November 2012, VOLUME130 /ISSUE Supplement 2

A Practice Pathway for the Identification, Evaluation, and Management of Insomnia in Children and Adolescents With Autism Spectrum Disorders

  1. Beth A. Malow, MD, MSa,b,c,
  2. Kelly Byars, PsyDd,
  3. Kyle Johnson, MDe,
  4. Shelly Weiss, MDf,
  5. Pilar Bernal, MDa,c,
  6. Suzanne E. Goldman, PhDg,
  7. Rebecca Panzer, MA, RD, LDh,
  8. Daniel L. Coury, MDi, and
  9. Dan G. Glaze, MDj
  1. Departments of aNeurology and
  2. bPediatrics and
  3. cKennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee;
  4. dDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Hospital Children’s Medical Center, Cincinnati, Ohio;
  5. eDepartment of Psychiatry, Oregon Health and Science University, Portland, Oregon;
  6. fHolland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada;
  7. gKaiser Permanente Northern, San Jose, California;
  8. hMassGeneral Hospital for Children, Boston, Massachusetts;
  9. iDepartment of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio; and
  10. jDepartments of Neurology and Pediatrics, Baylor College of Medicine, Houston, Texas


OBJECTIVE This report describes the development of a practice pathway for the identification, evaluation, and management of insomnia in children and adolescents who have autism spectrum disorders (ASDs).

METHODS The Sleep Committee of the Autism Treatment Network (ATN) developed a practice pathway, based on expert consensus, to capture best practices for an overarching approach to insomnia by a general pediatrician, primary care provider, or autism medical specialist, including identification, evaluation, and management. A field test at 4 ATN sites was used to evaluate the pathway. In addition, a systematic literature review and grading of evidence provided data regarding treatments of insomnia in children who have neurodevelopmental disabilities.

RESULTS The literature review revealed that current treatments for insomnia in children who have ASD show promise for behavioral/educational interventions and melatonin trials. However, there is a paucity of evidence, supporting the need for additional research. Consensus among the ATN sleep medicine committee experts included: (1) all children who have ASD should be screened for insomnia; (2) screening should be done for potential contributing factors, including other medical problems; (3) the need for therapeutic intervention should be determined; (4) therapeutic interventions should begin with parent education in the use of behavioral approaches as a first-line approach; (5) pharmacologic therapy may be indicated in certain situations; and (6) there should be follow-up after any intervention to evaluate effectiveness and tolerance of the therapy. Field testing of the practice pathway by autism medical specialists allowed for refinement of the practice pathway.

CONCLUSIONS The insomnia practice pathway may help health care providers to identify and manage insomnia symptoms in children and adolescents who have ASD. It may also provide a framework to evaluate the impact of contributing factors on insomnia and to test the effectiveness of nonpharmacologic and pharmacologic treatment strategies for the nighttime symptoms and daytime functioning and quality of life in ASD.

  • actigraphy
  • education
  • sleep
  • sleep latency
  • Abbreviations:
    autism spectrum disorder
    Autism Treatment Network
    Children’s Sleep Habits Questionnaire
    National Initiative for Children’s Healthcare Quality
    randomized controlled trial
  • Approximately 1 in 110 children fulfills the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, diagnostic criteria for autism spectrum disorders (ASDs) as defined by delayed or abnormal social interaction, language as used in social communication, and/or restricted repetitive and stereotyped patterns of behavior, interests, and activities.1 Children who have ASD are at greater risk for developing sleep problems than typically developing children. Research has documented that the prevalence of sleep disturbances ranges from 53% to 78% for children who have ASD compared with 26% to 32% for typically developing children.2,3

    The key components of pediatric insomnia are repeated episodes of difficulty initiating and/or maintaining sleep, including premature awakenings, leading to insufficient or poor-quality sleep. These episodes result in functional impairment for the child or other family members.4 In typically developing children, the primary cause of insomnia is behaviorally based.5 In the ASD population, however, insomnia is multifactorial. It includes not only behavioral issues but also medical, neurologic, and psychiatric comorbidities; it is also an adverse effect of the medications used to treat symptoms of autism and these comorbidities.6

    Typically developing children who have insomnia are at increased risk for neurobehavioral problems such as impairments in cognition, mood, attention, and behavior.5,79 Similar to the behavioral morbidity associated with pediatric insomnia that is observed in the general population, children who have ASD and sleep problems are prone to more severe comorbid behavioral disturbances compared with children without sleep disturbances.10 In addition, treating insomnia in children who have neurodevelopmental disorders may improve problematic daytime behaviors.11

    Despite the prevalence of and morbidity associated with pediatric insomnia, there is evidence that sleep disorders in children often go undetected and untreated.1214 Medical practitioners often do not ask about sleep concerns or parents do not seek assistance.15 Many parents have poor knowledge about sleep development and sleep problems.16 This is particularly relevant to children who have ASD, in that parents may present to the pediatrician with concerns regarding aggression, impulsivity, inattention/hyperactivity, or other behavioral issues that may be secondary to a sleep disorder. The contribution of the sleep disorder may be undetected due to emphasis on treating the behavioral issue as opposed to identifying and treating the underlying factors. This deemphasis of underlying factors may be due to the absence of a standardized approach for recognition and treatment of insomnia in children who have ASD.

    Guidelines exist for sleep screening and intervention in typically developing children.17,18 Guidelines and empirical support also exist for the effectiveness of behavioral treatment of bedtime problems and night wakings in children.1821 Specific behavioral treatments supported include the following: unmodified extinction: leaving the child’s bedroom after putting the child to bed and not returning until morning unless the child is ill or at risk for injury; extinction with parent presence: parent is present in the room with the child but does not interact with him or her; graduated extinction: parent returns to child’s bedroom to attend to child on request or agitation but increases the time in between requests by the child for the parent to return; preventive parent education: providing education to parent on sleep habits and bedtime routine; bedtime fading: delaying bedtime to promote sleep and then “fading” or advancing bedtime once child is falling asleep easier; and scheduled awakenings: awakening the child before a spontaneous awakening. Extinction and parent education have strong empirical support whereas the other interventions are less confidently supported.18 To our knowledge, however, there are no published guidelines related to management of insomnia in children who have ASD, including screening and treatment. The evidence that children who have ASD are at greater risk for insomnia and its morbidity suggests that sleep screening in this population of children is extremely important. The ideal evaluation of insomnia in children who have ASD involves a comprehensive sleep assessment, as outlined in a recent review.22

    To facilitate the evaluation of children with ASD for insomnia, the Autism Treatment Network (ATN) in association with the National Initiative for Children’s Healthcare Quality (NICHQ) worked collaboratively to develop the clinical practice pathway presented in this article. The intention of this clinical practice pathway is to emphasize the need for screening of sleep problems in ASD and to provide a framework for decision-making related to best practices in the care of children and adolescents with ASD in primary care settings, when seen by a general pediatrician, primary care provider, or autism medical specialist. The pathway is not intended to serve as the sole source of guidance in the evaluation of insomnia in children who have ASD or to replace clinical judgment, and it may not provide the only appropriate approach to this challenge.


    Guideline Development

    The ATN Sleep Committee consists of pediatric sleep medicine specialists as well as developmental pediatricians, neurologists, and psychiatrists. The clinical practice pathway was designed to assist primary care providers and others working directly with families affected by ASD in addressing the challenge of insomnia with regard to identification, assessment, and management.

    Insomnia was defined as “repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age-appropriate time and opportunity for sleep that results in daytime functional impairment for the child and/or family.”18 The responses of the parents to selected questions on the Children’s Sleep Habits Questionnaire (CSHQ)23 identified those patients who have insomnia.

    After performing a systemic review of the literature, expert opinion and consensus was used to form the basis of the practice pathway (Fig 1). The ATN Sleep Committee’s knowledge of the literature and applicability to clinical practice informed best practices, which in turn created an overarching approach to insomnia within ATN sites by the autism medical specialist.

    FIGURE 1

    Checklist for carrying out the practice pathway in children who have ASD and insomnia. CSHQ, Children's Sleep Habits Questionnaire.

    Systematic Review of the Literature

    We conducted a systematic literature review to find evidence regarding the treatment of insomnia in children diagnosed with ASD (questions and search terms available on request from the authors). We searched OVID, CINAHL, Embase, Database of Abstracts and Review Database of Abstracts of Reviews and Effects, and the Cochrane Database of Systematic reviews databases, with searches limited to primary and secondary research conducted with humans, published in the English language, involving children aged 0 to 18 years, and published between January 1995 and July 2010. Individual studies were graded by using an adaptation of the GRADE system24 by 2 primary reviewers and then reviewed by content experts for consensus. Discrepancies were resolved by a third party.

    Pilot Testing of the Pathway

    The ATN selected 4 pilot sites (Baylor University, Houston, Texas; Oregon Health and Science University, Portland, Oregon; Kaiser Permanente Northern, San Jose, California; University of Missouri, Columbia, Missouri) to test the feasibility of the practice pathway and provide information regarding needed modifications. The pilot sites collected data to document adherence to the practice pathway and participated in monthly conference calls to provide updates, understand variance, and recommend changes. Working with the NICHQ, members of the ATN Sleep Committee refined and finalized the practice pathway on the basis of feedback from the pilot sites. In response to recommendations from the pilot sites to increase feasibility, the NICHQ also developed a 1-page checklist designed to guide providers through the practice pathway (Fig 2).

    FIGURE 2

    Practice pathway for insomnia in children who have ASD.


    Results of the Literature Review

    The search identified 1528 articles. After removing review articles, commentaries, case studies with fewer than 10 subjects, studies that included children who did not have ASD, nonintervention trials, and articles that did not address our target questions, 20 articles remained (Table 1). We reviewed the literature for studies related to other aspects of the practice pathway (eg, screening for insomnia, identifying comorbidities, importance of follow-up) in the ASD population and were unable to identify evidence-based reports for aspects other than treatment. A comprehensive review25 and consensus statement26 related to the pharmacologic management of insomnia in children (not specific to ASD) were identified.

    TABLE 1

    Results of Systematic Literature Review

    The results of the systematic literature review demonstrate that treatment trials are limited in the ASD population. There are 3 categories of treatment: pharmacologic/biologic treatments, behavioral/educational interventions, and complementary and alternative medicine.

    The evidence base to date shows limited evidence for the use of medications to treat insomnia in children who have ASD. The most evidence exists for the use of supplemental melatonin, an indoleamine with sleep-promoting and chronobiotic (sleep phase shifting) properties considered a nutritional supplement by the US Food and Drug Administration. Several small, randomized controlled trials (RCTs) demonstrated the efficacy of supplemental melatonin in treating insomnia in children who have ASD,2729 although larger studies are needed. Melatonin seems to be relatively safe based on these trials and on other series.30 Other pharmacologic interventions such as risperidone, secretin, l-carnitine, niaprazine, mirtazapine, and clonidine, as well as multivitamins and iron, have limited evidence supporting their use in treating insomnia in ASD. The research evidence to date does not support the efficacy of other supplements or vitamins.

    Behavioral interventions are clearly beneficial for typically developing children experiencing significant insomnia.21 However, few treatment trials found that behavioral treatments provide consistent success rates in children who have ASD, particularly those experiencing sleep-onset insomnia. The systematic review of the literature identified 2 studies examining the efficacy of behavioral treatment of insomnia in children who have ASD.31,32 Each of these studies demonstrated statistically significant improvements in sleep posttreatment. Both studies used multicomponent treatments, although they varied with respect to the specific components of treatment. However, they were representative of treatments commonly used in clinical practice as well as supported as effective in the general pediatric population. Both studies used extinction and positive reinforcement as treatments. Both studies provided parent training, as follows: (1) identifying a treatment goal/treatment target for therapy; (2) discussion of how the sleep problem is maintained by conditioning/learning; and (3) emphasis on establishing a developmentally appropriate bedtime and a consistent bedtime routine. Other treatment components addressed in a single study included sleep hygiene instructions, use of effective instructions/directions to shape appropriate sleep behavior, and use of the bedtime pass protocol.23 The studies did not address relative efficacy of these individual treatment components.

    Complementary and alternative medicine therapies addressed in the literature review include massage therapy and aromatherapy.3335 The systematic review found no evidence to support these therapies for insomnia in children who have ASD. Neither of the graded studies examining the efficacy of massage therapy or aromatherapy for insomnia in children who have ASD led to statistically significant improvements in sleep posttreatment.3335

    Results of the Guideline Development

    Based on the feasibility testing, a number of observations resulted in the development of resources to assist clinicians in the application of the practice pathway. After reviewing the literature and conducting pilot testing, the ATN Sleep Committee developed and refined the insomnia practice pathway and made the following consensus recommendations:

    1. General pediatricians, family care providers, and autism medical specialists should screen all children who have ASD for insomnia.

    This screening is best done by asking a short series of questions targeting insomnia, such as those from the CSHQ, and asking if the parent considers these a problem. These questions are: (1) child falls asleep within 20 minutes after going to bed; (2) child falls asleep in parent's or sibling's bed; (3) child sleeps too little; and (4) child awakens once during the night. These questions were selected on the basis of review of the CSHQ and expert consensus. The ATN database was also reviewed (n = 4887), and we found that 81% of parents who reported that their child awakening more than once during the night was a problem also answered affirmatively to the question “Does your child awaken once during the night?” Therefore, to limit the questions asked, we did not include “Does your child awaken more than once during the night?” Asking specific questions is essential because parents may not volunteer concerns about insomnia given their concerns with behavioral issues (although these issues may be secondary to the insomnia). Identifying significant insomnia is paramount given its impact on daytime functioning, not only for the child with ASD but also the family. Table 2 lists available questionnaires.

    TABLE 2

    Sleep Questionnaire Options

    1. The evaluation of insomnia should include attention to medical contributors that can affect sleep (including neurologic conditions and other sleep disorders that contribute to insomnia).

    These contributors should be addressed because their treatment may improve insomnia. Within the ATN, we have developed a list of questions for medical contributors, including gastrointestinal disorders, epilepsy, pain, nutritional issues, and other underlying sleep disorders responsible for insomnia, including sleep-disodered breathing and restless legs symptoms (Table 3) that pediatricians can incorporate within their review of systems. Psychiatric conditions, such as anxiety, depression, and bipolar disorder, should be considered because these may contribute to insomnia. Finally, because many medications contribute to insomnia, a careful review of medications should be performed.

    TABLE 3

    Questionnaire to Help Identify Underlying Medical Conditions

    1. Educational/behavioral interventions are the first line of treatment, after excluding medical contributors. However, if an educational (behavioral) approach does not seem feasible, or the intensity of symptoms has reached a crisis point, the use of pharmacologic treatment is considered.

    Educational/behavioral approaches to the treatment of insomnia are advocated as a first-line treatment in typically developing children.21 In children who have ASD, educational/behavioral approaches are also recommended, especially because these children may not be capable of expressing adverse effects caused by the medications. The core behavioral deficits associated with ASD may impede the establishment of sound bedtime behaviors and routines. These include: (1) difficulty with emotional regulation (eg, ability to calm self); (2) difficulty transitioning from preferred or stimulating activities to sleep; and (3) deficits in communication skills affecting a child’s understanding of the expectations of parents related to going to bed and falling asleep. Conversely, given preferences for sameness and routine, children who have ASD may adapt well to establishment of bedtime routines, especially if visual schedules are implemented.

    The ATN has developed an educational toolkit for parents that consists of pamphlets to promote good sleep habits; a survey to assess for habits that may interfere with sleep; sample bedtime routines, including a visual supports library, tip sheets for implementing the bedtime routine, and managing night wakings; and a sleep diary. The toolkit is being tested for feasibility in an ongoing research project funded by the Health Resources and Services Administration of parent sleep education at 4 ATN sites and is also being used in clinical practice throughout the network. As with other educational/behavioral approaches, the success of this toolkit depends on appropriate implementation by parents, with the guidance provided by practitioners an essential element for many families. Families can often be encouraged to implement educational/behavioral strategies when presented with these tools, especially if they receive hands-on instruction in the tools and are provided with an explanation of why a behavioral approach is recommended. However, some families may be in a state of crisis or may not be willing or able to use the behavioral tools. These families may be challenged by difficult daytime behaviors in their child or by financial concerns. These children might require pharmacologic treatment. In addition, practitioners may not be able to provide sufficient instruction in the tools for a family to be successful with their implementation. Therefore, there is the option in the practice pathway (Fig 2, Box 5b) of medication or consultation to a sleep specialist if the family is unwilling or unable to use an educational approach, depending on the comfort level of the pediatrician.

    Behavioral Treatments for Insomnia

    The behavioral treatments most commonly used to treat insomnia in children who have ASD include behavioral modification strategies such as extinction (eg, withdrawal of reinforcement for inappropriate bedtime behaviors) and positive reinforcement of adaptive sleep behavior. Sleep hygiene instructions (eg, appropriate sleep schedules and routines) often accompany behavioral modification protocols. Behavioral interventions are effective in the treatment of insomnia in typically developing children.21 However, the evidence base for effectiveness of such interventions in children who have ASD is limited. The data from the literature review provide preliminary support for the use of behavioral modification to treat insomnia in children who have ASD. These data were the basis for the development of an educational toolkit used to guide behavioral management of insomnia in the insomnia practice pathway.

    Alternative Treatments for Insomnia

    The most common alternative therapy with a presence in the literature is massage therapy.33,35 However, the results do not demonstrate consistent, statistically significant improvements in sleep.

    Pharmacologic Treatments for Insomnia

    Although medications and supplements are often used to treat insomnia experienced by children and adolescents who have ASD, the evidence base for pharmacologic treatment is limited. At this time, there are no medications approved by the US Food and Drug Administration for pediatric insomnia. The most evidence exists for the use of melatonin.

    1. Clinicians should assure timely follow-up to monitor progress and resolution of insomnia.

    Assuring adequate follow-up is crucial when treating children who have ASD and significant insomnia. Follow-up should occur within 2 weeks to 1 month after beginning treatment. The provider and family should expect to see some benefits and improvements within 4 weeks. Follow-up may be conducted by telephone or in person. Timely follow-up allows for fine-tuning of treatment interventions, support of parents, and provision of referrals if needed. In addition to short-term follow-up (eg, 1–2 months), at long-term follow-up (eg, 1-year visit) the steps from the beginning of the practice pathway should be repeated.

    As outlined in the practice pathway, treatment of insomnia can be initiated by the general pediatrician, primary care provider, or autism medical specialist. Many children will improve with these initial interventions. Consultation with a sleep specialist is indicated if insomnia is not improving with these initial interventions or when the insomnia is particularly severe, causing significant daytime impairment or placing the child at risk for harm while awake during the night. For those children who have ASD and are taking multiple medications for sleep when initially assessed by the health care provider, consultation with a sleep specialist may be indicated, depending on the comfort level of the provider. Other indications for consultation with a pediatric sleep specialist may include when underlying sleep disorders are responsible for the sleeplessness symptoms (including sleep apnea, restless legs syndrome, periodic limb movements of sleep, and unusual nighttime behaviors [parasomnias] such as sleepwalking or sleep terrors).

    Results of the Field Testing

    Results of the pilot phase indicated challenges in implementing the practice pathway due to a number of conflicts, including: (1) competing demands on the pediatric provider in a busy clinical practice; (2) knowledge level of the pediatric provider; and (3) when consultation to the sleep specialist occurs, ensuring communication back to the pediatric provider.

    In response to these barriers, we developed the following resources: (1) a short set of screening questions for insomnia as well as a checklist for medical conditions contributing to insomnia (Table 3); and (2) a sleep education toolkit, available in hard copy as well as on the internal ATN Web site ( that will facilitate parent teaching.

    Additional issues were identified related to provider comfort level in the following areas: (1) assessing for medical or sleep contributors themselves rather than referring to a specialist, which led us to modify the practice pathway to allow for both options; (2) providing education to families in use of the toolkit, which affected the length at which follow-up occurred (eg, a second visit with a nurse educator might be needed for toolkit implementation if the provider was too busy to educate families at the time of the initial clinic visit); and (3) treating insomnia with medications on their own versus referring to a sleep specialist. When a child was referred to the sleep specialist, ensuring that the sleep specialist communicated back to the provider regarding recommendations was also an issue related to applying the practice pathway in our field testing, particularly as related to follow-up care.

    We modified the flow of the practice pathway in response to feedback during the field testing. Initially, the practice pathway prioritized evaluation and treatment of medical contributors before implementing educational measures, such as the toolkit. However, based on the feedback of clinicians, the evaluation/treatment of medical contributors and the implementation of educational measures became a parallel process as opposed to a sequential “first–then” approach.


    We report here on the development of a practice pathway for the evaluation and management of insomnia in children who have ASD. There are several key points of this practice pathway. First, general pediatricians, primary care providers, and autism medical specialists should screen all children who have ASD for insomnia because parents may not volunteer sleep concerns despite these concerns being contributors to medical comorbidities and behavioral issues. Second, the evaluation of insomnia should include attention to medical contributors that can affect sleep, including other medical problems that encompass gastrointestinal disorders, epilepsy, psychiatric comorbidities, medications, and sleep disorders including sleep-disordered breathing, restless legs syndrome (unpleasant sensations in the legs associated with an urge to move), periodic limb movements of sleep (rhythmic leg kicks during sleep), and parasomnias (undesirable movements or behaviors during sleep, such as sleepwalking, sleep terrors, or confusional arousals). In parallel with this screening, the need for therapeutic intervention should be determined. We also determined that educational/behavioral interventions are the first line of treatment, after excluding medical contributors. If an educational (behavioral) approach does not seem feasible, or the intensity of symptoms has reached a crisis point, the use of pharmacologic treatment is considered. Finally, clinicians should assure timely follow-up to monitor progress and resolution of insomnia.

    This practice pathway expands the literature that currently exists for typically developing children related to screening and management.5,79 The rationale for developing a practice pathway that uniquely addresses this population is because children who have ASD, and their families, have unique needs. For example, medical, neurologic, and psychiatric comorbidities are common in children who have ASD, as is the use of medications that influence sleep. In addition, parents of children who have ASD, struggling with the stressors related to their child’s disability and the often accompanying behavioral challenges, may not volunteer sleep to be of concern. In turn, pediatric providers may not ask about sleep due to competing medical and behavioral issues. Furthermore, sleep problems are more common in children who have ASD than in children of typical development,2,3 and their treatment may impact favorably on daytime behavior and family functioning. Given these factors, we do recognize that children who have other disorders of neurodevelopment could also benefit from this practice pathway, as they share common features with children who have ASD, including comorbid conditions, parental stressors, and prevalent sleep problems.

    The systematic review of the available treatment literature allowed for the recognition that evidence-based standards for the behavioral, pharmacologic, and other treatments of insomnia in ASD are not yet available. Thus, much of these guidelines reflect expert opinion given the absence of data. Additional studies are needed to establish the efficacy and safety of supplemental melatonin, as well as other pharmacologic agents, in large RCTs. Similar studies are needed to address the efficacy of parent-based sleep educational programs to address insomnia, as well as the combination of these educational programs with pharmacologic strategies. Finally, the role of nonpharmacologic methods (apart from educational therapies) warrants study as well. As additional research studies are performed, the clinical pathway will likely require modification. However, it is expected that the overarching approach to insomnia in the child who has ASD will not change. Although the practice pathway was piloted at 4 ATN sites, the next steps involve the wide dissemination of the practice pathway into pediatric practices. We would also like to develop a practice pathway for nonmedical health professionals who are likely to provide behavioral interventions, including psychologists.

    Strengths of the study include the gathering of the following groups: experts in sleep medicine from a variety of disciplines, including neurology, psychiatry, pulmonary medicine, and psychology; engaged pediatricians specializing in ASD; and parents of children who have ASD. Weaknesses include limited evidence-based studies on which to base the practice pathway, making it necessary to rely on expert opinion.


    The practice pathway regarding the identification of insomnia in children who have ASD requires future field testing in clinical settings but represents a starting point to managing insomnia in a growing population of children with the most common neurodevelopmental disability.


    The valuable assistance of the members of the ATN Sleep Committee in reviewing this document is gratefully acknowledged.


      • Accepted August 8, 2012.
    • Address correspondence to Beth Malow, MD, MS, Burry Chair in Cognitive Childhood Development, Director, Vanderbilt Sleep Disorders Division, 1161 21st Avenue South, Room A-0116, Nashville, TN 37232. E-mail: beth.malow{at}
    • This manuscript has been read and approved by all authors. This paper is unique and not under consideration by any other publication and has not been published elsewhere.

    • FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.