Special Issue "N-of-1 Trials in Healthcare"

A special issue of Healthcare (ISSN 2227-9032).

Deadline for manuscript submissions: closed (31 August 2019).

Special Issue Editors

Assoc. Prof. Dr. Jane Nikles
E-Mail Website
Guest Editor
UQ Centre for Clinical Research, University of Queensland, Brisbane, Australia
Interests: N-of-1 trials, clinical trials, personalised medicine
Dr. Suzanne McDonald
E-Mail Website
Guest Editor
UQ Centre for Clinical Research, University of Queensland, Brisbane 4001, Australia
Interests: development and application of n-of-1 methods to health psychology and behavioural medicine

Special Issue Information

Dear colleagues,

N-of-1 trials in healthcare: this Special Issue will cover new applications of N-of-1 trials or Single Case Experimental Designs in any health discipline, with a focus on patient experience, patients as collaborators, new conditions or new contexts or new methodologies/interventions, mobile health, data analysis, or pharmacogenomics. The articles can be reviews, systematic reviews, opinion pieces, original research or short reports.

Assoc. Prof. Dr. Jane Nikles
Dr. Suzanne McDonald
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Healthcare is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • N-of-1 trials
  • N=1 trials
  • N1 trials
  • Single Case Experimental Designs
  • patient experience
  • patients as collaborators
  • mobile health
  • data analysis
  • pharmacogenomics

Published Papers (14 papers)

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Editorial

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Editorial
N-of-1 Trials in Healthcare
Healthcare 2021, 9(3), 330; https://doi.org/10.3390/healthcare9030330 - 15 Mar 2021
Viewed by 296
Abstract
Interest in N-of-1 trials and single-case designs is increasing worldwide, particularly due to the movement towards personalised medicine and patient-centred healthcare [...] Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)

Research

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Communication
N-of-1 Trials: Evidence-Based Clinical Care or Medical Research that Requires IRB Approval? A Practical Flowchart Based on an Ethical Framework
Healthcare 2020, 8(1), 49; https://doi.org/10.3390/healthcare8010049 - 27 Feb 2020
Cited by 4 | Viewed by 1990
Abstract
N-of-1 trials can provide high-class evidence on drug treatment effectiveness at the individual patient level and have been given renewed interest over the past decade due to improvements of the initial single patient design. Despite these recent developments, there is still no consensus [...] Read more.
N-of-1 trials can provide high-class evidence on drug treatment effectiveness at the individual patient level and have been given renewed interest over the past decade due to improvements of the initial single patient design. Despite these recent developments, there is still no consensus under what circumstances N-of-1 trials should be considered as part of evidence-based clinical care and when they represent medical research with need for institutional review board (IRB) approval. This lack of consensus forms an obstacle for a more widespread implementation of N-of-1 trials. Based upon the existing literature, we as a group of researchers involved in N-of-1 trials and members of the IRB of a tertiary academic referral center, designed a practical flowchart based on an ethical framework to help make this distinction. The ethical framework together with a practical flowchart are presented in this communication. Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)
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Article
Investigating the Temporal Relationships between Symptoms and Nebuliser Adherence in People with Cystic Fibrosis: A Series of N-of-1 Observations
Healthcare 2020, 8(1), 22; https://doi.org/10.3390/healthcare8010022 - 21 Jan 2020
Cited by 3 | Viewed by 1862
Abstract
Treatment adherence in adults with cystic fibrosis (CF) is poor. One of the reasons identified for lack of adherence to nebulised treatments is that patients may not experience any immediate relief in their symptoms or notice changes as a result of taking their [...] Read more.
Treatment adherence in adults with cystic fibrosis (CF) is poor. One of the reasons identified for lack of adherence to nebulised treatments is that patients may not experience any immediate relief in their symptoms or notice changes as a result of taking their treatment, thus many report that they do not perceive there to be consequences of non adherence. The aim of the study was to investigate the temporal relationships between symptoms and adherence to nebulised treatments in adults with CF using an N-of-1 observational design. Six participants were recruited for a six-week period during which time they completed a daily online respiratory symptom questionnaire. Adherence to treatment was measured throughout the duration of the study using an eTrack® nebuliser that logged date and time of treatments taken. Data generated from each participant was analysed separately. There were significant relationships between pain and adherence for three participants, tiredness and adherence for one participant and cough and adherence for one participant. For all of these findings, the symptom and adherence were experienced on the same day. Extending the monitoring period beyond six weeks may provide increased insight into the complex relationship between symptoms and adherence in CF. Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)
Article
Clinical Usefulness of Bright White Light Therapy for Depressive Symptoms in Cancer Survivors: Results from a Series of Personalized (N-of-1) Trials
Healthcare 2020, 8(1), 10; https://doi.org/10.3390/healthcare8010010 - 30 Dec 2019
Cited by 4 | Viewed by 1921
Abstract
Purpose: Little is known about the effectiveness of bright white light therapy (BWL) for depressive symptoms in cancer survivors, many of whom prefer non-pharmacological treatments. The purpose of this study was to compare the effectiveness of BWL versus dim red light therapy [...] Read more.
Purpose: Little is known about the effectiveness of bright white light therapy (BWL) for depressive symptoms in cancer survivors, many of whom prefer non-pharmacological treatments. The purpose of this study was to compare the effectiveness of BWL versus dim red light therapy (DRL) on depressive symptoms within individual cancer survivors using personalized (N-of-1) trials. Methods: Cancer survivors with at least mild depressive symptoms were randomized to one of two treatment sequences consisting of counterbalanced crossover comparisons of three-weeks of lightbox-delivered BWL (intervention) or DRL (sham) for 30 min each morning across 12 weeks. A smartphone application guided cancer survivors through the treatment sequence and facilitated data collection. Cancer survivors tracked end-of-day depressive symptoms (primary outcome) and fatigue using visual analog scales. Within-patient effects of BWL were assessed using an autoregressive model with adjustment for linear time trends. Results: Eight of nine cancer survivors completed the 12-week protocol. Two survivors reported significantly (i.e., p < 0.05) lower depressive symptoms (−1.3 ± 0.5 and −1.30 ± 0.9 points on a 10-point scale), five reported no difference in depressive symptoms, and one reported higher depressive symptoms (+1.7 ± 0.6 points) with BWL versus DRL. Eight of nine cancer survivors recommended personalized trials of BWL to others. Conclusions: There were heterogeneous effects of three-week BWL on self-reported depressive symptoms among cancer survivors, with some finding a benefit but others finding no benefit or even harm. Implications for Cancer Survivors: Personalized trials can help cancer survivors learn if BWL is helpful for improving their depressive symptoms. Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)
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Article
Effects of Sleep Deprivation on Blood Glucose, Food Cravings, and Affect in a Non-Diabetic: An N-of-1 Randomized Pilot Study
Healthcare 2020, 8(1), 6; https://doi.org/10.3390/healthcare8010006 - 25 Dec 2019
Cited by 4 | Viewed by 3489
Abstract
Sleep deprivation is a prevalent and rising health concern, one with known effects on blood glucose (BG) levels, mood, and calorie consumption. However, the mechanisms by which sleep deprivation affects calorie consumption (e.g., measured via self-reported types of craved food) are unclear, and [...] Read more.
Sleep deprivation is a prevalent and rising health concern, one with known effects on blood glucose (BG) levels, mood, and calorie consumption. However, the mechanisms by which sleep deprivation affects calorie consumption (e.g., measured via self-reported types of craved food) are unclear, and may be highly idiographic (i.e., individual-specific). Single-case or “n-of-1” randomized trials (N1RT) are useful in exploring such effects by exposing each subject to both sleep deprivation and baseline conditions, thereby characterizing effects specific to that individual. We had two objectives: (1) To test and generate individual-specific N1RT hypotheses of the effects of sleep deprivation on next-day BG level, mood, and food cravings in two non-diabetic individuals; (2) To refine and guide a future n-of-1 study design for testing and generating such idiographic hypotheses for personalized management of sleep behavior in particular, and for chronic health conditions more broadly. We initially did not find evidence for idiographic effects of sleep deprivation, but better-refined post hoc findings indicate that sleep deprivation may have increased BG fluctuations, cravings, and negative emotions. We also introduce an application of mixed-effects models and pancit plots to assess idiographic effects over time. Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)
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Article
The Feasibility of Using N-Of-1 Trials to Investigate Deprescribing in Older Adults with Dementia: A Pilot Study
Healthcare 2019, 7(4), 161; https://doi.org/10.3390/healthcare7040161 - 12 Dec 2019
Cited by 3 | Viewed by 2122
Abstract
N-of-1 trials may provide insights into the impact of deprescribing medications in populations where evidence is currently lacking, such as the effect of statins on cognition in people with dementia. For this pilot, N-of-1, double-blinded, deprescribing trial, adults over 80 years of age [...] Read more.
N-of-1 trials may provide insights into the impact of deprescribing medications in populations where evidence is currently lacking, such as the effect of statins on cognition in people with dementia. For this pilot, N-of-1, double-blinded, deprescribing trial, adults over 80 years of age with dementia taking statins for at least 6-months were recruited from a hospital’s geriatric medicine outpatient clinic in Sydney, Australia. Participants discontinued and restarted statins over the study period. At enrolment, the hospital pharmacy—using a random number generator, randomised recruited participants to their usual statin or placebo regimen, with assessment and switching of treatment every 5 weeks from baseline (0-weeks) until Visit 4 (15-weeks). Primary outcome was measured using the rate of change in Alzheimer’s Disease Assessment Score-Cognitive Subscale (ADAS-CoG). Over 6-months, 81 participants were screened, 14 were eligible, and four were randomised. One participant (female, 88 years) completed all four assessments with no major harms reported. Cognitive impairment, as measured by ADAS-CoG score, was similar on placebo (15.5/70) compared to statin (15/70). This study suggests there are significant challenges in performing N-of-1 trials and recruiting people with dementia into deprescribing trials from outpatient settings. Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)
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Article
Randomized Single-Case Experimental Designs in Healthcare Research: What, Why, and How?
Healthcare 2019, 7(4), 143; https://doi.org/10.3390/healthcare7040143 - 13 Nov 2019
Cited by 2 | Viewed by 2063
Abstract
Health problems are often idiosyncratic in nature and therefore require individualized diagnosis and treatment. In this paper, we show how single-case experimental designs (SCEDs) can meet the requirement to find and evaluate individually tailored treatments. We give a basic introduction to the methodology [...] Read more.
Health problems are often idiosyncratic in nature and therefore require individualized diagnosis and treatment. In this paper, we show how single-case experimental designs (SCEDs) can meet the requirement to find and evaluate individually tailored treatments. We give a basic introduction to the methodology of SCEDs and provide an overview of the available design options. For each design, we show how an element of randomization can be incorporated to increase the internal and statistical conclusion validity and how the obtained data can be analyzed using visual tools, effect size measures, and randomization inference. We illustrate each design and data analysis technique using applied data sets from the healthcare literature. Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)
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Article
Comparison of Aggregated N-of-1 Trials with Parallel and Crossover Randomized Controlled Trials Using Simulation Studies
Healthcare 2019, 7(4), 137; https://doi.org/10.3390/healthcare7040137 - 06 Nov 2019
Cited by 7 | Viewed by 2293
Abstract
Background: N-of-1 trials offer an innovative approach to delivering personalized clinical care together with population-level research. While increasingly used, these methods have raised some statistical concerns in the healthcare community. Methods: We discuss concerns of selection bias, carryover effects from treatment, and trial [...] Read more.
Background: N-of-1 trials offer an innovative approach to delivering personalized clinical care together with population-level research. While increasingly used, these methods have raised some statistical concerns in the healthcare community. Methods: We discuss concerns of selection bias, carryover effects from treatment, and trial data analysis conceptually, then rigorously evaluate concerns of effect sizes, power and sample size through simulation study. Four variance structures for patient heterogeneity and model error are considered in a series of 5000 simulated trials with 3 cycles, which compare aggregated N-of-1 trials to parallel randomized controlled trials (RCTs) and crossover trials. Results: Aggregated N-of-1 trials outperformed both traditional parallel RCT and crossover designs when these trial designs were simulated in terms of power and required sample size to obtain a given power. N-of-1 designs resulted in a higher type-I error probability than parallel RCT and cross over designs when moderate-to-strong carryover effects were not considered or in the presence of modeled selection bias. However, N-of-1 designs allowed better estimation of patient-level random effects. These results reinforce the need to account for these factors when planning N-of-1 trials. Conclusion: N-of-1 trial designs offer a rigorous method for advancing personalized medicine and healthcare with the potential to minimize costs and resources. Interventions can be tested with adequate power with far fewer patients than traditional RCT and crossover designs. Operating characteristics compare favorably to both traditional RCT and crossover designs. Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)
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Article
Power and Design Issues in Crossover-Based N-Of-1 Clinical Trials with Fixed Data Collection Periods
Healthcare 2019, 7(3), 84; https://doi.org/10.3390/healthcare7030084 - 02 Jul 2019
Cited by 3 | Viewed by 2122
Abstract
“N-of-1,” or single subject, clinical trials seek to determine if an intervention strategy is more efficacious for an individual than an alternative based on an objective, empirical, and controlled study. The design of such trials is typically rooted in a simple crossover strategy [...] Read more.
“N-of-1,” or single subject, clinical trials seek to determine if an intervention strategy is more efficacious for an individual than an alternative based on an objective, empirical, and controlled study. The design of such trials is typically rooted in a simple crossover strategy with multiple intervention response evaluation periods. The effect of serial correlation between measurements, the number of evaluation periods, the use of washout periods, heteroscedasticity (i.e., unequal variances among responses to the interventions) and intervention-associated carry-over phenomena on the power of such studies is crucially important for putting the yield and feasibility of N-of-1 trial designs into context. We evaluated the effect of these phenomena on the power of different designs for N-of-1 trials using analytical theory based on standard likelihood principles assuming an autoregressive lag 1, i.e., AR(1), serial correlation structure among the measurements as well as simulation studies. By evaluating the power to detect effects in many different settings, we show that the influence of serial correlation and heteroscedasticity on power can be substantial, but can also be mitigated to some degree through the use of appropriate multiple evaluation periods. We also show that the detection of certain types of carry-over effects can be heavily influenced by design considerations as well. Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)
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Other

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Opinion
Practice-Based Research in Complementary Medicine: Could N-of-1 Trials Become the New Gold Standard?
Healthcare 2020, 8(1), 15; https://doi.org/10.3390/healthcare8010015 - 08 Jan 2020
Cited by 10 | Viewed by 2079
Abstract
Complementary medicines and therapies are popular forms of healthcare with a long history of traditional use. Yet, despite increasing consumer demand, there is an ongoing exclusion of complementary medicines from mainstream healthcare systems. A lack of evidence is often cited as justification. Until [...] Read more.
Complementary medicines and therapies are popular forms of healthcare with a long history of traditional use. Yet, despite increasing consumer demand, there is an ongoing exclusion of complementary medicines from mainstream healthcare systems. A lack of evidence is often cited as justification. Until recently, high-quality evidence of treatment efficacy was defined as findings from well-conducted systematic reviews and meta-analyses of randomized controlled trials. In a recent and welcome move by the Oxford Centre for Evidence-Based Practice, however, the N-of-1 trial design has also been elevated to the highest level of evidence for treatment efficacy of an individual, placing this research design on par with the meta-analysis. N-of-1 trial designs are experimental research methods that can be implemented in clinical practice. They incorporate much of the rigor of group clinical trials, but are designed for individual patients. Individualizing treatment interventions and outcomes in research designs is consistent with the movement towards patient-centered care and aligns well with the principles of holism as practiced by naturopaths and many other complementary medicine practitioners. This paper explores whether rigorously designed and conducted N-of-1 trials could become a new ‘gold standard’ for demonstrating treatment efficacy for complementary medicine interventions in individual patients in clinical practice. Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)
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Protocol
Protocol: Using Single-Case Experimental Design to Evaluate Whole-Body Dynamic Seating on Activity, Participation, and Quality of Life in Dystonic Cerebral Palsy
Healthcare 2020, 8(1), 11; https://doi.org/10.3390/healthcare8010011 - 31 Dec 2019
Cited by 1 | Viewed by 2004
Abstract
Introduction: People with hyperkinetic movement disorders, including dystonia, experience often painful, involuntary movements affecting functioning. Seating comfort is a key unmet need identified by families. This paper reports a protocol to assess the feasibility and preliminary evidence for the efficacy of dynamic seating [...] Read more.
Introduction: People with hyperkinetic movement disorders, including dystonia, experience often painful, involuntary movements affecting functioning. Seating comfort is a key unmet need identified by families. This paper reports a protocol to assess the feasibility and preliminary evidence for the efficacy of dynamic seating to improve functional outcomes for young children with dystonic cerebral palsy (DCP). Design: A series of single-case experimental design N-of-1 trials, with replications across participants, with a random baseline interval, and one treatment period (n = 6). Methods: Inclusion criteria: DCP; 21.5 cm < popliteal fossa to posterior sacrum < 35 cm; Gross Motor Function Classification System level IV–V; mini-Manual Ability Classification System level IV–V; difficulties with seating. Intervention: Trial of the seat (8 weeks), with multiple baseline before, during and after intervention and 2 month follow up. The baseline duration will be randomised per child (2–7 weeks). Primary outcomes: Performance Quality Rating Scale; Canadian Occupational Performance Measure; seating tolerance. The statistician will create the randomization, with allocation concealment by registration of participants prior to sending the allocation arm to the principal investigator. Primary outcomes will be assessed from video by an assessor blind to allocation. Analysis: Participant outcome data will be plotted over time, with parametric and non-parametric analysis including estimated size effect for N-of-1 trials. Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)
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Protocol
N-of-1 Trials as a Decision Support Tool in Clinical Practice: A Protocol for a Systematic Literature Review and Narrative Synthesis
Healthcare 2019, 7(4), 136; https://doi.org/10.3390/healthcare7040136 - 06 Nov 2019
Cited by 2 | Viewed by 1773
Abstract
The n-of-1 trial can utilized in clinical practice as a decision support tool, which may improve patient outcomes by providing both the patient and the clinician with objective evidence to inform personalized treatment decisions. As its use broadens, it will be important to [...] Read more.
The n-of-1 trial can utilized in clinical practice as a decision support tool, which may improve patient outcomes by providing both the patient and the clinician with objective evidence to inform personalized treatment decisions. As its use broadens, it will be important to study whether the added time and effort of an n-of-1 trial results in measurable improvements in important patient outcomes compared to usual clinical practice. Parallel-group randomized clinical trials testing the n-of-1 approach versus usual care have been undertaken in a number of medical settings. A systematic review will be performed according to PRISMA guidelines, using MEDLINE, Embase, Cochrane, CINAHL, PsycINFO, Scopus, and Web of Science to search for randomized clinical trials in humans, without date or language restriction. Reports from the gray literature and ongoing studies in trial registries will be included. Articles will be screened by two independent reviewers with a third reviewer consulted to adjudicate disagreement. The quality of included studies will be assessed using the Cochrane Collaboration’s tool for assessing risk of bias. A narrative synthesis will explore the differing methodological approaches of the included studies. The protocol will be registered in the PROSPERO registry, and the results of the review will be published in a peer-reviewed journal. To our knowledge, this systematic review will be the first to comprehensively assess the existing research on randomized trials testing the n-of-1 trial approach in clinical practice. Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)
Discussion
Personalised Medicine Using N-of-1 Trials: Overcoming Barriers to Delivery
Healthcare 2019, 7(4), 134; https://doi.org/10.3390/healthcare7040134 - 05 Nov 2019
Cited by 1 | Viewed by 2067
Abstract
In this paper we discuss the value of N-of-1 trials in personalising health care. We describe the challenges faced in implementing N-of-1 trials in the United Kingdom’s National Health Service and suggest how making greater use of these personalised trials might be facilitated. [...] Read more.
In this paper we discuss the value of N-of-1 trials in personalising health care. We describe the challenges faced in implementing N-of-1 trials in the United Kingdom’s National Health Service and suggest how making greater use of these personalised trials might be facilitated. Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)
Protocol
Evaluating the Comparative Effectiveness of Two Diets in Pediatric Inflammatory Bowel Disease: A Study Protocol for a Series of N-of-1 Trials
Healthcare 2019, 7(4), 129; https://doi.org/10.3390/healthcare7040129 - 01 Nov 2019
Cited by 3 | Viewed by 2100
Abstract
Inflammatory bowel disease (IBD) affects 3 million children and adults in the US. Treatment involves medications with considerable risk profiles. Dietary modification, such as the specific carbohydrate diet (SCD), may be helpful in treating IBD, but there is insufficient evidence of its effectiveness. [...] Read more.
Inflammatory bowel disease (IBD) affects 3 million children and adults in the US. Treatment involves medications with considerable risk profiles. Dietary modification, such as the specific carbohydrate diet (SCD), may be helpful in treating IBD, but there is insufficient evidence of its effectiveness. N-of-1 trials are ideal for addressing this important research question. The Personalized Research on Diet in Ulcerative Colitis and Crohn’s Disease (PRODUCE) study employs a series of 50 individual N-of-1 trials that compare the SCD to a modified SCD. Treatment periods are assigned in blocks of two, with each patient completing two balanced treatment blocks. Patients are randomized to start with the SCD or modified SCD and alternate between conditions for four eight-week periods. A mobile app guides collecting and viewing data, transitioning diets, and reviewing personal results. Primary outcomes include patient reported outcomes (PROs) of stool frequency, stool consistency, pain interference, and gastrointestinal (GI) symptom severity. We examine changes in inflammation via fecal calprotectin. Participants will receive a personalized answer regarding comparative effectiveness between the SCD and a less restrictive diet option (modified SCD), as well as compared to their baseline diet. We will aggregate the results of completed N-of-1 trials across patients to estimate population level comparative effectiveness of these treatments and the effectiveness of each diet. Full article
(This article belongs to the Special Issue N-of-1 Trials in Healthcare)
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