimate intervention efficacy. Results were compared with intention-to-treat (ITT), instrumental-variable-adjusted ITT, per-protocol (PP), and as-treated (AT) analyses. RESULTS The ITT estimated an intervention effect of a 1.5% reduction in cost, but 56.7% of intervention-group participants did not receive health coaching. The PP and AT found an increase in cost of 9.4% and 17.1%, respectively. The matching method estimated a 12.3% reduction in cost. After adjustment for baseline covariates, the intervention group had lower same-day admission cost (13.6%; 95% CI: 7.3%-20.0%; P < 0.001) and shorter hospital stay (11.2%; 95% CI: 2.6%-19.9%; P = 0.021). CONCLUSION Opt-in/opt-out strategies in RCTs misled intervention comparisons and the matching approach improved estimation of intervention efficacy.
Collapse
Affiliation(s)
- Shu Kay Ng
- School of Medicine and Menzies Health Institute Queensland, Griffith University, Nathan Q4111, Australia.
| | - Joshua Byrnes
- School of Medicine and Menzies Health Institute Queensland, Griffith University, Nathan Q4111, Australia
| | - Paul Scuffham
- School of Medicine and Menzies Health Institute Queensland, Griffith University, Nathan Q4111, Australia
| |
Collapse
|
|
34
|
Engeda JC, Stackhouse A, White M, Rosamond WD, Lhachimi SK, Lund JL, Keyserling TC, Avery CL. Evidence of heterogeneity in statin-associated type 2 diabetes mellitus risk: A meta-analysis of randomized controlled trials and observational studies. Diabetes Res Clin Pract 2019; 151:96-105. [PMID: 30954511 PMCID: PMC6544490 DOI: 10.1016/j.diabres.2019.04.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 03/15/2019] [Accepted: 04/01/2019] [Indexed: 12/31/2022]
Abstract
AIMS To conduct a meta-analysis of statin-associated type 2 diabetes mellitus (T2D) risk among randomized controlled trials (RCTs) and observational studies (OBSs), excluding studies conducted among secondary prevention populations. METHODS Studies were identified by searching PubMed (1994-present) and EMBASE (1994-present). Articles had to meet the following criteria: (1) follow-up >one year; (2) >50% of participants free of clinically diagnosed ASCVD; (3) adult participants ≥30 years old; (4) reported statin-associated T2D effect estimates; and (5) quantified precision using 95% confidence interval. Data were pooled using random-effects model. RESULTS We identified 23 studies (35% RCTs) of n = 4,012,555 participants. OBS participants were on average younger (mean difference = 6.2 years) and had lower mean low-density lipoprotein cholesterol (LDL-C, mean difference = 20.6 mg/dL) and mean fasting plasma glucose (mean difference = 5.2 mg/dL) compared to RCT participants. There was little evidence for publication bias (P > 0.1). However, evidence of heterogeneity was observed overall and among OBSs and RCTs (PCochran = <0.05). OBS designs, younger baseline mean ages, lower LDL-C concentrations, and high proportions of never or former smokers were significantly associated with increased statin-associated T2D risk. CONCLUSIONS Potentially elevated statin-associated T2D risk in younger populations with lower LDL-C merits further investigation in light of evolving statin guidelines targeting primary prevention populations.
Collapse
Affiliation(s)
- Joseph C Engeda
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, United States.
| | - Ashlyn Stackhouse
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Mary White
- School of Information and Library Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Wayne D Rosamond
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Stefan K Lhachimi
- Research Group Evidence-Based Public Health, Leibniz Institute for Epidemiology and Prevention Research (BIPS), Bremen, Germany; Health Sciences Bremen, Institute for Public Health and Nursing, University of Bremen, Bremen, Germany
| | - Jennifer L Lund
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Thomas C Keyserling
- Division of General Medicine and Clinical Epidemiology, University of North Carolina, Chapel Hill, NC, United States; Center for Health Promotion and Disease Prevention, University of North Carolina, Chapel Hill, NC, United States
| | - Christy L Avery
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| |
Collapse
|
|
35
|
Spence JD, Viscoli CM, Inzucchi SE, Dearborn-Tomazos J, Ford GA, Gorman M, Furie KL, Lovejoy AM, Young LH, Kernan WN. Pioglitazone Therapy in Patients With Stroke and Prediabetes: A Post Hoc Analysis of the IRIS Randomized Clinical Trial. JAMA Neurol 2019; 76:526-535. [PMID: 30734043 PMCID: PMC6515584 DOI: 10.1001/jamaneurol.2019.0079] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 10/26/2018] [Indexed: 12/12/2022]
Abstract
Importance In the Insulin Resistance Intervention After Stroke (IRIS) randomized clinical trial, pioglitazone, an insulin-sensitizing agent, reduced the risk for recurrent stroke or myocardial infarction (MI) among patients with insulin resistance. However, insulin resistance is not commonly measured in clinical practice. Objective To analyze the effects of pioglitazone in patients with good adherence as well as intention-to-treat effects of pioglitazone in patients with prediabetes in the IRIS trial. Design, Setting, and Participants The IRIS trial was a randomized multicenter clinical trial in patients with prior stroke or transient ischemic attack as well as insulin resistance but not diabetes. Patients were enrolled from February 2005 to January 2013, and the median follow-up was 4.8 years. The post hoc analyses reported here were performed from June to September 2018. Per American Diabetes Association criteria, prediabetes was defined as having a hemoglobin A1c level of 5.7% to 6.4% or fasting plasma glucose level of 100 mg/dL to 125 mg/dL (to convert to mmol/L, multiply by 0.0555). Good adherence was defined as taking 80% or more of the protocol dose. Fasting glucose and hemoglobin A1c, used to define prediabetes, and adherence of 80% or higher, stipulated in the protocol as defining good adherence, were prespecified subgroups in the analysis plan. Interventions Participants were randomized to 15 mg of pioglitazone, with dose titrated to target of 45 mg daily, or matching placebo. Main Outcomes and Measures The primary outcome was recurrent stroke or MI. Secondary outcomes included stroke, acute coronary syndrome, stroke/MI/hospitalization for heart failure, and progression to diabetes. Results Among 3876 participants analyzed in the IRIS trial, 2885 were included in this analysis (1456 in the pioglitazone cohort and 1429 in the placebo cohort). The mean (SD) age of patients was 64 (11) years, and 974 (66.9%) and 908 (63.5%) of patients were men in the pioglitazone and placebo cohort, respectively. In the prediabetic population with good adherence (644 of 1456 individuals [44.2%] in the pioglitazone group and 810 of 1429 [56.7%] in the placebo group), the hazard ratios (95% CI) were 0.57 (0.39-0.84) for stroke/MI, 0.64 (0.42-0.99) for stroke, 0.47 (0.26-0.85) for acute coronary syndrome, 0.61 (0.42-0.88) for stroke/MI/hospitalization for heart failure, and 0.18 (0.10-0.33) for progression to diabetes. There was a nonsignificant reduction in overall mortality, cancer, and hospitalization, a slight increase in serious bone fractures, and an increase in weight gain and edema. Intention-to-treat results also showed significant reduction of events but to a lesser degree. Hazard ratios (95% CI) were 0.70 (0.56-0.88) for stroke/MI, 0.72 (0.56-0.92) for stroke, 0.72 (0.52-1.00) for acute coronary syndrome, 0.78 (0.63-0.96), for stroke/MI/hospitalization for heart failure, and 0.46 (0.35 to 0.61) for progression to diabetes. Conclusions and Relevance Pioglitazone may be effective for secondary prevention in patients with stroke/transient ischemic attack and with prediabetes, particularly in those with good adherence. Trial Registration ClinicalTrials.gov identifier: NCT00091949.
Collapse
Affiliation(s)
- J. David Spence
- Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Ontario, Canada
| | | | | | | | - Gary A. Ford
- Radcliffe Department of Medicine, University of Oxford, United Kingdom
| | - Mark Gorman
- Department of Neurology, Maine Medical Center, Portland, Maine
| | - Karen L. Furie
- Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Anne M. Lovejoy
- Department of Medicine, Yale School of Medicine, New Haven, Connecticut
| | - Lawrence H. Young
- Department of Medicine, Yale School of Medicine, New Haven, Connecticut
| | - Walter N. Kernan
- Department of Medicine, Yale School of Medicine, New Haven, Connecticut
| |
Collapse
|
|
36
|
Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, Poole JE, Noseworthy PA, Rosenberg YD, Jeffries N, Mitchell LB, Flaker GC, Pokushalov E, Romanov A, Bunch TJ, Noelker G, Ardashev A, Revishvili A, Wilber DJ, Cappato R, Kuck KH, Hindricks G, Davies DW, Kowey PR, Naccarelli GV, Reiffel JA, Piccini JP, Silverstein AP, Al-Khalidi HR, Lee KL. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019; 321:1261-1274. [PMID: 30874766 PMCID: PMC6450284 DOI: 10.1001/jama.2019.0693] [Citation(s) in RCA: 987] [Impact Index Per Article: 164.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
IMPORTANCE Catheter ablation is effective in restoring sinus rhythm in atrial fibrillation (AF), but its effects on long-term mortality and stroke risk are uncertain. OBJECTIVE To determine whether catheter ablation is more effective than conventional medical therapy for improving outcomes in AF. DESIGN, SETTING, AND PARTICIPANTS The Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation trial is an investigator-initiated, open-label, multicenter, randomized trial involving 126 centers in 10 countries. A total of 2204 symptomatic patients with AF aged 65 years and older or younger than 65 years with 1 or more risk factors for stroke were enrolled from November 2009 to April 2016, with follow-up through December 31, 2017. INTERVENTIONS The catheter ablation group (n = 1108) underwent pulmonary vein isolation, with additional ablative procedures at the discretion of site investigators. The drug therapy group (n = 1096) received standard rhythm and/or rate control drugs guided by contemporaneous guidelines. MAIN OUTCOMES AND MEASURES The primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Among 13 prespecified secondary end points, 3 are included in this report: all-cause mortality; total mortality or cardiovascular hospitalization; and AF recurrence. RESULTS Of the 2204 patients randomized (median age, 68 years; 37.2% female; 42.9% had paroxysmal AF and 57.1% had persistent AF), 89.3% completed the trial. Of the patients assigned to catheter ablation, 1006 (90.8%) underwent the procedure. Of the patients assigned to drug therapy, 301 (27.5%) ultimately received catheter ablation. In the intention-to-treat analysis, over a median follow-up of 48.5 months, the primary end point occurred in 8.0% (n = 89) of patients in the ablation group vs 9.2% (n = 101) of patients in the drug therapy group (hazard ratio [HR], 0.86 [95% CI, 0.65-1.15]; P = .30). Among the secondary end points, outcomes in the ablation group vs the drug therapy group, respectively, were 5.2% vs 6.1% for all-cause mortality (HR, 0.85 [95% CI, 0.60-1.21]; P = .38), 51.7% vs 58.1% for death or cardiovascular hospitalization (HR, 0.83 [95% CI, 0.74-0.93]; P = .001), and 49.9% vs 69.5% for AF recurrence (HR, 0.52 [95% CI, 0.45-0.60]; P < .001). CONCLUSIONS AND RELEVANCE Among patients with AF, the strategy of catheter ablation, compared with medical therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest. However, the estimated treatment effect of catheter ablation was affected by lower-than-expected event rates and treatment crossovers, which should be considered in interpreting the results of the trial. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00911508.
Collapse
Affiliation(s)
| | - Daniel B. Mark
- Duke Clinical Research Institute, Duke University, Durham, North Carolina
| | | | | | | | | | | | - Yves D. Rosenberg
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Neal Jeffries
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | | | | | - Evgeny Pokushalov
- E. Meshalkin National Medical Research Center of the Ministry of Health of the Russian Federation, Novosibirsk, Russia
| | - Alexander Romanov
- E. Meshalkin National Medical Research Center of the Ministry of Health of the Russian Federation, Novosibirsk, Russia
| | | | | | - Andrey Ardashev
- Medical Science Center of Moscow State University, Moscow, Russia
| | | | | | | | | | | | | | - Peter R. Kowey
- Sidney Kimmel Medical College, Thomas Jefferson University, Wynnewood, Pennsylvania
| | | | | | | | | | | | - Kerry L. Lee
- Duke Clinical Research Institute, Duke University, Durham, North Carolina
| |
Collapse
|
|
37
|
Mostazir M, Taylor RS, Henley W, Watkins E. An overview of statistical methods for handling nonadherence to intervention protocol in randomized control trials: a methodological review. J Clin Epidemiol 2019; 108:121-131. [DOI: 10.1016/j.jclinepi.2018.12.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 10/29/2018] [Accepted: 12/04/2018] [Indexed: 11/24/2022]
|
|
38
|
Affiliation(s)
- Catalin Tufanaru
- Research Associate The Joanna Briggs Institute Adelaide, South Australia, Australia
| |
Collapse
|
|
39
|
Dodd S, Williamson P, White IR. Adjustment for treatment changes in epilepsy trials: A comparison of causal methods for time-to-event outcomes. Stat Methods Med Res 2019; 28:717-733. [PMID: 29117780 PMCID: PMC6419234 DOI: 10.1177/0962280217735560] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND When trials are subject to departures from randomised treatment, simple statistical methods that aim to estimate treatment efficacy, such as per protocol or as treated analyses, typically introduce selection bias. More appropriate methods to adjust for departure from randomised treatment are rarely employed, primarily due to their complexity and unfamiliarity. We demonstrate the use of causal methodologies for the production of estimands with valid causal interpretation for time-to-event outcomes in the analysis of a complex epilepsy trial, as an example to guide non-specialist analysts undertaking similar analyses. METHODS Two causal methods, the structural failure time model and inverse probability of censoring weighting, are adapted to allow for skewed time-varying confounders, competing reasons for treatment changes and a complicated time to remission outcome. We demonstrate the impact of various factors: choice of method (structural failure time model versus inverse probability of censoring weighting), model for inverse probability of censoring weighting (pooled logistic regression versus Cox models), time interval (for creating panel data for time-varying confounders and outcome), choice of confounders and (in pooled logistic regression) use of splines to estimate underlying risk. RESULTS The structural failure time model could adjust for switches between trial treatments but had limited ability to adjust for the other treatment changes that occurred in this epilepsy trial. Inverse probability of censoring weighting was able to adjust for all treatment changes and demonstrated very similar results with Cox and pooled logistic regression models. Accounting for increasing numbers of time-varying confounders and reasons for treatment change suggested a more pronounced advantage of the control treatment than that obtained using intention to treat. CONCLUSIONS In a complex trial featuring a remission outcome, underlying assumptions of the structural failure time model are likely to be violated, and inverse probability of censoring weighting may provide the most useful option, assuming availability of appropriate data and sufficient sample sizes. Recommendations are provided for analysts when considering which of these methods should be applied in a given trial setting.
Collapse
Affiliation(s)
- Susanna Dodd
- MRC North West Hub for Trials
Methodology Research, Department of Biostatistics, Institute of Translational
Medicine, University of Liverpool, Liverpool, UK
| | - Paula Williamson
- MRC North West Hub for Trials
Methodology Research, Department of Biostatistics, Institute of Translational
Medicine, University of Liverpool, Liverpool, UK
| | - Ian R White
- MRC Biostatistics Unit, Cambridge
Institute of Public Health, Cambridge, UK
- MRC Clinical Trials Unit at UCL,
Institute of Clinical Trials & Methodology, London, UK
| |
Collapse
|
|
40
|
Leight J, Sharma V, Brown W, Costica L, Abdulaziz Sule F, Bjorkman Nyqvist M. Associations between birth kit use and maternal and neonatal health outcomes in rural Jigawa state, Nigeria: A secondary analysis of data from a cluster randomized controlled trial. PLoS One 2018; 13:e0208885. [PMID: 30586441 PMCID: PMC6306201 DOI: 10.1371/journal.pone.0208885] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 11/27/2018] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The burden of maternal and neonatal mortality remains persistently high in Nigeria. Sepsis contributes significantly to both maternal and newborn mortality, and safe delivery kits have long been promoted as a cost-effective intervention to ensure hygienic delivery practices and reduce sepsis. However, there is limited evidence on the effectiveness of home birth kit distribution by community health workers, and particularly the impact of this intervention on health outcomes. This paper reports a secondary analysis of data from a cluster randomized trial in rural northern Nigeria in which birth kits were distributed by community health workers to pregnant women in their homes, analyzing non-experimental variation in receipt and use of birth kits. More specifically, associations between pregnant women's baseline characteristics and receipt and use of birth kits, and associations between birth kit use, care utilization and maternal and newborn outcomes were assessed. METHODS AND FINDINGS Baseline, post-birth and endline data related to 3,317 births observed over a period of three years in 72 intervention communities in Jigawa state, Nigeria, were analyzed using hierarchical, logistic regression models. In total, 140 women received birth kits, and 72 women used the kits. There were no associations between baseline demographic characteristics, health history, and knowledge and attitudes and receipt of a kit, suggesting that community health workers did not systematically target the distribution of birth kits. However, women who used the kit reported reduced odds of past pregnancy complications (OR = 0.44, 95% CI: 0.19-1.00) as well as significantly higher odds of feeling generally healthy at baseline (OR = 2.00, 95% CI: 1.06-3.76), of exposure to radio media (OR = 1.97, 95% CI: 1.21-3.22), and of perceiving themselves as having a low-risk pregnancy (OR = 3.05, 95% CI:1.39-6.68). While there were no significant associations between birth kit use and facility based delivery, skilled birth attendance or post-natal care, women who used a kit exhibited significantly lower odds of completing four or more ANC visits (adjusted OR = 0.39, 95% CI: 0.18-0.85) and significantly higher odds of reporting prolonged labor (adjusted OR = 4.75, 95% CI: 1.36-16.59), and post-partum bleeding (adjusted OR = 3.25, 95% CI: 1.11-9.52). CONCLUSIONS This evidence suggests that use of birth kits is low in a rural population characterized by minimal baseline utilization of maternal and neonatal health services, and the use of birth kits was not associated with reductions in maternal or neonatal morbidity. While further research is required to understand how the effectiveness of birth kits may be shaped by the mechanism through which women access and utilize the kits, our findings suggest that the provision of kits to women outside of the formal health system may be associated with increased risk of adverse outcomes.
Collapse
Affiliation(s)
- Jessica Leight
- Economics Department, American University, Washington, D.C., United States of America
| | - Vandana Sharma
- Harvard T.H. Chan School of Public Health, Cambridge, MA, United States of America
| | - Willa Brown
- Abdul Latif Jameel Poverty Action Lab, Massachusetts Institute of Technology, Cambridge, MA, United States of America
| | - Laura Costica
- Planned Parenthood Federation of Nigeria, Abuja, Nigeria
| | - Fatima Abdulaziz Sule
- Economics Department, American University, Washington D.C., United States of America
| | | |
Collapse
|
|
41
|
Allman PH, Aban IB, Tiwari HK, Cutter GR. An introduction to Mendelian randomization with applications in neurology. Mult Scler Relat Disord 2018; 24:72-78. [PMID: 29960142 DOI: 10.1016/j.msard.2018.06.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 06/19/2018] [Indexed: 10/28/2022]
Abstract
Mendelian randomization studies have become increasingly common due to the maturation of genome-wide association studies and its potential to ascertain causal relationships. With the increasing use of this method comes the need for medical practitioners and clinicians to develop an understanding of its rationale, limitations, and interpretation. Mendelian randomization attempts to ascertain a causal relationship between some risk factor of interest and some outcome or disease of interest. It exploits Mendel's law on the random assortment of genetic variants. This random assortment of genetic variants mimics the main principle of randomization used in clinical trials; with the genetic variant replacing the randomly allocated treatment. In this paper we provide a readable introduction to the rationale behind Mendelian randomization and its limitations. We also discuss and interpret several examples of Mendelian randomization analyses which pertain to neurological diseases.
Collapse
Affiliation(s)
- Phillip H Allman
- University of Alabama at Birmingham, Department of Biostatistics. Ryals Public Health Bldg. RPHB 327, AL, USA.
| | - Inmaculada B Aban
- University of Alabama at Birmingham, Department of Biostatistics. Ryals Public Health Bldg. RPHB 327, AL, USA
| | - Hemant K Tiwari
- University of Alabama at Birmingham, Department of Biostatistics. Ryals Public Health Bldg. RPHB 327, AL, USA
| | - Gary R Cutter
- University of Alabama at Birmingham, Department of Biostatistics. Ryals Public Health Bldg. RPHB 327, AL, USA.
| |
Collapse
|
|
42
|
Carmody T, Greer TL, Walker R, Rethorst CD, Trivedi MH. A Complier Average Causal Effect Analysis of the Stimulant Reduction Intervention using Dosed Exercise Study. Contemp Clin Trials Commun 2018; 10:1-8. [PMID: 29682627 PMCID: PMC5898532 DOI: 10.1016/j.conctc.2018.02.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Objective Exercise is a promising treatment for substance use disorders, yet an intention-to-treat analysis of a large, multi-site study found no reduction in stimulant use for exercise versus health education. Exercise adherence was sub-optimal; therefore, secondary post-hoc complier average causal effects (CACE) analysis was conducted to determine the potential effectiveness of adequately dosed exercise. Method The STimulant use Reduction Intervention using Dosed Exercise study was a randomized controlled trial comparing a 12 kcal/kg/week (KKW) exercise dose versus a health education control conducted at nine residential substance use treatment settings across the U.S. that are affiliated with the National Drug Abuse Treatment Clinical Trials Network. Participants were sedentary but medically approved for exercise, used stimulants within 30 days prior to study entry, and received a DSM-IV stimulant abuse or dependence diagnosis within the past year. A CACE analysis adjusted to include only participants with a minimum threshold of adherence (at least 8.3 KKW) and using a negative-binomial hurdle model focused on 218 participants who were 36.2% female, mean age 39.4 years (SD = 11.1), and averaged 13.0 (SD = 9.2) stimulant use days in the 30 days before residential treatment. The outcome was days of stimulant use as assessed by the self-reported TimeLine Follow Back and urine drug screen results. Results The CACE-adjusted analysis found a significantly lower probability of relapse to stimulant use in the exercise group versus the health education group (41.0% vs. 55.7%, p < .01) and significantly lower days of stimulant use among those who relapsed (5.0 days vs. 9.9 days, p < .01). Conclusions The CACE adjustment revealed significant, positive effects for exercise. Further research is warranted to develop strategies for exercise adherence that can ensure achievement of an exercise dose sufficient to produce a significant treatment effect.
Collapse
Affiliation(s)
| | | | | | | | - Madhukar H. Trivedi
- Corresponding author. Julie K. Hersh Chair for Depression Research and Clinical Care, Betty Jo Hay Distinguished Chair in Mental Health, Director, Center for Depression Research and Clinical Care, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9119, USA.
| |
Collapse
|
|
43
|
Tein JY, Mazza GL, Gunn HJ, Kim H, Stuart EA, Sandler IN, Wolchik SA. Multigroup Propensity Score Approach to Evaluating an Effectiveness Trial of the New Beginnings Program. Eval Health Prof 2018; 41:290-320. [PMID: 29635949 DOI: 10.1177/0163278718763499] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
We used a multigroup propensity score approach to evaluate a randomized effectiveness trial of the New Beginnings Program (NBP), an intervention targeting divorced or separated families. Two features of effectiveness trials, high nonattendance rates and inclusion of an active control, make program effects harder to detect. To estimate program effects based on actual intervention participation, we created a synthetic inactive control comprised of nonattenders and assessed the impact of attending the NBP or active control relative to no intervention (inactive control). We estimated propensity scores using generalized boosted models and applied inverse probability of treatment weighting for the comparisons. Relative to the inactive control, NBP strengthened parenting quality as well as reduced child exposure to interparental conflict, parent psychological distress, and child internalizing problems. Some effects were moderated by parent gender, parent ethnicity, or child age. On the other hand, the effects of active versus inactive control were minimal for parenting and in the unexpected direction for child internalizing problems. Findings from the propensity score approach complement and enhance the interpretation of findings from the intention-to-treat approach.
Collapse
Affiliation(s)
- Jenn-Yun Tein
- 1 Department of Psychology, REACH Institute, Arizona State University, Tempe, AZ, USA
| | - Gina L Mazza
- 1 Department of Psychology, REACH Institute, Arizona State University, Tempe, AZ, USA
| | - Heather J Gunn
- 1 Department of Psychology, REACH Institute, Arizona State University, Tempe, AZ, USA
| | - Hanjoe Kim
- 2 University of Houston, Houston, TX, USA
| | | | - Irwin N Sandler
- 1 Department of Psychology, REACH Institute, Arizona State University, Tempe, AZ, USA
| | - Sharlene A Wolchik
- 1 Department of Psychology, REACH Institute, Arizona State University, Tempe, AZ, USA
| |
Collapse
|
|
44
|
Kramer MS, Davies N, Oken E, Martin RM, Dahhou M, Zhang X, Yang S. Infant feeding and growth: putting the horse before the cart. Am J Clin Nutr 2018; 107:635-639. [PMID: 29635502 DOI: 10.1093/ajcn/nqy008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 01/08/2018] [Indexed: 11/13/2022] Open
Abstract
Background Previous observational studies have consistently shown slower weight and length gains in infants with prolonged breastfeeding than in those who were formula-fed from birth or breastfed for a shorter duration. These studies inferred that prolonged breastfeeding causes slower growth in infancy. Objective We compared infant growth associated with ≥12 mo of breastfeeding with a shorter duration of breastfeeding on the basis of 3 different analytic approaches to the same data from a randomized trial: intention-to-treat (ITT; "as randomized"), observational ("as fed"), and instrumental variable (IV; by using randomization as an "instrument" to achieve ≥12 mo of breastfeeding). Design This was a cluster-randomized trial of a breastfeeding-promotion intervention. Anthropometric measurements were obtained at birth and at 1, 2, 3, 6, 9, and 12 mo. Results The 3 analytic approaches yielded different results. The ITT approach showed more rapid growth in the first 2 mo among infants randomly assigned to the breastfeeding-promotion intervention than among control infants, with a decreasing difference over the ensuing months and nearly identical weight, length, and body mass index by 12 mo. The observational analysis showed a different trend: higher weight and length in infants who were breastfed ≥12 mo than in those who were breastfed <12 mo during the first 3 mo and no difference by 6 mo, while infants who were breastfed <12 mo showed increasingly higher weight and length from 6 to 12 mo. The IV analysis showed a temporal pattern that was similar to that seen in the ITT analysis, but with larger (and less precise) differences between infants breastfed for ≥12 compared with <12 mo. Conclusions We observed major differences in experimental (ITT and IV) compared with observational approaches to analyzing data obtained from the same children. These approaches lead to opposite causal inferences about the relation between infant feeding and growth and underline the importance of ensuring that the postulated cause (feeding) temporally precedes its hypothesized effect (growth). This trial is registered at http://www.isrctn.org/ as ISRCTN37687716.
Collapse
Affiliation(s)
- Michael S Kramer
- Departments of Pediatrics and Epidemiology, Biostatistics and Occupational Health, McGill University Faculty of Medicine, Montreal, Canada.,Departments of Epidemiology, Biostatistics and Occupational Health, McGill University Faculty of Medicine, Montreal, Canada
| | - Neil Davies
- School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
| | - Emily Oken
- Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA
| | - Richard M Martin
- School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.,National Institute for Health Research, Bristol Biomedical Research Center, Bristol, United Kingdom
| | - Mourad Dahhou
- Departments of Pediatrics and Epidemiology, Biostatistics and Occupational Health, McGill University Faculty of Medicine, Montreal, Canada
| | - Xun Zhang
- Departments of Pediatrics and Epidemiology, Biostatistics and Occupational Health, McGill University Faculty of Medicine, Montreal, Canada
| | - Seungmi Yang
- Departments of Epidemiology, Biostatistics and Occupational Health, McGill University Faculty of Medicine, Montreal, Canada
| |
Collapse
|
|
45
|
Uswatte G, Taub E, Bowman MH, Delgado A, Bryson C, Morris DM, Mckay S, Barman J, Mark VW. Rehabilitation of stroke patients with plegic hands: Randomized controlled trial of expanded Constraint-Induced Movement therapy. Restor Neurol Neurosci 2018. [PMID: 29526860 DOI: 10.3233/rnn-170792] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
PURPOSE To evaluate the efficacy of an expanded form of Constraint-Induced Movement Therapy (eCIMT) that renders CIMT, originally designed for treating mild-to-moderate upper-extremity hemiparesis, suitable for treating severe hemiparesis. METHODS Twenty-one adults ≥1 year after stroke with severe upper-extremity hemiparesis (with little or no capacity to make movements with the more-affected hand) were randomly assigned to eCIMT (n = 10), a placebo-control procedure (n = 4), or usual care (n = 7). The participants who received usual care were crossed over to eCIMT four months after enrollment. The CIMT protocol was altered to include fitting of orthotics and adaptive equipment, selected neurodevelopmental techniques, and electromyography-triggered functional electrical stimulation. Treatment was given for 15 consecutive weekdays with 6 hours of therapy scheduled daily for the immediate eCIMT group and 3.5 hours daily for the cross-over eCIMT group. RESULTS At post-treatment, the immediate eCIMT group showed significant gains relative to the combination of the control groups on the Grade-4/5 Motor Activity Log (MAL; mean = 1.5 points, P < 0.001, f = 4.2) and a convergent measure, the Canadian Occupational Performance Measure (COPM; mean = 2.3, P = 0.014, f = 1.1; f values ≥0.4 are considered large, on the COPM changes ≥2 are considered clinically meaningful). At 1-year follow-up, the MAL gains in the immediate eCIMT group were only 13% less than at post-treatment. The short and long-term outcomes of the crossover eCIMT group were similar to those of the immediate eCIMT group. CONCLUSIONS This small, randomized controlled trial (RCT) suggests that eCIMT produces a large, meaningful, and persistent improvement in everyday use of the more-affected arm in adults with severe upper-extremity hemiparesis long after stroke. These promising findings warrant confirmation by a large RCT.
Collapse
Affiliation(s)
- Gitendra Uswatte
- Department of Psychology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.,Department of Physical Therapy, UAB, Birmingham, AL, USA
| | - Edward Taub
- Department of Psychology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
| | - Mary H Bowman
- Department of Psychology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
| | - Adriana Delgado
- Department of Psychology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
| | - Camille Bryson
- Department of Psychology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
| | - David M Morris
- Department of Physical Therapy, UAB, Birmingham, AL, USA
| | - Staci Mckay
- Department of Psychology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
| | - Joydip Barman
- Department of Psychology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
| | - Victor W Mark
- Department of Psychology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.,Department of Physical Medicine and Rehabilitation, UAB, Birmingham, AL, USA.,Department of Neurology, UAB, Birmingham, AL, USA
| |
Collapse
|
|
46
|
Estimating Causal Effects of Treatment in a Randomized Trial When Some Participants Only Partially Adhere. Epidemiology 2018; 29:78-86. [DOI: 10.1097/ede.0000000000000771] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
47
|
Dodd S, White IR, Williamson P. A framework for the design, conduct and interpretation of randomised controlled trials in the presence of treatment changes. Trials 2017; 18:498. [PMID: 29070048 PMCID: PMC5657109 DOI: 10.1186/s13063-017-2240-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 10/06/2017] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND When a randomised trial is subject to deviations from randomised treatment, analysis according to intention-to-treat does not estimate two important quantities: relative treatment efficacy and effectiveness in a setting different from that in the trial. Even in trials of a predominantly pragmatic nature, there may be numerous reasons to consider the extent, and impact on analysis, of such deviations from protocol. Simple methods such as per-protocol or as-treated analyses, which exclude or censor patients on the basis of their adherence, usually introduce selection and confounding biases. However, there exist appropriate causal estimation methods which seek to overcome these inherent biases, but these methods remain relatively unfamiliar and are rarely implemented in trials. METHODS This paper demonstrates when it may be of interest to look beyond intention-to-treat analysis for answers to alternative causal research questions through illustrative case studies. We seek to guide trialists on how to handle treatment changes in the design, conduct and planning the analysis of a trial; these changes may be planned or unplanned, and may or may not be permitted in the protocol. We highlight issues that must be considered at the trial planning stage relating to: the definition of nonadherence and the causal research question of interest, trial design, data collection, monitoring, statistical analysis and sample size. RESULTS AND CONCLUSIONS During trial planning, trialists should define their causal research questions of interest, anticipate the likely extent of treatment changes and use these to inform trial design, including the extent of data collection and data monitoring. A series of concise recommendations is presented to guide trialists when considering undertaking causal analyses.
Collapse
Affiliation(s)
- Susanna Dodd
- Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GS UK
| | - Ian R. White
- MRC Biostatistics Unit, Institute of Public Health, Robinson Way, Cambridge, CB2 0SR UK
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, Aviation House, 125 Kingsway, London, WC2B 6NH UK
| | - Paula Williamson
- Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GS UK
| |
Collapse
|
|
48
|
Affiliation(s)
- Miguel A Hernán
- From the Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health (M.A.H., J.M.R.), and the Harvard-MIT Division of Health Sciences and Technology (M.A.H.), Boston
| | - James M Robins
- From the Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health (M.A.H., J.M.R.), and the Harvard-MIT Division of Health Sciences and Technology (M.A.H.), Boston
| |
Collapse
|
|
49
|
Hardin JM. The Principle of Intention to Treat Analysis in Clinical Studies: Its Use and Controversies. J Pharm Pract 2016. [DOI: 10.1177/089719009801100402] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The principle of intention-to-treat (ITT) has become the standard policy for comparing treatment and control groups in clinical studies. Yet, ITT is not without its critics, controversies, and misunderstandings. To properly judge results reported from clinical studies, it is imperative that pharmacists be able to assess the underlying assumptions and the methodological issues associated with ITT. This article will provide an exposition of the history, assumptions, definitions, methodology, and controversies of ITT.
Collapse
Affiliation(s)
- J. Michael Hardin
- Professor, Health Informatics and Biostatistics, Department of Health Services Administration, School of Health Related Professions, and Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, Phone: 205-934-3509, FAX: 205-975-6608, E-mail:
| |
Collapse
|
|
50
|
Abstract
Occupational therapists reading reports of randomised controlled trials and trying to interpret the reliability and size of effects stated are frequently frustrated by poor standards of reporting. They need to be able to evaluate the profession's interventions critically: to stop the ineffective, to reduce the hazardous and to promote the effective. Without good quality trials and trial reports, the profession will continue to be dogged by systematic reviews that conclude that there is insufficient evidence to support or refute the use of occupational therapy. These, in turn, will mean that the use of occupational therapy cannot be promoted strongly in national guidelines and, therefore, services may become restricted. This review covers some of the issues to be considered when writing or reading a report of a randomised controlled trial of a complex intervention, such as occupational therapy.
Collapse
|