Over the last decade, increased research on therapy, pathogenesis, epidemiological and genetic aspects of restless legs syndrome/Willis-Ekbom Disease (RLS/WED) has necessitated development of diagnostic instruments specific to RLS. The Movement Disorder Society commissioned a task force to formally evaluate the available evidence on diagnostic instruments in RLS.
A literature search identified 4 instruments specific to RLS. Each instrument was evaluated by 3 criteria, which included (a) use in RLS, (b) use by groups other than the group that developed the instrument, and (c) formal validation and adequate clinimetric properties. Instruments were then qualified as “Recommended” when all 3 criteria were met, “Suggested” when used for RLS but only one of the other criteria are met, and “Listed” when used in RLS but there is absence of the other 2 criteria. Details regarding the development, use, and clinimetric properties of each instrument are summarized, along with the recommendations of the committee.
Results and Conclusion:
The Recommended diagnostic instruments are the Hening Telephone Diagnostic Interview (HTDI), the Cambridge-Hopkins diagnostic questionnaire for RLS (CH-RLSq), and the RLS Diagnostic Index (RLS-DI). An unmet need is the development of a diagnostic instrument for pediatric RLS. Diagnostic instruments are particularly useful in studies where patients are not personally interviewed or examined in the office setting.
Walters AS, Frauscher B, Allen R, Benes H, Chaudhuri KR, Garcia-Borreguero D, Lee HB, Picchietti DL, Trenkwalder C, Martinez-Martin P, Stebbins GT, Schrag A; MDS Committee on Rating Scales. Review of diagnostic instruments for the restless legs syndrome/Willis-Ekbom Disease (RLS/WED): critique and recommendations. J Clin Sleep Med 2014;10(12):1343-1349.
Several diagnostic instruments for restless legs syndrome/ Willis-Ekbom Disease (RLS/WED) have been developed. These facilitate more accurate diagnoses of RLS in large population surveys that preclude office interviews and examinations where disorders that mimic or resemble RLS are more readily excluded.1–3 The Task Force reviewed the evidence on instruments in the existing literature that were designed to improve diagnosis in RLS/WED and developed recommendations as to the usefulness of the instruments. Rating scales for severity of adult and pediatric RLS, augmentation, and quality of life of RLS are addressed in separate publications.
The new criteria for the diagnosis of RLS are listed in Table 1. These are exactly the same as the old criteria, except that they formalize the need to do a proper differential diagnosis and exclude mimics (see criterion # 5 and accompanying footnote).
IRLSSG Consensus Diagnostic Criteria for RLS/WED (2012).
IRLSSG Consensus Diagnostic Criteria for RLS/WED (2012).
The exclusion of mimics is important to the accurate diagnosis of RLS. One study indicates that if one asks about the 4 criteria for RLS to a general population without doing a proper differential diagnosis, 16% of subjects who do not have RLS will be misclassified as having RLS.3 Some of the disorders that can superficially meet all 4 diagnostic criteria for RLS include leg cramps, leg edema, venous stasis, positional discomfort, muscle aches, habitual foot tapping, and occasionally arthritis.
None of the instruments examined have been validated in children, nor are they necessarily thought to be appropriate for the pediatric age group. An unmet need therefore is the development of a diagnostic instrument for pediatric RLS.
Administrative Organization and Critique Process
This project was organized under the guidance of the Movement Disorder Society (MDS). The senior author of the project (AW) was asked to head and form the working group on the current submission with the goal of evaluating diagnostic instruments specific to RLS.
Literature Search and Selection of Instruments
A Pub Med literature search was conducted. When the terms “restless legs syndrome” or “RLS” were crossed with the term “diagnostic instrument,” 53 articles were obtained. If an RLS instrument not captured by the literature review was mentioned in an article, the paper evaluating the instrument was also obtained. A total of 4 RLS instruments were obtained, reviewed, and thought to be pertinent. Only articles that did the original description of the diagnostic instruments or did validation studies of the diagnostic instruments were considered. The articles found to be not pertinent were (a) those that were false positive in the sense that the literature search brought up articles totally unrelated to RLS diagnostic instruments; or (b) the articles were quoting previous primary studies; or (c) the articles utilized previously validated scales in studies but did not validate the scales further.
The following criteria employed by the Movement Disorder Task Force (MDS-TF) were used to designate an instrument as “Recommended,” “Suggested,” or “Listed” for use in RLS (Table 2). If an RLS diagnostic instrument has been applied to RLS-related populations, has been employed by investigators other than the group that originally developed it, and has satisfactory clinimetric properties, that instrument is “Recommended”; if it has been applied to RLS but meets only one of the other 2 requirements it is “Suggested,” and if it has only been applied to RLS but does not meet either of the other two criteria it is “Listed.” Abstracts where the instrument in question has been used extensively despite the absence of a full publication are not discussed or rated. Columns 2-4 of Table 3 list how each individual scale complies with the 3 criteria for evaluation, and Column 6 of Table 3 lists the final level of endorsement of the scale. Table 4 summarizes the detailed analyses for each individual instrument.
Definitions of the categories for evaluation of RLS instruments.
Definitions of the categories for evaluation of RLS instruments.
Evaluation of different diagnostic instruments for RLS.
Evaluation of different diagnostic instruments for RLS.
Detailed analysis of diagnostic instruments.
Detailed analysis of diagnostic instruments.
Four instruments pertinent to the diagnosis of RLS were identified. One instrument incorporates all of the fundamental diagnostic criteria for RLS into a single self-administered question. The RLS Diagnostic Index (RLS-DI) incorporates the non-essential and essential criteria for RLS into an algorithm to improve diagnosis and is based upon patient interview and the collection of objective data from chart review and polysomnography. The Hening Telephone Diagnostic Interview (HTDI) is a telephone interview for the diagnosis of RLS. The Cambridge Hopkins diagnostic questionnaire for RLS (CH-RLSq) is a self-administered questionnaire for the diagnosis of RLS. Augmentation is a paradoxical worsening of RLS symptoms by dopaminergic treatment when RLS symptoms are improved at night by nighttime dopaminergic therapy but the RLS symptoms are then pushed in to the daytime as a result of the therapy itself. Although a fifth instrument, an instrument for the diagnosis of augmentation was identified, the Structured Interview for the Diagnosis of Augmentation (SIDA), it is published in abstract form only and is not discussed further, as there is a fairly significant disagreement in the field as to the proper criteria for the diagnosis of augmentation itself. It is important to note that in the evaluation of the diagnostic instruments to follow, the instruments were, in general, evaluated against a clinical interview which, as has always been true, includes a differential diagnosis to exclude mimics. In the case of the self-completed Cambridge-Hopkins diagnostic questionnaire for RLS, the validation was done against the previously validated Hening Telephone Diagnostic Interview which was, in turn, validated against a standard clinical interview which included the exclusion of mimics.
Instruments for the Diagnosis of RLS (for definition Table 1)
Single Question to Screen for the Possible Diagnosis of RLS
A single screening question for the diagnosis of RLS was developed for use in a busy office setting.4 The question incorporates the original 4 NIH consensus criteria for RLS and reads as follows: “When you try to relax in the evening or sleep at night, do you ever have unpleasant, restless feelings in your legs that can be relieved by walking or movement?”
This tool has been used in RLS patients (Criterion 1), but it has not been studied by multiple research teams (Criterion 2). Considering clinimetric properties (Criterion 3), the validation of this question was done in Italian with translation and back translation to ensure comparability with the English version. A group of 521 subjects (252 females and 269 males, mean age 60.7 years), who were referred to a neurology clinic for various reasons, were examined by 2 independent clinical experts and classified (or diagnosed) as either RLS or non-RLS. A control group of non-neurologic referrals (n = 45, 29 females, and 16 males, mean age 68.2 years) was also evaluated. When all subject groups were analyzed together the single question demonstrated sensitivity of 100%, specificity 96.8%, positive predictive value 89.6%, and negative predictive value 100% for the determination of RLS when compared to expert clinical classification (or diagnosis). When the control group was evaluated separately, the specificity decreased slightly to 95.5%.4
STRENGTHS AND WEAKNESSES
The single question is developed for rapid screening of patients in a clinical setting so that individuals who screen positive can be interviewed in more detail to determine the presence of RLS. It is important to note that it is only validated in that setting. The high sensitivity and specificity suggest that the single question could be useful in large epidemiologic studies, but further validation in this setting would be needed. One weakness is that the question does not exclude mimics. However, the excellent sensitivity, specificity, positive predictive value, and negative predictive value against a standard clinical interview where mimics were excluded indicate that this is not a major problem.
The single question meets MDS criteria for a “Suggested” Tool: it has been applied to RLS populations and had adequate clinimetric properties in a single limited validation study. However, to our knowledge this specific single question has not been utilized by other investigators. Although a single question that includes diagnostic criteria may not be considered a diagnostic instrument separate from the usual clinical interview, the standardized use of the single question may be useful as a preliminary screener for the diagnosis of RLS.
The RLS Diagnostic Index
The RLS Diagnostic Index (RLS-DI) was developed to test the possibility that ancillary non-essential features, frequently but not universally seen in RLS, might help make the diagnosis of RLS more accurate.5,6 It is primarily applicable to a clinical setting and has not been used for diagnoses in a general population. The RLS-DI has 10 items, 5 of which probe the essential diagnostic features of RLS and 5 of which probe associated and supportive criteria for RLS, such as sleep disturbance, positive family history of RLS, improvement of RLS symptoms with dopaminergic therapy, and the presence of periodic limb movements (PLMs).5,6 It is to be noted that the presence of PLMs has to be determined objectively by polysomnography, actigraphy, or the suggested immobilization test (SIT); the presence of PLMS is therefore optional for the RLS-DI.
This tool has been utilized in RLS patients (Criterion 1) and by multiple research teams (Criterion 2). In terms of clinimetric properties (Criterion 3), the RLS-DI was administered to 86 patients with RLS as diagnosed by 2 sleep experts and 93 patients with other sleep disorders. A score ≥ 11 points was determined by a receiver operating characteristic plot (ROC) to provide optimal sensitivity and specificity when the RLS-DI total score was compared to the diagnosis of the 2 independent sleep experts. The sensitivity was 93%,the specificity was 98.9%, the positive predictive value 98.8%, and the negative predictive value was 93.9% for the determination of RLS status when comparing an RLS-DI score ≥ 11 points to the physician-based diagnosis, which served as the gold standard for the study.5 In a separate study analyzing the same cohort, the authors showed in a regression analysis that adding in the associated and supportive features of RLS to the basic 4 criteria optimizes the use of the entire RLS-DI in the diagnosis of RLS.6 The RLS-DI has excellent internal consistency as measured by item-total correlations which are all > 0.8 and reasonable internal consistency as measured by Cronbach α of 0.68.5 It has excellent discriminant validity compared to subjects with other diagnoses with a p < 0.001 by Mann-Whitney U test and it also has excellent interrater reliability, with κ = 0.93. It has 2 factors explaining 47.7% of the variance.
STRENGTHS AND WEAKNESSES
The RLS-DI has excellent clinimetric properties and may improve the accuracy of RLS diagnosis. Although an optional part of the RLS-DI, if one is to employ PLMs as a measure to improve the diagnosis of RLS, one of the weakness of the instrument is that polysomnography may not be available in many laboratories and the time, expense, and scheduling problems in most laboratories preclude the measurement of periodic limb movements in sleep (PLMS) in studies involving large numbers of patients. The RLS-DI deals with the problems of mimics well, because in common clinical use the interview is intended to be used based upon access to medical records and a more extensive clinical interview. For example, it includes one general question that the patients alone cannot answer: “Can urge to move/unpleasant sensations be sufficiently explained by other medical factors/concomitant diseases?”
The RLS-DI is designed for use in RLS, has excellent diagnostic attributes and has been used by other investigators. It is therefore “Recommended.”
The Hening Telephone Diagnostic Interview
The need to accurately determine the diagnosis of RLS in large telephone surveys led to the development of the Hening Telephone Diagnostic Interview ([HTDI] originally named the Johns Hopkins Telephone Diagnostic Interview but changed posthumously in honor of its developer Wayne Hening, M.D., Ph.D.). The interview uses the NIH criteria for RLS. The original version of the validated questionnaire included questions to eliminate leg cramps as a mimic of RLS. In later versions, additional questions were added to exclude positional discomfort as a mimic of RLS, but to our knowledge these later versions have not yet been validated.7,8
This tool has been utilized in RLS patients (Criterion 1) and by multiple research teams (Criterion 2). In terms of clinimetric properties (Criterion 3), in a preliminary validation of the instrument, 37 patients previously diagnosed with RLS by expert clinicians and 38 controls were each interviewed by 3 independent evaluators over the telephone. Each of the evaluators was blinded to the responses obtained by the other evaluators and to the previously determined RLS status.7 The previous diagnosis of RLS by clinician experts was employed as the gold standard in the study. The interrater reliability for the diagnosis of RLS had an intraclass correlation coefficient (ICC) = 0.95. The minimum interviewer sensitivity was 97% and the minimum interviewer specificity was 92% for the diagnosis of RLS as determined by the Hening Telephone Diagnostic interview compared to the gold standard clinician based diagnosis of RLS.7 There was a mean of 12 months between the administration of the Hening Telephone Diagnostic Interview and the determination of RLS status by clinical experts, and this should be considered a weakness of the study. However, the excellent results obtained from the study suggest that the subjects' reports of symptoms are constant and stable.8
STRENGTHS AND WEAKNESSES
The Hening Telephone Diagnostic interview has excellent clinimetric properties and the original validated version includes questions to eliminate leg cramps as a mimic of RLS. A second version of the questionnaire that includes questions to eliminate positional discomfort as an additional mimic of RLS has not yet been validated to our knowledge. It may be impossible to design a diagnostic instrument that excludes all possible mimics of RLS, and although the validated version of the Hening Telephone Diagnostic Interview excludes only one major mimic, i.e., leg cramps, this does not seem to be a major problem as reflected by the excellent sensitivity and specificity of the instrument as measured against a standard clinical interview that excludes mimics. The administrators of the scale are allowed to re-interpret the questions for the patient, and thus the administrators should be familiar with the basic clinical features of RLS. The administrators therefore need some training. In its current form there are 14 questions with multiple parts that are 10 pages in length, and the interview takes some time to administer. Because the interviewed subjects are allowed to ask for clarifications, the exact time of administration cannot be determined, but the interview normally takes approximately 45 minutes. It can be administered in a face-to-face interview format to confirm the diagnosis in a clinical setting. Although the face-to-face format of the scale has not been tested psychometrically, there is no apparent reason to think the results would be different from a telephone administration. However, a separate validation of the face-to-face interview format would be needed to draw definitive conclusions.
The Hening Telephone Diagnostic Interview has been developed for use in RLS, has been utilized by groups other than the group that developed it and has excellent clinimetric properties. The Hening Telephone Diagnostic Interview is therefore “Recommended” in telephone surveys to determine the diagnosis of RLS.
The Cambridge-Hopkins Diagnostic Questionnaire for RLS
The Cambridge-Hopkins diagnostic questionnaire for RLS (CH-RLSq) is a self-completed questionnaire for the diagnosis of RLS. It was developed to allow large scale diagnosis of patients without the need of a trained interviewer. The short form of the questionnaire employs 13 questions that probe the 4 basic criteria of RLS as well as mimics of RLS such as positional discomfort and leg cramps.9
This tool has been utilized in RLS patients (Criterion 1) and by multiple research teams (Criterion 2). In terms of clinimetric properties (Criterion 3), subsequent to validation of the Hening Telephone Diagnostic Interview (HTDI, see above), the Cambridge Hopkins diagnostic questionnaire for RLS was, in turn, validated against an independent blinded administration of the HTDI in a study of 185 subjects from a blood donor population. Because of the large number of subjects involved, the HTDI was chosen as the gold standard for this study rather than a personal patient interview. The Cambridge Hopkins diagnostic questionnaire for RLS had sensitivity of 87.5%, specificity of 94.4%, and positive predictive value of 87.2%. Previous versions of the scale that did not exclude mimics had a positive predictive value of only 39.2%.9 The authors point out that the positive predictive value of 87.2% may be an overestimation given the enriched percentage of RLS patients in this blood donor population. However, they provide an estimate of a positive predictive value of 63.4% in the general population based upon an RLS prevalence of 10%. This is still much better than the 39.2% figure for the previous study where mimics were not excluded.
STRENGTHS AND WEAKNESSES
The Cambridge Hopkins diagnostic questionnaire for RLS has the advantage that it includes items to exclude positional discomfort and leg cramps, two common mimics of RLS, and it can be completed without the intervention of a trained interviewer in a short amount of time. The change in positive predictive value from 39.2% to 87.2% when questions that excluded mimics were included in the questionnaire shows the importance of excluding mimics in this particular diagnostic instrument. Although it was validated against the Hening Telephone Diagnostic Interview rather than directly against a standard clinical interview, the Hening Telephone Diagnostic Interview itself was validated against a standard clinical interview where mimics were excluded. It is the only diagnostic scale that has been evaluated in a general as well as a clinical population.
The self-completed Cambridge Hopkins diagnostic questionnaire for RLS was developed for RLS; it has been employed by other investigators and has satisfactory clinimetric properties. This scale is therefore “Recommended.”
The four reviewed instruments in this article have been developed for RLS, have excellent clinimetric properties as a whole and, in most cases, have been applied to the populations where the instruments would most be used. In other cases, cogent arguments have been made as to the probable generalizability of the scales beyond the populations in which they were validated. Based on the MDS criteria, three of the four evaluated diagnostic tools have, in addition, been used by groups other than those that developed them, and they therefore meet all 3 MDS criteria to be “Recommended” (Hening Telephone Diagnostic Interview, the Cambridge Hopkins Diagnostic Questionnaire for RLS, and the RLS Diagnostic Index). The single question for RLS needs to be used more widely before it can be given full endorsement.
A major issue facing the RLS field from the point of view of developing diagnostic instruments has been the recent understanding that mimics confound its diagnosis.2,3 The single question for RLS does not require the exclusion of mimics. The RLS Diagnostic Index is meant for clinical use, where clinicians have more intimate contact with the patients and therefore have access to important medical information that can help in the exclusion of mimics. The Hening Telephone Diagnostic Interview requires the exclusion of leg cramps, and the Cambridge Hopkins diagnostic questionnaire for RLS requires the exclusion of leg cramps and positional discomfort as mimics of RLS. The four diagnostic instruments reviewed here have excellent clinimetric properties as a whole, suggesting that in the case of the single question the mimics do not impair the performance of the instrument and that in the other instruments, the problem of mimics has been adequately addressed. Still, other potential mimics of RLS such as anxiety, habit spasm, agitated depression, neuroleptic-induced akathisia, hypotensive akathisia, and other pain disorders, e.g., arthritis and neuropathy have not been specifically probed in any of the instruments.7,8 As aforementioned, it may not be realistically possible to design questionnaires that exclude all possible mimics and that are readily understood without further explanation.
Another issue has been the evolution of our understanding of what is required for the diagnosis of childhood RLS in a population where language skills are not yet optimal (or fully developed). A previous more complex approach to the diagnosis of childhood RLS has been abandoned, and the childhood criteria for the diagnosis of RLS have been merged with the adult criteria (Table 1). However, the requirement for diagnosis of RLS in childhood that the child be able to describe leg discomfort in their own words has been maintained. Future development of instruments for the diagnosis, severity, and quality of life of childhood RLS will have to take into account these changes.
Yet another issue has been our evolution in the understanding of what is required for the diagnosis of augmentation. There is disagreement in the field as to which definition of augmentation services the field best and which risk factors—or even mimics of augmentation—have to be considered.10,11 When a consensus is reached, either the Structured Interview for the Diagnosis of Augmentation (SIDA), which is based upon the NIH criteria for augmentation (Table 2) and has only been published in abstract form should be published as a full paper, or an alternative scale should be developed and validated based upon the alternate set of criteria for augmentation (the Max Planck criteria for Augmentation) or a third alternative set of criteria.12
A final consideration is the use of laboratory instruments for evaluation of RLS. This is seen in that the RLS-DI incorporates the presence or absence of periodic limb movements in sleep (PLMS) as an optional aid in the diagnosis of RLS. The use of other tools such as polysomnography, actigraphy, and sleep logs for the evaluation of RLS has been reviewed in detail by Allen.13,14
The Hening Telephone Diagnostic Interview, the Cambridge Hopkins diagnostic questionnaire for RLS and the RLS Diagnostic Index are “Recommended” for use because they have been developed for use in RLS, have adequate clinometric properties, and have been employed by groups other than the one that developed them. The single question for RLS does not exclude mimics. However, the excellent clinimetric properties of the question when measured against a standard clinical interview where mimics were excluded indicate that this is not a major problem. On the other hand, the single question for RLS needs to be used more widely before it can be given full endorsement. Given the availability of three adequate tools, there does not appear to be a need to develop additional diagnostic tools for adult RLS. On the contrary the same cannot be said for the diagnosis of augmentation, where a sound assessment tool is much needed. Whether the Structured Interview for the Diagnosis of Augmentation (SIDA) may ultimately serve that role is dependent upon an agreement in the field as to whether it properly reflects the diagnosis of augmentation. If such is not the case, another instrument needs to be developed and validated based upon an agreed upon definition for augmentation. An unmet need is the development of a diagnostic instrument for pediatric RLS.
This was not an industry supported study. Dr. Walters served as a consultant for and has received research funding from UCB Pharma and Mundi Pharma. He has also received funding from the USA National Institutes of Health. He has also served as an expert witness in a single legal case involving restless legs syndrome. Dr. Frauscher has received research funding from the Austrian Science Fund, a Schroedinger Fellowship Abroad, and the National Bank of Austria Anniversary Fund. Dr. Allen served as a consultant for Luitpold Pharmaceuticals, Pfizer, Pharmacosmos, Impax Pharmaceuticals, and UCB Pharma and has received research support from Glaxo Smith Kline, Pharmacosmos, and the USA National Institutes of Health. Dr. Benes has received payment for lectures and has served on the medical advisory boards of UCB Pharma and MundiPharma. Dr. Chaudhuri has consulted for UCB Pharma and Abbott, received honoraria from Boehringer-Ingelheim, Britannia, Abbott, Cephalon, and UCB, and has received research support from Parkinson's UK, PDNMG, and the UK Department of Health. Dr. Garcia-Borreguero has received honoraria for advisory boards or lectures from Xenoport, UCB Pharma, Pfizer, Impax Pharmaceuticals, and MSD. Dr. Picchietti has served on the advisory board of the Willis-Ekbom Disease Foundation and has received royalties for updating a book chapter. Dr. Trenkwalder has received honoraria from Boehringer-Ingelheim, UCB Pharma, Glaxo Smith Kline, MundiPharma, Desitin, and Novartis. Dr. Stebbins has received consulting fees from and has Advisory Board Membership with honoraria from Acadia Pharmaceuticals, Adamas Pharmaceuticals, Inc, Ceregene, Inc, CHDI Management, Inc., Ingenix Pharmaceutical Services (i3 Research), and Neurocrine Biosciences, Inc.; has received research support from the National Institutes of Health, the Michael J. Fox Foundation for Parkinson's Research, and the Dystonia coalition; and has received honoraria from the Movement Disorder Society, the American Academy of Neurology, and the Michael J. Fox foundation for Parkinson's Research. Dr. Schrag has consulted for Novartis Pharmaceuticals, Merck Pharmaceuticals, and Boehringer-Ingelheim Pharmaceuticals; has served on the Medical Advisory Board of and has received honoraria from Boehringer-Ingelheim Pharmaceuticals; has received grant funding from AMGEN Pharmaceuticals, Acadia Pharmaceuticals, the EU Commission, Parkinson's UK, and GE Healthcare; and has received royalties from Oxford University Press for publications on Rating Scales in Parkinson's disease. Dr. Martinez-Martin has received honoraria from speaking engagements at scientific meeting of Italfarmaco and TEVA, and from serving in a scientific advisory board of AbbVie and has received research support from the Carlos III Institute of Health (FIS), IMSERSO, the Michael J. Fox Foundation, and the Reina Sofia Foundation. Dr. Lee has indicated no financial conflicts of interest.
MDS Committee on Rating Scales Development
The authors thank Patience Bridges, CAP for her help in the preparation of this manuscript. This manuscript is dedicated to the memory of our dear and recently departed colleague Dr. Ralf Kohnen who was the developer and validation leader for many of the scales and evaluative instruments we employ in RLS/WED research today including the widely used RLS-6 and the RLS Quality of Life scales. For the RLS/ WED community he was the principal person to whom we all turned for advice and help in the development and validation of these instruments. He will be much missed.
Author Roles: Drs. Walters, Frauscher, Martinez-Martin, Stebbins, and Schrag were involved in the conception, organization, execution, review, and critique of the project and manuscript. Dr. Walters wrote the first and all subsequent drafts of the manuscript. Drs. Allen, Benes, Chaudhuri, Garcia-Borreguero, Lee, Picchietti, and Trenkwalder were involved in the conception, review, and critique of the project and manuscript.
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