Typical treatment plans for attention-deficit/hyperactivity disorder (ADHD) utilize nonpharmacological  and/or pharmacological interventions. Limited accessibility to behavioral therapies and concerns over adverse effects of pharmacological treatments prompted research for alternative ADHD therapies such as natural product-derived treatments and nutritional supplements. In this study, we reviewed the herbal preparations and nutritional supplements evaluated in clinical studies as potential ADHD treatments and discussed their performance with regard to safety and efficacy in clinical trials. We also discussed some evidence suggesting that adjunct treatment of these agents  may be a promising approach to treat ADHD. The analysis indicated mixed findings with regard to efficacy of natural product-derived ADHD interventions. Nevertheless, these treatments were considered as a “safer” approach than conventional ADHD medications. More comprehensive and appropriately controlled clinical studies are required to fully ascertain efficacy and safety of natural product-derived ADHD treatments. Studies that replicate encouraging findings on the efficacy of combining botanical agents and nutritional supplements with other natural product-derived therapies and widely used ADHD medications are also warranted. In conclusion, the risk-benefit balance of natural product-derived ADHD treatments should be carefully monitored when used as standalone treatment or when combined with other conventional ADHD treatments.  Attention-deficit/hyperactivity disorder (ADHD), a neurodevelopmental disorder characterized by the core symptoms of hyperactivity, inattentiveness, and impulsivity , is currA number of treatment strategies have been suggested for ADHD since its recognition as a specific disorder in the 1970s. Presently, typical treatment plans utilize a nonpharmacological  and pharmacological interventions or a combination of both . A promiADHD has been associated with abnormalities in catecholaminergic function in the brain . The useWhile pharmacological treatments generally improve ADHD symptoms for most children, 20–30% of affected individuals are nonresponders or are unable to tolerate adverse side effects of these drugs , 18. SomDue to concerns over the safety and efficacy of current pharmacological ADHD interventions, there has been growing interest in the development of alternative treatments such as natural product-derived ADHD treatments including botanical or herbal medicines, vitamins, minerals, and amino acids –11. ThesSearches were made in the electronic databases PubMed, PyschINFO, and The Cochrane Library for English language articles from 2001 up to December 1, 2015. PubMed was used to search ADHD search terms in combination with particular natural product-derived treatments. The search strategy employed included combining these keywords: “natural products,” “plant”, “vitamins,” “minerals,” “essential fatty acids,” “amino acids”, “combination natural products,” or “combination with methylphenidate” and “ADHD” or “attention-deficit/hyperactivity disorder.” This process yielded 671 papers covering a wide range of research article types. As we were interested only in natural product-derived ADHD treatments which were evaluated in clinical trials, we concentrated on open-label, randomized controlled trials, as well as observational studies. Moreover, the inclusion criteria included samples consisting of children and adolescent ADHD patients (below 18 years of age), as well as sample size ≥ 10. The number of English language articles that were reviewed for this paper was 30.Pinus pinaster). This extract is rich in catechin, phenolic acids, procyanidins, and taxifolin, each with multiple biologic effects ) [ G. biloba (50 mg) and ginseng (200 mg) up to 4 weeks after treatment. Reported side effects of G. biloba were observed; for example, subjects became more impulsive, hyperactive, aggressive, emotional, and tired and manifested increased sweating [ G. biloba's beneficial effects have been linked to various activities such as improvement in cerebrovascular blood flow , reversal of serotonergic (5-HT) 1A and noradrenergic receptor reductions, and inhibition of both monoamine oxidase- (MAO-) A and MAO-B in the brain [ G. biloba did produce improvement in ADHD symptoms, a trial by Salehi et al. [n = 50 children) found that G. biloba (80–120 mg/day) was inferior to methylphenidate in efficacy endpoint. More formal clinical trials are required with longer duration and rigorous clinical endpoints in order to prove the worth of G. biloba in ADHD treatment.A unique species of tree native to East Asia, effects . Currentpairment , 49. Stun et al.  reportedsweating . G. bilohe brain . While Gi et al.  conducteValeriana officinalis) is a perineal plant with sedative and antispasmodic effect. It has also been traditionally used in the treatment of insomnia, anxiety, and restlessness [A receptor [Valerian . Deficireceptor . Valeriareceptor , 10, 33.n = 36) or 1 mg/kg/day methylphenidate (n = 36) for a period of 8 weeks, reported that NDG was equally effective as methylphenidate in improving ADHD symptoms [Ningdong granule (NDG) is a widely used Chinese medicinal preparation for various medicinal purposes. NDG showed promise in treating Tourette's syndrome, which invited studies to determine its efficacy in ADHD . A randosymptoms . Accordisymptoms . One of symptoms .Bacopa monnieri) is an Ayurvedic medicine, also known as Brahmi or water hyssop. This natural remedy has been used for centuries to modulate memory, concentration, and learning [Bacopa  or methylphenidate , dosed on a weight-adjusted basis, for 8 weeks. Both parent and teacher rating scores revealed no significant difference in the clinical benefits of Passiflora and methylphenidate treatment in ADHD children over the course of the trial . Moreover, side effect profile of Passiflora was less compared with methylphenidate [Passion flower is comprised of the fragmented or cut, dried aerial parts ofand ADHD , 59. Eff Scutellaria baicalensis Georgi, a herb commonly found in East Asia [A receptor [Oroxylin A  is a flavonoid isolated from the root ofast Asia . Oroxylireceptor . Furtherreceptor , 62. The G. biloba and ginsenoside Rg3 from ginseng. A recent study showed improvement of ADHD-like symptoms, induced by Aroclor1254, in mice given YY1612 [YY162 is a combination pharmaceutical product consisting of terpenoid-strengthenedn YY1612 . The degn YY1612 . Further Sideritis plant, species “Sideritis scardica,” has been used traditionally in the Mediterranean region as teas and flavoring agents and also for treatment purposes [ S. scardica extracts may have an inhibitory effect on the reuptake of three key monoamines: dopamine, serotonin, and noradrenaline [ Sideritis treatment in rats induced frequency patterns comparable to those produced by methylphenidate [ Sideritis in the treatment of mental disorders, including ADHD. Further in vivo studies measuring its efficacy in ADHD are warranted.The genuspurposes . Studiesrenaline . Moreovehenidate . OverallRhodiola rosea) has been shown to stimulate CNS activity and exert adaptogenic and neuroprotective effects [Rhodiola . Thus, a wide range of nutritional supplements  have been proposed as potential adjunct and alternative ADHD treatments. Because these agents are closer to food substances than drugs, they do not have similar rigorous restrictions by the Federal Drug Administration that drugs do have and can be purchased over the counter .Vitamins have been used as potential adjuncts or alternative treatments for ADHD based on anecdotal evidence that they produced improvement in attentiveness and concentration in normal children . As an eThe effects of vitamin C treatment with alpha linolenic acid- (ALA-) rich nutritional supplementation in the form of flax oil on blood fatty acids composition and behavior in children with ADHD were also examined . This stCurrently, there is another ongoing clinical study evaluating the effect of tocotrienols for children with ADHD, of which findings are not yet reported: Tocotrienols for School-going Children With ADHD (TOCAT). Tocotrienol is a form of vitamin E which is described to exert antioxidative properties . MoreoveWhile vitamins may not directly affect symptoms of ADHD, they have the added benefit of replenishing any deficiencies due to poor dietary habits . NeverthAnother proposed alternative intervention for ADHD is mineral supplementation. Mineral deficiencies have also been implicated in the etiology of this disorder, making supplementation a potential means of improving ADHD symptoms. Minerals, as cofactors, have a role in the synthesis, uptake, and breakdown of crucial neurotransmitters associated with ADHD , 76, 78.A 12-week double-blind study found that children supplemented with zinc sulfate (150 mg) showed reduced impulsiveness, hyperactivity, and socialization difficulties . A studyIron is another well-studied mineral that has undergone clinical trial for the treatment of ADHD. Iron is a cofactor in the synthesis of both norepinephrine and dopamine , 18. As Another mineral shown to improve ADHD symptoms is magnesium. The involvement of this mineral in neurotransmitter synthesis supports its potentiality as an ADHD treatment . In a prd = 1.2–2.2) on ADHD symptoms during intervention phases [In general, these findings indicate the worth of mineral supplementation in ADHD. Nevertheless, a strategy suggested to advance the use of minerals (as well as vitamins) in ADHD treatment is to combine these nutrients to adequately affect the complicated biochemical pathways that may be defective in ADHD patients  and to mn phases . This stn phases , 80.A number of amino acids have been shown to exert direct or indirect effects on the levels of specific neurotransmitters. Thus, they have the potential to be used in treating ADHD. Amino acids, glycine, L-theanine, L-tyrosine, taurine, acetyl-L-carnitine (ALC), GABA, 5-hydroxytryptophan (5-HTP), and s-adenosyl-L-methionine (SAMe), are all considered potential complementary ADHD interventions , 10. A sTheanine is an amino acid found in both green and black teas . This noγ-linolenic acid 96 mg, vitamin E 60 IU, cis-linoleic acid 864 mg, AA 42 mg, and thyme oil 8 mg). The influence of these fatty acids on signal transduction relevant to neuronal structure, development, and functions may play a role in EFA-induced improvement of ADHD symptoms [The effects of essential fatty acids  in treating ADHD in children have been recently investigated. Supplementation with these fatty acids has shown modest success in controlling ADHD symptoms , 83. A ssymptoms . Anothersymptoms . Furthersymptoms  reportedsymptoms  also repsymptoms . The exasymptoms –40, 82. symptoms , 40, 82.In contrast, other studies including randomized clinical trials reported no significant effects/benefits in ADHD patients treated with EFAs compared with the placebo group –43. A meGiven the multifactorial characteristic of ADHD, the management of this disorder may benefit from a multimodal approach. Presently, ADHD management trends are favoring treatment of ADHD with a combination of various treatment approaches , 89. MulMost multimodal treatment approaches employ the use of stimulant medications, given their wide use in managing ADHD, and behavioral/psychosocial therapy. A multisite clinical trial, the Multimodal Treatment of ADHD (MTA) study, revealed that combination  and medicinal management (methylphenidate) interventions were significantly superior to behavioral or community care alone for managing ADHD symptoms . MoreoveIn contrast, only a few studies have evaluated combination therapy utilizing nutritional/botanical supplements with behavioral therapy or pharmacological ADHD agents . What isTwo Chinese medicine herbal treatments have been previously evaluated as adjunct treatments to methylphenidate. A 2-week trial in children randomized to receive Yizhi mixture (a combination of 10 herbs designed to affect Yin/Yang liver functions), methylphenidate, or combination treatment reported more significant improvement of ADHD symptoms in children subjected to combination treatment than in those randomized to either individual treatment. There were also fewer side effects in children given Yizhi mixture alone or combination treatment than in those assigned to the methylphenidate group . In anotIn another study, Akhondzadeh et al.  performe Panax quinquefolium (200 mg), and Ginkgo biloba extracts (50 mg) to alleviate ADHD symptoms was evaluated in 36 children aged 3–17 years [The efficacy of combining American ginseng extract,17 years . Results17 years . NeverthThere are a number of available treatment options for ADHD; however, some of them may pose risks to patients . The botAlthough the use of natural medications for ADHD has been considered as a “safer” approach, natural products are still far from being called as standard ADHD treatments due to the lack of comprehensive and appropriately controlled clinical studies that interrogate both their efficacy and safety. Moreover, it is challenging to compare efficacy profiles of herb therapy with conventional pharmacological ADHD treatments, mainly because herbal preparations are not standardized, and question regarding their purity, reliability, safety, and toxicity profiles will always arise . TherefoThe findings from recent, albeit few, studies which evaluated efficacy of adjunct therapy of botanical agents and nutritional supplements with a pharmacological ADHD treatment or another botanical agent suggest that combination therapy may be a promising approach in ADHD treatment. Nevertheless, positive findings from above-mentioned studies need to be replicated, and evidence for long-term effectiveness and safety should be aptly demonstrated. Efficacy of combining other botanical agents with pharmacological agents including other medications aside from methylphenidate  or with behavioral therapy should also be explored in future studies. As herbs usually contain more than one psychoactive substance and may have additive or interactive effects with the combined treatment, the risk-benefit balance of natural product-derived ADHD treatments should be carefully considered when combined with other medications.


The positive average performance observed in the three groups in most tasks perhaps indicates the possibility that music can, in some way, positively modulate the symptoms of inattention in ADHD.ADHD involves cognitive and behavioral aspects with impairments in many environments of children and their families’ lives. Music, with its playful, spontaneous, affective, motivational, temporal, and rhythmic dimensions can be of great help for studying the aspects of time processing in ADHD. In this article, we studied time processing with simple sounds and music in children with ADHD with the hypothesis that children with ADHD have a different performance when compared with children with normal development in tasks of time estimation and production. The main objective was to develop sound and musical tasks to evaluate and correlate the performance of children with ADHD, with and without methylphenidate, compared to a control group with typical development. The study involved 36 participants of age 6–14 years, recruited at NANI-UNIFESP/SP, subdivided into three groups with 12 children in each. Data was collected through a musical keyboard using Logic Audio Software 9.0 on the computer that recorded the participant’s performance in the tasks. Tasks were divided into sections: spontaneous time production, time estimation with simple sounds, and time estimation with music. Results: (1) performance of ADHD groups in temporal estimation of simple sounds in short time intervals (30 ms) were statistically lower than that of control group ( ADHD involves cognitive and behavioral aspects that impact many environments of children and their families’ lives. Mainly, in social interaction and academic performance, there are frequent associations with psychiatric comorbidities . DifficuTime processing disorders are present in many neurodevelopmental disorders like ADHD, but also in degenerative neurological diseases, such as Parkinson’s and Alzheimer’s disease, manifesting symptoms of dysfunctional processing of time estimation, production, and reproduction tasks , 47. Chit-score < 60) and good school performance. All children in the study were previously submitted to interdisciplinary evaluation that included medical and musical history, neurological, psychiatric, pedagogical, and neuropsychological assessment. Control group consisted of 12 children with typical development without symptoms of inattention or hyperactivity , IQ > 85 (WISC – III estimated), normal hearing and no health impairments. The control group was recruited with a letter to the school requesting permission from the board direction and the teachers. All participants and parents signed a consent form. The study excluded individuals with autism spectrum disorder, psychiatric comorbidities, and formal music study in order to avoid possible strategies of implementation and performance on tasks. Data was recorded through evaluation sheets, and the performance of participants was recorded in the computer through the keyboard connected to a digital interface for musical instruments (Avid MC-400). Data analysis was performed using SPSS 20.0  (p < 0.05). The study was held in an appropriate room with all the necessary instruments and a comfortable and quiet environment to allow for the most accurate results. Figure The total sample consisted of 36 participants recruited by Núcleo de Atendimento Neuropsicológico Infantil Interdisciplinar (NANI) at UNIFESP, São Paulo, Brazil of ages 6–14, divided into three groups with 12 participants in each. The clinical sample consisted of 24 children with ADHD, subdivided into two subgroups: Group 1 – no medication (ADHD/NM) at least 7 days prior to the test; Group 2 – medication (ADHD/M) for at least 30 days prior to the performance of the test. Inclusion criteria considered for the study group: presence of at least six symptoms of inattention and/or hyperactivity/impulsivity in the DSM IV  , estimatciences)  with nonThe Ethics Committee of the Federal University of São Paulo, who had prior knowledge about the topic and research steps for participants and their families, approved this research. The protocol contained temporal estimation and temporal production tasks with many levels that assessed aspects of time perception and time expression through sensory estimations and motor time production activities. The tasks were conducted on the computer with the participant using the musical keyboard to perform the task. The tasks were performed with headphones to mitigate the influence of external stimuli. The headphones also ensured auditory perception of better sound quality, speed, and efficiency in the transmission of sound codes. The hearing level of the tasks was set to 60 dB. Sound stimuli and music were recorded in the laboratory with LogicAudio-9 software for music composition, editing, and audio recording; Yamaha electric piano; AKG microphone AK-400; AK-K141 headphones; an iMAC computer; and an audio and MIDI interface – Avid-MC400 . Compared to the other two groups, this difference was not statistically significant. However, participants in Group ADHD without medication conducted the beats in <10 s (Fast), while Group ADHD under medication played 21 beats in >10 s (Slow). In the control group, the performance was more balanced as shown in Table p < 0.05), where the difference in the duration of the two stimuli was only 3% (30 ms).A statistically significant difference was observed when the three groups performed the stimulus 18, after a minute (p < 0.05), where all participants in the control group chose music “a”, as longer, and ADHD groups chose music “b” as longer. It was observed that the choice of the participants regarding the longer music was well balanced, when the density of musical notes in the music was higher, as shown in Figure There was a statistically significant difference between the control group and ADHD groups in Track 7 (According to Mithen , the spoThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


N = 347, mean age 11.4 years) in late adolescence and early adulthood. At study entry and follow-up (mean age 17.4 years), participants were comprehensively assessed on ADHD and comorbid disorders by structured psychiatric interviews and multi-informant questionnaires. Overall functioning was assessed by the Children’s Global Assessment Scale. The retention rate was 75.6 %. The majority of participants (86.5 %) persisted in a DSM-5 ADHD diagnosis, 8.4 % had a subthreshold diagnosis, and 5.1 % remitted from the disorder at follow-up. Comorbidities decreased strongly; oppositional defiant disorder: 58 > 31 %, conduct disorder: 19 > 7 %. At follow-up, mood- and anxiety disorders were virtually non-existent following strict criteria (1–3 %). Percentage of children having had pharmacological treatment at any time increased from 79 to 91 %. On the Children’s Global Assessment Scale, 48.5 % of participants were still functionally impaired at follow-up. Parental ADHD, higher ADHD symptom severity at baseline and higher parent-reported impairment at baseline positively predicted current ADHD symptom severity (R2 = 20.9 %). Younger baseline age, higher ADHD symptom severity at baseline and higher parent-reported impairment at baseline were positively associated with poorer overall functioning (R2 = 17.8 %). Pharmacological treatment had no  impact on either ADHD symptom severity or overall functioning. Results confirm that ADHD is largely persistent into late adolescence with severity and family history for the disorder as important risk factors.There are very few studies on the long-term outcome of children and adolescents with ADHD-combined type in Europe. The objective of the present study is to assess the 6-year outcome  of a large cohort of participants with ADHD-combined type (The online version of this article (doi:10.1007/s00787-016-0820-y) contains supplementary material, which is available to authorized users. Attention-deficit/hyperactivity disorder (ADHD) is characterized by symptoms of inattention and/or hyperactivity/impulsivity that lead to functional impairments in multiple domains . Twenty As symptoms of ADHD may persist in adulthood and are related to worse outcomes in adult life, it is of great clinical relevance to investigate predictors of the course of ADHD. Retrospective studies in large representative population samples report that more family adversities , greatern = 9) [It is important to note that above-mentioned studies were limited in several ways. Most studies investigated the prediction of ADHD persistence using dichotomous outcomes (diagnosis yes/no) –9, as opn = 9) . FinallyAn important aspect in studies looking at predictors for ADHD outcome is age. As significant developmental processes  of an individual are ongoing from childhood through adolescence into adulthood, with a marked transition period in adolescence , predictThe main aim of the present 6-year follow-up of a large cohort of participants with ADHD-combined type was (1) to investigate outcome, i.e. ADHD persistence rates, comorbidity rates, symptom severity and overall functioning, considering age effects, (2) to investigate baseline predictors of both ADHD symptom severity and overall functioning including demographics, ADHD familiality, ADHD severity, comorbidities and pharmacological treatment, considering age effects, and (3) to investigate the impact of continued pharmacological treatment until follow-up within the prediction models of ADHD symptom severity and overall functioning.N = 459) was contacted and invited for follow-up on average 6.0 years (SD = 0.7) after enrolment; 75.6 % (N = 347) was retained successfully.A sample of 347 participants with ADHD-combined type (ADHD/C) aged 5–19 years participated in this study. This sample was based on the Dutch part of the International Multicenter ADHD Genetics (IMAGE) study. Between 2003 and 2006, the IMAGE study recruited families with at least one child with clinically diagnosed ADHD/C and at least one additional sibling regardless of possible ADHD status. Clinical diagnosis of each participant was assessed by health-care professionals from clinical child care centers in The Netherlands. In addition, the diagnosis was confirmed, using an extensive assessment protocol described below. The original sample , Hyperactivity/impulsivity (M), and Total symptoms (N), and scores ≥90th percentile on the SDQ Hyperactivity subscale were considered clinical. Participants scoring clinically on any of these subscales were administered the Parental Account of Children’s Symptoms (PACS), a semi-structured, standardized, investigator-based interview with the parents as informants [Selection procedures have been detailed previously . Brieflyformants . See [21At follow-up, participants were screened for ADHD using the Schedule for Affective Disorders and Schizophrenia for school-age children—present and lifetime version (K-SADS), a semi-structured, standardized, investigator-based interview with the parents as informants, and when children were 12 years or older, also with the child (separately) . ParticiFor both the K-SADS and the PACS, interviewers underwent comprehensive training by a team under the supervision of E. Taylor at the London Institute of Psychiatry  or JB at the Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen (K-SADS). If additional interviewers were used, each center was responsible for their training and supervision. Inter-rater agreement for the PACS was 0.88 (range 0.71–1.00) and for the K-SADS 0.94 (ADHD), 0.89 (ODD), and 0.95 (CD) , 25. TheL (Inattention), M (Hyperactivity/impulsivity), and N  [N, L and M, respectively. Scores on the Conners’ ADHD subscales represent combined measures of the number and severity of symptoms.To assess dimensional persistence, symptom change scores were calculated by subtracting follow-up raw scores from baseline raw scores on the CPRS-R:L ADHD scales ymptoms) . CurrentTo measure current overall functioning, the Global Assessment Scale-score of the K-SADS (K-GAS) was administered at follow-up. After finishing the K-SADS interview, the interviewer rated psychological, social and academic functioning, resulting in an overall measure of the current level of functioning ranging between 1 (worst possible level of functioning) and 9 (best possible level of functioning) .Demographic variables: age, sex, and socio-economic status (SES) were measured. SES was calculated from the average educational levels of the parent(s), with educational levels ranging between 0 (no education) and 11 (university), according to an adapted Hollingshead scale [ADHD familiality: ADHD familiality was investigated by measuring the percentage of siblings with ADHD according to the PACS interview [ADHD characteristics: ADHD characteristics included ADHD symptom severity, impairment and age of ADHD onset. Symptom severity was measured by the raw score on scale N (range 0–54) of the CPRS-R:L [r = 0.18 and were not combined). Age of onset of ADHD was assessed using the PACS interview [Comorbidities: Comorbid DSM-IV defined ODD (yes/no), CD (yes/no) and a screening of the presence of mood/anxiety symptoms (yes/no) were assessed with the PACS [Pharmacological treatment: cumulative intake of psychostimulants from age of onset until our baseline measurement and from age of onset until follow-up were calculated. Lifetime medication transcripts from pharmacies were available for 87 % and covered the lifespan for 31 % of participants. In addition, a questionnaire was administered to all participants and parents, which assessed lifetime history of psychostimulant medication. When pharmacy transcripts did not fully cover the self-reported treatment period, medication parameters of the missing period(s) were calculated from the questionnaire data and were added to the measures derived from the pharmacy. To optimally take into account daily dose and duration of pharmacological treatment, cumulative intake was calculated by multiplying the mean daily dose  were investigated. ad scale  fitting nterview , and by CPRS-R:L . ImpairmCPRS-R:L  and teacnterview . Comorbithe PACS . Pharmacidelines  and giveidelines ).Two potential covariates were investigated. If the univariate relationship between follow-up interval and outcome measures was significant, follow-up interval was entered as a covariate in all subsequent analyses. In addition, study site was entered as a covariate in the final prediction models.At baseline, families were recruited from clinics and via advertisements. Testing took place at the VU University Amsterdam or at the Donders Institute in Nijmegen. Participants were 48 h off medication during both baseline and follow-up assessments. All ratings of behavioral functioning pertained the participant’s functioning off medication. Families were financially compensated for participating in the study. Informed consent was signed by all participants at both measurements, and parents signed for all children in their family as well. The study was approved by the national ethics committee.L: 9 participants, scale M: 18 participants). K-GAS-scores were normalised by applying a Van der Waerden transformation.The percentage of missing data was <5 % for ADHD diagnoses, current ADHD symptom severity and overall functioning measures, 19 % for parental ADHD status, and between 0 and 9 % for the other predictors. Missing value analysis (expectation maximization) was performed for participants with one or two missing items on CPRS-R:L subscales, using all data reported in this study , with current ADHD symptom severity or overall functioning as outcome measure respectively. The mean correlation between all predictors was 0.09 (0.001 < r < 0.45), indicating no collinearity. For all predictors, we tested linear effects with outcome measures, except for age. Literature indicated a possible non-linear (quadratic) relationship for the relation between age and our outcome measures [p value <0.15 in step 1 were entered into the final GEE model. Finally, in step 3, a backward selection (variables deleted when p >0.05) procedure was performed for model optimization. Additionally, to investigate possible moderating effects of age on the models for ADHD symptom severity and overall functioning, interactions between both age (assessed at baseline) and age2 and significant predictors of outcome were added to the final model. When an interaction-effect with age or age2 was significant, the finding was further explored by testing the final model in subsamples subdivided based on age at baseline (<12 years and ≥12 years). Final models were further tested separately for symptom severity of inattention and separately for hyperactivity/impulsivity as outcome measures, to explore whether the model was applicable to both symptom dimensions. Further, as the reliability and validity of the CPRS-R:L is only established for children under 18 years of age, we tested whether results of the final model for current ADHD symptom severity replicated in a subsample of children younger than 18 years. Second, the effect of missing data on the final models for both outcome measures was investigated, testing the final model using only participants with complete data. For our third research question, the first three steps of our GEE model were repeated, except that pharmacological treatment until baseline was replaced by pharmacological treatment until follow-up.For our first research question, ADHD persistence rates, percentage of comorbidities, mean symptom change and overall functioning scores were calculated. It was tested whether symptom severity decreased significantly over time and whether changes in hyperactivity/impulsivity symptom severity over time differed from changes in inattention symptom severity. To optimally correct for the familial dependency in our data, Generalized Estimating Equation analyses (GEE) were used, with an exchangeable correlation structure. Additionally, interaction-effects of symptom change between baseline and follow-up with age/agemeasures . In stepp < 0.95).Attrition was investigated by comparing participants successfully followed up (75.6 %) with participants lost to follow-up on variables reported in this study available at baseline. No significant group differences were found . Regarding comorbidities at baseline, ODD was apparent in 58.0 % of the participants, CD in 18.9 % of the participants. At follow-up, ODD was apparent in 30.8 % of the participants, CD in 6.6 %, tic disorders (any type) in 2.1 %, mood disorders (depression or dysthymia) in 1.8 %, and anxiety disorders in 2.5 % of the participants. Regarding pharmacological treatment, at baseline, 78.8 % of the participants have had pharmacological treatment for their ADHD symptoms at any time, compared to 90.9 % of the participants at follow-up. At follow-up, 87.1 % of participants used methylphenidate (immediate release) at any time, 65.4 % used methylphenidate (extended release), and 6.5 % of participants used dexamphetamine.Table N decreased from 35.51 to 23.27 . Inattentive raw symptom severity on the CPRS-R:L scale L decreased from 18.59 to 13.85 , and hyperactive/impulsive raw symptom severity on the CPRS-R:L scale M decreased from 16.92 to 9.42 . The decrease in hyperactivity/impulsivity was larger than the decrease in inattention (p < 0.001). Interaction effects of symptom change between baseline and follow-up with age/age2 were significant for inattention , showing that inattentive symptoms decreased more in older than younger children, then leveling off around the age of 16–18 (age at follow-up).Total raw ADHD symptom severity on the CPRS-R:L scale b = 0.09, p < 0.001).Of 332 participants with current K-GAS-scores available, 161 participants (48.5 %) were functionally impaired at follow-up (K-GAS-score ≤6). Eight participants (2.4 %) had optimal functioning scores (K-GAS-score = 9). Of 288 participants with persistent ADHD and current K-GAS scores available, 153 participants (53.1 %) were functionally impaired at follow-up. Two participants (0.7 %) with persistent ADHD had optimal functioning scores. Older age was associated with better overall functioning, as reflected in a higher current K-GAS-score . For current overall functioning, there was a significant interaction between age and parent-reported impairment (p = 0.029). Further exploration showed that parent-reported impairment was a significant predictor of current overall functioning only in the subsample of younger participants (p < 0.001) and not in the subsample of older participants (p = 0.64). The prediction model for current ADHD symptom severity  remained significant (0.000 < p < 0.027) when tested for ADHD inattention symptom severity (R2 = 14.7 %) and ADHD hyperactivity/impulsivity symptom severity (R2 = 20.2 %).For current ADHD symptom severity none of the predictors interacted significantly with age or agep < 0.010, R2 = 16.9 %), demonstrating that the findings were not the result of applying the CPRS-R:L in children of 18–24 years old. Findings for current ADHD symptom severity replicated when cases without complete data were removed from the analyses . Predictors in the final model for current overall functioning remained significant (baseline symptom severity) or marginally significant .All predictors in the final model for current ADHD symptom severity remained significant with similar relationships when tested in a subsample with children younger than 18 years . The total model explained 22.5 % of variance. For overall functioning, continued pharmacological treatment until follow-up did not contribute to the model.To investigate whether continued pharmacological treatment is related to better outcomes (hypothesis 3), pharmacological treatment until follow-up was added to the model predicting current ADHD symptom severity and overall functioning. In the first model, one additional predictor was now significant; more continued pharmacological treatment also predicted higher symptom severity , but not to ADHD symptom severity , and therefore was added to the model of overall functioning as a covariate for all subsequent analyses. Further, study site was a non-significant predictor in both the final model of ADHD symptom severity  and of overall functioning . Adding this covariate to these final models did neither change direction of effects of predictors, nor their significance (p < 0.05).Follow-up interval was significantly related to the K-GAS-score , independent of age. The greater part of ADHD persisters still met combined type criteria (51.4 %). About half (48.5 %) of participants were still functionally impaired at follow-up . At follAs noted above, ADHD symptom severity decreased significantly, but symptom decrease was only slight, and many adolescents and young adults still fulfilled criteria for a DSM-classification. Although this prospect was expected for the younger part of our sample, a striking finding is that persistence rates were similarly high in the older part of the sample (age up to 25). An important explanation may be our stringent inclusion criteria applied at baseline: ADHD-combined criteria had to be met by all participants, a subtype that was found highly predictive of a persistent course . AdolescOur study clearly confirms that ADHD/C is a strongly pervasive disorder at least until adolescence/young adulthood. The relative stability of ADHD symptoms is especially important given that the adolescent brain develops strongly during the transition from puberty into adulthood, marked by increased reward seeking activities leading to problematic decision-making processes . In combCurrent symptoms and overall functioning were predicted by a few variables only, which together explained up to 20 % of variance. Not surprisingly, having many symptoms and being highly impaired at baseline predict worse future outcomes, which was also reported by other , 35, butInterestingly, our prediction models for ADHD outcomes were largely independent of the developmental phase of participants, confirming the stability of our predictors in a sample of children with ADHD/C with a large age range. Only for current overall functioning parent-reported impairment was a significant predictor in younger children, which may be explained by the smaller involvement of parents when children grow older, with a decrease in correct judgement of impairment levels of their child accordingly.Cumulative intake of psychostimulant medication neither at baseline nor at follow-up had a beneficial impact on ADHD outcomes or overall functioning in our sample. Moreover, higher cumulative intake at follow-up predicted worse outcomes in terms of ADHD severity. Although ADHD symptoms have been shown to decrease with stimulant treatment, our findings do not support long-term positive effects on outcome. Three other studies also found that ADHD treatment (any type) positively predicted ADHD persistence , 36, or Although we were able to explain a moderate amount of variance in current symptom severity and overall functioning, many of the baseline predictor variables were unrelated to outcomes including sex, SES, age of onset, and comorbidities. As we investigated sets of predictors together, it may be that comorbidities were not included in the model as they may overlap with ADHD symptom severity measures. Indeed, ODD was related to ADHD symptom severity in the separate class analyses but did not retain in the model with other predictor variables. Two other studies showed a somewhat larger role for the predictive value of CD , 40. TheAlthough we studied a relatively large sample of participants with ADHD/C compared to other studies, the sample may have been relatively small for our analyses including interaction-effects with age. Second, including participants with other types of ADHD (such as ADHD/I) would have allowed us to investigate whether these subtypes showed higher remittance rates than ADHD/C. Further, participants were all of Caucasian origin, limiting generalisation to a broader ethnic population. Fourth, interviewers were not systematically blinded for diagnostic status when administering diagnostic interviews. However, since both families and interviewers had no specific interest in the outcome measures in our study, we don’t consider this a major bias in the results. Fifth, different diagnostic interviews were used at baseline (PACS) and at follow-up (K-SADS). As both interviews systematically investigated similar DSM criteria for ADHD, we do not expect this difference to have a major impact on our results. Finally, our study was restricted to children with a clinical diagnosis, whereas some previous studies recruited participants with ADHD symptoms from the general population , 41 who As the majority of variance in ADHD outcomes remain unexplained, far more studies are warranted for a more accurate prediction of future ADHD outcomes. For example, studies should include other variables that relate to family-environmental factors, such as upbringing style or attachment style. Perhaps multiple domains can be integrated in one model, by also including genetic variations, structural and functional brain measures, and neurocognitive factors –45.Our study demonstrates that combined type ADHD strongly persists into late adolescence and young adulthood, posing a challenge for adolescence and adult mental health care as problems do not disappear. Risk factors for worse outcomes in adolescence or young adulthood include high ADHD symptom severity and impairment, younger age, parental ADHD, and more continued pharmacological treatment. The developmental phase of participants was of little importance for our predictors for ADHD outcome, showing the importance of these predictors for the entire ADHD sample. In an era in which pharmacological treatment is the preferred type of intervention, our finding that pharmacological treatment had no positive predictive value for ADHD-related outcomes is clinically important and substantiates further study into this topic. Finally, it is of great relevance for future work to discover the factors that cover the 80 % unexplained variance of our models that predict future outcome, to give direction to develop newer and potentially more effective interventions.Supplementary material 1 (DOCX 25 kb)Below is the link to the electronic supplementary material.


To assess progress in the provision of drinking water and sanitation in relation to national socioeconomic indicators.n = 67) and/or sanitation (n = 61). To enable comparison of progress between countries with different initial levels of access, the calculated rates of change were normalized to fall between –1 and 1. In regression analyses, we investigated associations between the normalized rates of change in population access and national socioeconomic indicators: gross national income per capita, government effectiveness, official development assistance, freshwater resources, education, poverty, Gini coefficient, child mortality and the human development index.We used household survey data for 73 countries – collected between 2000 and 2012 – to calculate linear rates of change in population access to improved drinking water (The normalized rates of change indicated that most of the investigated countries were making progress towards achieving universal access to improved drinking water and sanitation. However, only about a third showed a level of progress that was at least half the maximum achievable level. The normalized rates of change did not appear to be correlated with any of the national indicators that we investigated.In many countries, the progress being made towards universal access to improved drinking water and sanitation is falling well short of the maximum achievable level. Progress does not appear to be correlated with a country’s social and economic characteristics. The between-country variations observed in such progress may be linked to variations in government policies and in the institutional commitment and capacity needed to execute such policies effectively. We used a new indicator of progress – the normalized rate of change in access – to allow countries to be compared, regardless of their initial coverage levels.We obtained estimates of the percentage of national populations with access to improved sanitation and water – for various years between 2000 and 2012 – from the 2013 Country Files of the Joint Monitoring Programme for Water Supply and SanitationWe included shared toilet facilities in our improved-sanitation category because data for both shared sanitation and total improved sanitation including shared sanitation – i.e. the two data sets needed to investigate total improved sanitation excluding shared sanitation – were only available for four of our study countries. The Joint Monitoring Programme currently discounts shared sanitation from total improved sanitation by applying a fixed ratio for each country.i as its normalized rate of change in access:i,jnormalized rate is the normalized rate of change for country i that had a baseline coverage level j in the year 2000; i,jrate is the absolute rate of change for country i at coverage level j; jmax. rate is the maximum rate achievable by any country at coverage level j  and the jmin. rate is set at zero (no progress). Each country’s absolute rate of change was calculated from the earliest available year (2000 in most cases) using linear regression.To compare countries with differing initial levels of population access to improved sanitation and water, we defined the progress of country ,We determined values for the maximum rate achievable at each coverage level using the frontier approach.A polynomial curve was fitted through the frontier points to obtain the frontier curve – with the requirement that the curve must pass through the point corresponding to 100% coverage and 0% increase in coverage per year. The frontier curve allowed the maximum achievable rates of improvement in water and sanitation coverage to be estimated for all countries, depending on their initial level of coverage . Using tWe used regression analyses to investigate the relationship between progress in water and sanitation and the following national socioeconomic indicators: (i) gross national income per capita – in current United States dollar (US$) values that had been derived using the Atlas method;We initially considered data from the World Health Organization’s Global Analysis and Assessment of Sanitation and Drinking Water reports, which provide policy and economic indicators such as the per-capita budget for drinking water and sanitation from the year 2010P-values of 0.05 and 0.10 for the addition and deletion of variables, respectively – was also used to identify a subset of the three synthetic independent variables for the regression analyses.Several of the nine national characteristics we investigated were highly correlated. We therefore used principal components analysis on the nine national indicators to obtain uncorrelated synthetic independent variables . However1β to iβ are the fitted model coefficient values and 1x to ix are the independent variables. Countries with negative normalized rates were excluded from the fractional logistic regressions because, for these, the output parameter must lie between 0 and 1. These regressions therefore focused only on countries that had made progress in increasing access to improved sanitation and water. We re-ran the models using the synthetic independent variables.Univariate and multivariate regression analyses were performed in Stata version 12 . We ran models using the data from all of our study countries and, separately, using only the data from those study countries that had no armed conflict between 2000 and 2012.We selected countries where, despite similar initial coverage, we observed marked differences in progress. To understand possible reasons for these differences in progress, we chose discordant pairs of countries within the same geographic region and with similar characteristics – as defined by the country clusters of Onda et al.National access to improved sanitation and water in the year 2000 and historical absolute rates of change are shown in ,The frontier curves used to calculate the maximum rates of change in While positive and negative absolute rates indicate countries with increasing and decreasing coverage, respectively, only the normalized rates in P ≤ 0.05; 2R < 0.2) and Using the normalized rate as our indicator of progress, only two univariate regression models for access to drinking water – and no models for sanitation – were statistically significant overall .http://www.who.int/bulletin/volumes/94/2/15-162974).An analysis of the illustrative pairs of countries with differing progress indicate that no single indicator was consistently associated with progress in coverage for water or sanitation  was markedly lower than that for South Africa (0.49) – indicating that South Africa was making greater progress than Kenya.–National socioeconomic characteristics may not be primary determinants of progress in access to water and sanitation. For example, from the illustrative country pairings, Peru might be expected to make better progress than Paraguay – since, per capita, Peru has the greater gross national income, external financial assistance and renewable freshwater resources. However, the normalized rates that we calculated indicate that, over our study period, Paraguay was making good progress whereas Peru was making no progress. Factors other than the nine national indicators we investigated are probably more important than those indicators in determining progress towards universal access. For example, government policies – and variation in the provision of the institutional commitment and capacity needed to execute such policies effectively – may be important determinants of such progress. The lack of association we observed between progress and per-capita level of official development assistance is consistent with previous studiesOur study has several limitations. We calculated absolute rates of change in coverage of water and sanitation using a linear fit to the data points – even though progress may have been nonlinear during our study period. This may affect the estimated rates of change, the identification of frontier countries and consequently, the frontier curve, the corresponding maximum rates and the normalized rates. Household surveys used as our data sources did not include extra-household settings – e.g. educational institutions, workplaces and health-care settings – and therefore did not represent sanitation and water access for all dimensions of society. Neither did the surveys distinguish between the different levels of improved sanitation or water services – e.g. between a household tap and a community hand pump or between a pit latrine and a sewer connection. Furthermore, inequalities in access often exist. Coverage and service levels tend to be relatively poor among marginalized and vulnerable groups and this may not be captured by national surveys. Identification of the disadvantaged groups in each country is needed so that progress among these groups can be compared with that in the general population.With respect to our regression analyses, we recognize that the variables we used as national economic indicators may not accurately reflect the levels of investment in sanitation and water. For example, such indicators exclude the many household investments, particularly in sanitation, that occur in developing countries. In addition, the data for the nine national indicators that we investigated were for a single year and did not cover all of our 2000–2012 study period. Alternatives to linear and logistic regression, such as generalized additive models, need to be tested in future studies.Use of normalized rates allowed countries to be compared regardless of their coverage level, aligns with the human rights principle of progressive realization and could be extended to measure progress in other health sectors – e.g. to measure rates of improvement in the maternal mortality ratio. Use of such quantitative measures of progress allow policy-makers to make evidence-based decisions and provide the human rights community and others with an objective method for country comparison. Our results indicate that, in many countries, the progress being made towards universal access to improved drinking water and sanitation is far from the maximum achievable. The lack of relationship between the normalized rates of change and the nine national indicators that we investigated is important – particularly with respect to the economic variables. The finding that official development assistance is not correlated to our indicator of progress suggests that investment alone is not sufficient to ensure progress. In future studies, the effect on progress of additional variables that assess the enabling environment and governance should be investigated.


The current study was designed to test if an objective measure of both attention and movement would differentiate children with Oral Language Disorders (OLD) from those with comorbid Attention Deficit/Hyperactivity Disorder (ADHD) and if stimulant medication improved performance when both disorders were present.The sample consisted of thirty-three children with an identified oral language disorder (of which 22 had comorbid ADHD) ages 6 to 13 who were enrolled in a yearlong intensive learning intervention program. Those on a stimulant medication were tested at baseline and again a year later on and off medication.Objective measures that included an infrared motion analysis system which tracked and recorded subtle movements discriminated children with OLD from those with a comorbid ADHD disorder whereas classic attention measures did not. There were better attention scores and fewer movements in children while on-medication.Use of an objective measurement that includes movement detection improves objective diagnostic differential for OLD and ADHD and provides quantifiable changes in performance related to medication for both OLD and ADHD. A language impairment (LI) or language disorder is a deficit or delay in receptive language (the understanding of spoken language by others) and/or expressive language . An assortment of terms have been used to refer to this LI condition, including specific language impairment (SLI), developmental language disorder, expressive language disorder, developmental dysphasia or aphasia , and varDue to inattention and impulsivity in children with OLD, they are frequently mistaken for symptoms of ADHD. Studies have found that children with deficits in pragmatic language displayed excessive talking, provided insufficient information upon responding, had poor turn-taking skills, and demonstrated difficulty maintaining topics and staying on task ,12. FurtDue to overlapping symptoms and similar behavior disturbance, differential diagnostic accuracy can be challenging. It is important to establish an accurate diagnostic differential to guide appropriate treatment intervention . There is a need for an objective measure to improve differential diagnostic acumen for co-occurring OLD and ADHD as a precursor to medication intervention. Medication is one of the most common approaches to treat ADHD symptoms in children and has been successfully associated with improvements in functioning . A myriaFortunately, an objective measure of attention such as the Continuous Performance Test (CPT) has proven an effective, popular, and efficient means of objectively assessing attention , especiaThe Quotient® ADHD System is a classic objective measure of various CPT go, no-go, attention variables , but unlike other CPTs, it is the only one combined with infrared motion detectors   . PreviouThe study reported here tested both attention and movement measurements in children with an OLD and those with both disorders (OLD/ADHD). Additionally, since research supports that stimulant medication improves attention and body control, we assessed the effects of being on- versus off- medication differences for OLD/ADHD at baseline and following focused training for language impairment again a year later where individuals had been on stimulant medication at both time points. An initial dissertation study at baseline had hypothesized that both attention and movement scores would differentiate OLD from OLD/ADHD but only movement was found to discriminate the two (30). Based on that finding, for the longitudinal follow-up study a year later, it was hypothesized that only movement measures would differentiate those with OLD from a group with a comorbid OLD/ADHD diagnosis (31). It was further hypothesized that the effects of stimulant medication treatment would improve attention scores for those with ADHD, while decreasing movement, and that these effects could be seen at baseline and replicated a year later.Thirty-three participants were between the ages of 6 and 13 years  from an original sample of 67. The participants in the study attended a specially designed early language intervention program at the Shelton School , a largeTo determine if the child had ADHD, the parent and the child separately were administered the Kiddie Schedule for Affective Disorders and Schizophrenia in School Age Children, Present and Lifetime (K-SADS-P/L)  which usThe Quotient® is a computerized continuous performance test assessing a participant’s ability to pay attention and ability to sit still . It provThis study was reviewed and approved by the Shelton School Internal Review Board (IRB) and the University of Texas Southwestern Medical Center IRB. Both the child and parent gave informed verbal and written assent and consent to participate in the study.Baseline data Time 1 (T1) data were collected during the Spring  and TimeDemographic characteristics for the overall sample are described using the sample mean and standard deviation for continuous variables and the frequency and percentage for categorical variables. To test the Quotient® ADHD attention and movement variables, the basic design was a two-group (OLD vs. OLD/ADHD), by Time (T1 and T2) repeated measures Analysis of Variance (ANOVA) design using SPSS Version 19. A secondary analysis of medication (ON or OFF) by Time analysis was conducted for an OLD/ADHD subgroup of 16 participants taking stimulant medication at both time points .M =9.4 years, SD = 2.1) who completed all testing. All had an OLD diagnosis and 22 (62.9%) also met criteria for a diagnosis of ADHD. A separate secondary analysis was performed on all participants who were also taking a stimulant medication at both time points on and off of medication , verbal cognitive ability (Slosson Intelligence Test-Revised), and nonverbal cognitive ability . Teacher reports on the Behavioral Assessment System for Children (BASC) were examined to determine if groups differed with respect to internalizing symptoms , externalizing symptoms , overall behavioral symptoms  and adaptive behavior (Adaptability Composite). No differences were found and hence, none of these measures were used as covariates for the analyses that follow.To assess if the OLD and OLD/ADHD groups were equivalent in overall functioning and severity with regard to language and cognitive functioning, independent-samples F = 8.54, p < .007, η2 = 0.23, a large effect size. Effect size is a partial eta-squared (η2) where values of .01, .06, and .14 represent small, medium, and large effects sizes , response consistency was significantly greater when children were tested on medication compared to their performance off medication F = 32.28, p < .00, η2 = .68. These attention scores clearly indicate that stimulant medication improves attention performance during a fifteen minute continuance performance task with significantly better accuracy, fewer omission errors, faster response time, and less variability.The means and standard deviations for the various Quotient® ADHD System attention variables are reported in Table F = 4.66, p < .05, η2 = .24, spent a lower percentage of time in a “distracted” attention state, and less time in the “minimal responding” attention state profile  F = 4.92, p < .04, η2 = .25.Additional measures calculated by the Quotient® ADHD System are known as attention state variables. For example, attention shifts and the number of shifts in attention state are defined as On Task (percent of time hit many targets and few non-targets), Distracted , Impulsive (percent of time hits many targets and some non-targets), Random Responding , Minimal Responding , and Contrary (response accuracy is significantly worse than chance). The analyses of these variables indicate that the children spent more time responding “on task” when they were tested on medication This study found that children with oral language disorder (OLD) and comorbid ADHD performed significantly different from those with an OLD-only diagnosis based on subtle, measureable movement scores but not classic CPT attention variables. Importantly, movement measures such as position changes, larger displacement of head movements , larger area of movement, and more temporal scaling  as measured by the Quotient® ADHD System do significantly differentiate the two groups with good statistical group classification and sensitivity and specificity. This suggests that relying on CPT-like measures alone (without movement measurements) would probably not meaningfully differentiate the two groups. Unlike other CPTs that do not measure movement, these additional movement variables are valuable additions to tests to distinguish the overlap of core ADHD symptoms in children with OLD and would assist diagnostic classification. These findings lend support to Ohashi et al.’s  contentiCPTs have proven to be a reliable and valid clinical tool to include as part of a clinical assessment battery for ADHD but not for differentiating ADHD from OLD and learning disabilities in general, as both disorders have similar difficulty with various attention variables ,20,21,36While research suggests that stimulant medication improves attention and body control, the role of medication on attention and movement in children with OLD and ADHD has not been explored in terms of 1) does medication improve attention and/or movement, and 2) does medication improve attention and/or movement over time. By testing a subsample of the children who were on prescribed medication on separate days both on and off of their medications, and repeating the procedure a year later, individuals with both OLD and ADHD were found to have better body control  when on stimulant medication and that the findings were stable over time. The current study’s findings were consistent with other studies identifying stimulant medication to improve body control in children with ADHD ,15,37. EThe current study also investigated the role of medication (on medication versus off medication) on attention state in OLD and ADHD children using the Quotient® ADHD System. It was expected that children tested on medication would have fewer attention shifts and more on task, less distracted, less impulsive, less random, less minimal, and less contrary attending. Results indicated that medication improved remaining on task , being less distracted , and minimal response patterns . However, there were no significant differences in on versus off medication performance on attention shifts, impulsive responding, random responding, and contrary attention states.Despite significant findings for differentiating diagnostic categories and effects of stimulant medication as identified by the Quotient® ADHD System, some limitations for the current study are considered. As noted earlier, the small sample size may not have detected important group, time, and interaction differences. Power analyses for the attention measures suggested that a fairly large number of subjects would be required . Nonetheless, for the movement measures it is important to note that a number of significant differences had large effects sizes supporting that the differences were large enough to be detected with small sample sizes which supports that the findings are nonetheless robust. Likewise, the findings were corroborated when replicated a year later.A second limitation suggests caution in generalizing findings. Children in the study represented a sample of opportunity selected from a pool of participants enrolled in a specially developed language intervention program  at a lar


While Attention Deficit Hyperactivity Disorder (ADHD) often persists into adulthood, little is known about the needs and service use among adolescents and young adults with ADHD. The present study followed-up a cohort diagnosed with ADHD as children and assessed their: 1) needs, 2) correlates of contact with clinical services, and 3) experiences of transition from child to adult health services.Ninety one young people aged 14–24 were recruited from the UK subset of the International Multi-Centre ADHD Genetics (IMAGE) Project. Affected young people and parents conducted face-to-face interviews and self-completion questionnaires including a modified version of the Client Services Receipt Inventory, The Barkley’s ADHD rating scale, The Clinical Interview Schedule-Revised, and the Zarit Burden Interview. Changes in key need characteristics (e.g. ADHD symptoms and impairments) over a 3-year period were examined using fixed effect models. Generalised Estimating Equations (GEE) were used to explore how key characteristics (such as ADHD symptoms) were associated with contact with clinical services across the three years.At baseline 62 % met diagnostic criteria for ADHD and presented with a range of ADHD related impairments, psychiatric comorbidities, and significant caregiver burden. While ADHD symptoms and related impairments lessened significantly over the three years, psychiatric comorbidities and caregiver burden remained stable. The strongest correlate of contact with clinical services was age (OR 0.65 95 % CI 0.49–0.84) with the odds of reported contact with clinical services decreasing by 35 % for each year increase in age at baseline and by 25 % for each year increase in age over time. Only 9 % of the sample had experienced a transfer to adult services, with the majority reporting unmet needs in healthcare transition.Despite continuing needs, few were in contact with adult health services or had received sufficient help with transition between child and adult health services. The main determinant of health service use for adolescents and young adults with ADHD is age – not needs. Service models should address the needs of ADHD individuals who are no longer children.The online version of this article (doi:10.1186/s12913-016-1509-0) contains supplementary material, which is available to authorized users. Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder (affecting 6–7 % of the population) that often persists into adulthood. Up to two-thirds of ADHD children still warrant the diagnosis in adulthood  and thisHowever, despite continuing symptoms and needs, few young adults with ADHD or their families are in receipt of treatments –12. In fLikely reasons for the low use of adult health services among those with ADHD include a lack of (or difficulty accessing) appropriate services during this transitional period alongside individual and caregiver factors that are unique to this developmental stage –22. For The research that does exist has been carried out mostly in children with ADHD and has identified multiple factors that are associated with service use. These include high levels of caregiver burden, low levels of caregiver network support, comorbid psychiatric symptoms, functional impairments of the child and parent or teacher rated ADHD symptom severity –33. A feNevertheless, there is prior evidence to suggest that factors other than clinical severity (such as ADHD symptom severity) may be more important for health service use among adolescents and young adults with ADHD. In one study, using the UK General Practice Research Database to examine prescriptions of drugs to ADHD patients aged 15–21 years, drug prescribing fell steeply at the age of 17 with an almost complete disengagement from services by the age of 21 . It seemHowever, in order to devise appropriate interventions for adolescents and young adults with ADHD it is not only necessary to consider the correlates of health service use but also to identify the needs and unmet needs of young people with ADHD during this transitional period. Healthcare transition refers to the process that starts with preparing a patient to leave a health-care setting and finishes when the patient is received in the next setting . NICE guAlthough transition planning and management is recognised as a key element in the organisation and delivery of health services –38, for To date, very few studies have investigated healthcare transition among young people with ADHD. A recent scoping review of transition from child to adult mental health services for young people with ADHD identified only four studies which have sought to evaluate the journey of young people with ADHD between mental health services, despite a clear need for transition being identified . More loTherefore, for the first time, we explored the experiences of the healthcare transition  from both the young person’s and parent’s perspectives and investigated both needs and contact with clinical services among those with a childhood diagnosis of ADHD who were now at transition to adolescence and young adulthood.This prospective longitudinal study was conducted at the young person’s family home in England or at the Institute of Psychiatry in London, with all travel expenses reimbursed. Around half of young people and their families lived in Greater London while the remainder were spread throughout England from Cornwall to Lincolnshire in the North East. All young people aged 14 to 24 in the IMAGE research database were invited by the research team to participate in the study. Young people and parents were each sent separate letters of invitation and information sheets explaining the study together with an update form to state their interest in the study together with a stamped addressed return envelope. Invitation letters and information sheets explained (i) the rationale of the study; (ii) what the study would involve , and (iii) the confidential aspects of the study .n = 91) and one of their parents . Families were recruited through their child’s childhood clinical diagnosis of combined type ADHD from the UK subset of the International Multi-Centre ADHD Genetics (IMAGE) Project research database. Families had originally been recruited to the IMAGE study by referral from child and adolescent clinics in the southeast of England on the basis that they had received a clinical diagnosis of combined type ADHD (as defined in the DSM-IV) and had at least one surviving biological sibling aged 5–17 years of age. ADHD probands and their siblings were included in the IMAGE study if they were between the ages of 5–17, had an IQ of 70 or higher, were of European or Caucasian descent, and had at least one biological parent willing to provide DNA samples. As the IMAGE study was a molecular and genetic study participants were excluded if they had been diagnosed with: autism, epilepsy, IQ below 70, brain disorders, and/or any genetic or medical disorder associated with externalising behaviours that might mimic ADHD based on both history and clinical assessment.We included 91 families consisting of young people aged 14 to 24 (n = 15) or did not have young person-parent interviews for at least two waves (n = 2). Diagnostic threshold for ADHD was defined using the informant version of the Barkley’s ADHD rating scale for adults [χ2 = 3.35, p = 0.07).Families were followed-up over a 3 year period with data collection beginning in March 2009 and ending in January 2013, with an average follow-up time of 2.35 years (SD = 0.89). Significant efforts were placed on participant retention, for instance repeated attempts to contact families. Thus only 18 % (17/91) of our sample contributed only one year’s observation  to capture service use and transitions from child to adult services . This veWe also used the modified version of the CSRI to capture predisposing and enabling factors. Measures included the socio-economic and demographic backgrounds of both the young person and parent. We considered age to be a predisposing characteristic and parent’s education, an enabling factor. Parent’s education was categorised into two groups: those with low educational levels (i.e. A levels/higher education certificate or below) versus those with high educational levels (i.e. higher education diploma or above).We used several different measures of need including indicators of the severity and frequency of ADHD symptoms and related impairments, psychiatric comorbidities, and parent caregiver burden. We used the informant version of the Barkley’s ADHD rating scale for adults administered to the parent to measure current (i.e. in the previous six months) ADHD symptoms (as described above) and related impairments . This scPsychiatric co-morbidities were assessed using The Clinical Interview Schedule-Revised (CIS-R) , a standCaregiver burden was measured using the Zarit Burden Interview—12 Item . It captDescriptive statistics at baseline were produced to explore the demographic characteristics of the sample, need characteristics, experiences of healthcare transition and contact with clinical services. Logistic regression was conducted to investigate the predisposing, enabling and need factors associated with contact with clinical services . In this and all subsequent models (described below) the score reflecting the frequency and severity of ADHD symptoms was used rather than the binary measure capturing whether participants scored above or below the threshold for ADHD.n = 53), or at least two waves (n = 21). Analyses (not shown) found no significant differences in any of the key characteristics between the 17 young people who were not included in the analysis for the reasons previously stated and the 74 who were. Fixed effects models were used to examine changes in key need characteristics (e.g. ADHD symptoms and impairments) over the 3-year period. We also used Generalised Estimating Equations (GEE) to explore how key characteristics (such as ADHD symptoms) were associated with contact with clinical services across the three years [Longitudinal analyses were then conducted on the 74 families with young person-parent interviews for at least 2 time points: with young person-parent interviews at either all three waves .The average age of young people was 17.7 years and most were male (90 %), still living at home (85 %), and in education (66 %) (Table The majority (62 %) of young people at baseline met DSM-IV criteria for ADHD Table . Ninety Twenty five percent of young people at baseline scored above cut-off (score >12) on the CIS-R, indicating the likelihood of comorbid psychopathology. For example, close to a third of young people reported significant levels of worry and over one in four reported significant levels of depression (data not shown).Despite a high prevalence of ADHD and associated mental health symptoms, 45 % of young people were no longer in contact with clinical services at baseline. 31 % were still in contact with children’s health services and close to 1 in 6 (15 %) reported attending an ADHD service without age boundaries (Table n = 8) of young people reported having experienced a transfer to adult care or were currently receiving help from services in preparing for this move. Only one family out of the total sample at baseline reported having received a written transition plan as recommended in clinical guidelines. Moreover, approximately 75 % of young people and parents reported that a professional had not spoken to them about the move from child to adult services, and the 25 % who responded that a professional had spoken to them about this reported that it had been only a brief conversation. Around half of all young people  reported a need for more support from services in: 1) accessing information regarding which services are available when they grow up; 2) the co-ordination of transition planning, and 3) and having someone to talk to about their practical as well as emotional needs. Analyses showed no age-related differences in young person’s and parents’ experiences of transition or support received from health services in regards to moving to adult health services.Nine percent (Table p = 0.01) with a one year increase in the young person’s age reducing the odds of being in contact with services by 35 %. Only one other factor, parent reported impairment was significantly associated with contact with clinical services . The proportion of variance explained by the models was 0.25 using Cox and Snell R, and 0.33 using Nagelkerke R square, indicating that between 25 and 33 % of the variance is explained by this model.Table Table Table To our knowledge, this is the first longitudinal analysis of needs and services use among adolescents and young adults with a childhood diagnosis of ADHD. A key strength of our study includes the high retention rate  and the use of face-to-face interviews using reliable diagnostic and outcome measures. Moreover, our use of separate face-to-face interviews with young people and their parents enabled us to gain a more comprehensive picture of the wide range of needs among this group. Another strength lies in our consideration of multiple potential factors that may be associated with contact with clinical services. This allowed us to better quantify the relative, and independent, contribution of various factors that influence service use among this clinical group. Last, our exploration of young people’s (and their parents’) experiences of healthcare transition, enabled us to identify unmet needs in healthcare delivery from the perspectives of both the affected young person and their carers, e.g. insufficient access to information, lack of co-ordination of transition, and insufficient attention to the individual needs of young people and parents.Our finding that close to two-thirds of adolescents still warranted DSM-IV diagnostic criteria at the start of the study is comparable to a previous findings on threshold and subthreshold cases of ADHD . SimilarThe results of this study suggest that irrespective of the severity of ADHD symptoms, impairments, comorbidities and carer burden, contact with health services among adolescents and young adults with ADHD is mainly determined by age. The only other factor that was associated with service use was impairments. This may be caused, at least in part, to a lessening of parental control over treatments during the transition from adolescence to young adulthood which may lead to a further elevation of functional impairment or ADHD symptoms. Such declines in impairments may result in further difficulties in managing time and appointments which in turn are likely to increase the risk of disengagement with services . It is iWe found that only 9 % had transferred to adult services (or received transition planning) which is broadly in keeping with a recent audit of transitional care for adolescents with ADHD in a North West England district which found that only about 15 % of young people made the transition . In addiHowever, it is also important to acknowledge that one of the main reasons for the lack of a transition may be the lack of appropriate adult services. There are limited ADHD-specific services for adults , therefoOur study does have some limitations. Given that individuals in our sample had been in contact with child and adolescent mental health services in childhood, and were also participants in research studies of ADHD, our findings may not generalise to the wider population. However, given such previous experience we would expect the individuals in our sample to be more knowledgeable and motivated to access services and thus suggest that the situation in regards to transition may be even worse in the general population. Prior contact with such child and adolescent mental health services may also have resulted in a bias toward presenting with higher levels of psychological problems at follow-up in comparison to those with no previous contact with mental health services. Nevertheless, rates of psychiatric comorbidity in our study are consistent with those reported in previous studies of ADHD –70.Furthermore, as only those with a childhood IQ over 70 were included it is possible that our findings represent an under-estimate of needs among those with intellectual disabilities. This is important as previous studies have shown that adults with borderline and mild intellectual disability (ID) may have more impairments and more severe ADHD symptoms in adulthood when compared to those with ADHD but no ID .In addition, as this study was initially selected for genetic studies and is thus an all-White one it is not possible to say how representative the current findings are for women and/or ethnic minorities. As previous studies have indicated, there are significant variations in service use by gender and ethnicity among young people with ADHD –74, whicDespite continuing needs, few ADHD adolescents and young adults are in contact with health services. Currently, the main determinant of health service use among this group is age – not needs. Service models should address the needs of ADHD individuals who are no longer children and improve the planning, co-ordination and continuity of healthcare during the transition to adult services to reduce the long-term health, social and economic consequences of untreated ADHD .ADHD, attention deficit hyperactivity disorder; CIS-R, clinical interview schedule-revised; CSRI, client services receipt inventory; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition; GEE, generalised estimating equations; ID, intellectual disability; IMAGE, International Multi-Centre ADHD Genetics Project; SAS, statistical analysis system


The Questionnaire: Children with Difficulties (QCD) is a parent-assessed questionnaire designed to evaluate child’s difficulties in functioning during specific periods of the day. This study aimed to evaluate difficulties in daily functioning of children and adolescents with pervasive developmental disorder (PDD) using the QCD. Results were compared with those for a community sample.A case–control design was used. The cases comprised elementary school students  and junior high school students  with PDD, whereas a community sample of elementary school students  and junior high school students  was enrolled as controls. Their behavior was assessed using the QCD, the Tokyo Autistic Behavior Scale (TABS), the ADHD-rating scale (ADHD-RS), and the Oppositional Defiant Behavior Inventory (ODBI) for elementary and junior high school students, respectively. Effects of gender and diagnosis on the QCD scores were analyzed. Correlation coefficients between QCD and TABS, ADHD-RS, and ODBI scores were analyzed.The QCD scores for the children with PDD were significantly lower compared with those from the community sample (P < 0.001). Significantly strong correlations were observed in more areas of the ADHD-RS and ODBI scores compared with the TABS scores.Children with PDD experienced greater difficulties in completing basic daily activities; moreover, their QCD scores revealed stronger associations with their ADHD-RS and ODBI scores in comparison with their TABS scores. The difficulties of PDD, ADHD and OBDI symptoms combined in children makes it necessary to assess all diagnoses before any therapy for PDD is initiated in order to be able to evaluate its results properly. Pervasive developmental disorder (PDD), one of the most common developmental disorders, is a neurodevelopmental disorder presenting with persistent core symptoms of qualitative and quantitative failure of communication and delay in language development . It has th edition (DSM-5), include ADHD for comorbid disorders. Furthermore, ADHD is often comorbid with other neuropsychiatric disorders [Symptoms of attention deficit hyperactivity disorder (ADHD) such as hyperactivity, impulsiveness, and inattention are frequent among individuals with PDD –7. The disorders , of whicisorders . TherefoThe application of pharmacotherapy in ADHD is determined thorough a detailed assessment of symptoms and developmental levels in the child . In JapaADHD-RS, a Japanese version of the ADHD-Rating Scale-IV published in 2008 ,15, is wUsing the QCD, this study aimed to evaluate difficulties in daily functioning of children and adolescents with PDD. The primary hypothesis was that the QCD scores of children with PDD would significantly correlate with PDD, ADHD and ODD symptoms at all time periods of the day. In addition, we had two minor hypotheses. First, we hypothesized that the QCD scores of children with PDD would more strongly correlate with PDD symptoms than ADHD and ODD symptoms during all time periods of the day. Second the QCD scores of males with PDD would be significantly lower compared with those of females. These hypotheses indicated that when clinicians want to evaluate the difficulties in daily life of children with PDD, they should' not only evaluate PDD symptoms but also ADHD and ODD symptoms in these children.A retrospective case—control design was used to evaluate the daily life of children and adolescents with PDD using the QCD. Participants were divided into a PDD group (cases) and a community group (controls) for elementary and junior high school students, respectively. Groups comprised elementary and junior high school students from Ichikawa City, which is situated in the western part of Chiba Prefecture, facing Tokyo, across the Edogawa River. Located approximately 20 km from Tokyo’s metropolitan area, the city has fully developed into a residential area and a center of education. The population is estimated at 471,104 (as of April 2008), the fourth largest in the prefecture.Our investigation is conducted according to the principles expressed in the Declaration of Helsinki.Informed consent was received from the subjects in accordance to the "Ethical Guidelines for Clinical Epidemiology Research" Ministry of Health, Labour and Welfare. The guidelines state "It is not always necessary to obtain informed consent from study participants. However, researchers must publish information on the implementation of the study, including the purpose of the study" for observational studies only using past clinical records and not human tissue samples.The study’s purpose, method, inquiry, and how to refuse participation was posted in the hospital’s outpatient clinic. In addition, verbal consent was obtained from the subjects, and the dates used in this study were anonymized because date-patient correspondence was unnecessary throughout the study.The ethical committee of the National Center for Global Health and Medicine approved this consent procedure of this study in reference to both the PDD group and the control community group.The ethical committee of the National Center for Global Health and Medicine approved this retrospective study.All individuals in the PDD group were examined and diagnosed with PDD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (DSM-IV-TR) . All diaWe explained the study outline to members of the educational committee in Ichikawa City and obtained their approval to perform a survey of public elementary and junior high school students. A consent form, an assent form, and four questionnaires  were distributed by teachers to parents of 10,000 randomly selected children between September 20, 2008 and September 30, 2008. The dates were anonymized at that point. Data, such as name and birth date were anonymized. We only use the data such as age and the results of questionnaires without personal information.QCD comprises 20 questions related to activities during specific time periods of the day: questions 1–4, early morning and before going to school; 5–7, during school; 8–10, after school; 11–14, during the evening; 15–18, at night; and, 19–20, overall behavior See . Each quThis is an 18-item measure of ADHD symptoms used with children . Tanaka This tool comprises 39 items that are provisionally grouped in four areas: interpersonal—social relationship, language—communication, habit—mannerism, and others. It is used by a child’s caretaker to rate the child’s autistic behaviors on a three-point scale. Higher scores indicate multiple and more severe symptoms .This comprised 41 questions, covering DSM-IV-TR diagnostic criteria for ADHD, ODD, and conduct disorder (CD). Items are worded as closely as possible to DSM-IV-TR, using a rating scale format. Each item is rated on a four-point scale from “0”  to “3” (very much). Subjects with ODBI scores over 20 were considered to have ODD (a high ODBI subgroup). Internal consistency, test—retest reliability, concurrent validity, and divergent validity of ODBI have previously been examined .Scores for questions in each of the six subcategories and total QCD scores were separately determined and were statistically compared between the PDD group and the community sample using an unpaired t-test, and effect sizes were calculated.Effects of gender and diagnosis (PDD group vs. community sample) on total QCD scores were analyzed using two-way analysis of variance (ANOVA). We considered the interaction to examine whether there were differences in the QCD scores by combined factors such as gender, diagnosis. Spearman’s correlation coefficient was calculated to determine whether total QCD scores and subscores correlated with TABS, ADHD-RS, and ODBI scores.All statistical tests were two-tailed, and the significance threshold was defined as P < 0.05. The absolute value of the correlation coefficient was regarded as a significantly strong correlation of 0.4 or more. Analyses were performed using the PASW Statistics 18.0 statistical software (IBM Japan Incorporated). Raw data used for analyses described in this manuscript are available upon request.The PDD group comprised 233 elementary and 139 junior high school students diagnosed with PDD according to DSM-IV-TR and the community sample group comprised 1,147 public elementary and 363 public junior high school students.In elementary school, 233 individuals , with an average age of 8.76 ± 1.83 years  were included in the PDD group. Among the junior high school students, 139 individuals  with an average age 13.3 ± 1.00 years  were included in the PDD group.Questionnaires were retrieved from 1,802 parents who provided informed consent to the mailed survey. Of these, 1,510 questionnaires that were completely filled were analyzed. Therefore, the community sample group comprised 1,147 public elementary school students  and 363 junior high school students . The average age of participants in public elementary students was 8.63 ± 1.75 years . The average age of participants in public junior high school students was 13.1 ± 0.92 years .The age difference between the cases (8.76 ± 1.83) and controls (8.63 ± 1.75) for elementary school students was not significantly. However, the age difference between the cases (13.3 ± 1.00) and controls (13.1 ± 0.92) for junior high school students was significantly(p<0.05 and effect size 0.21).QCDs that were completely filled were collected from parents of children from both the PDD group and community sample Tables  and 2. ATotal QCD scores and six QCD subscores of children in the PDD group were compared on the basis of the gender of participants Tables  and 4. TCorrelations of total QCD scores and six QCD subscores with total TABS, ADHD-RS, and ODBI scores are presented in Tables To the best of our knowledge, this may well be the first study to examine the QCD scores in relation to TABS, ADHD-RS and OBDI scores during different time periods of the day between a community sample and children diagnosed with PDD. We observed that the QCD scores were significantly lower for the children with PDD than those for the community sample at each time period for both elementary and junior high school students. As we mentioned in the paragraph of Outcome data, the primary hypothesis that the QCD scores of children with PDD would significantly correlate with PDD, ADHD and ODD symptoms at all time periods of the day was partly confirmed, but significantly strong correlations were observed in more areas of the ADHD-RS and ODBI scores compared with the TABS scores. The association of the QCD scores was greater with ADHD-RS and ODBI scores than that with TABS scores. Therefore, the minor hypothesis that the QCD scores of children with PDD would correlate significantly with PDD symptoms at all time periods of the day was rejected.Although other measures such as the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule may alter observed correlations, our results indicate that children with PDD experience difficulties in daily functioning. Particularly, these are associated with both ADHD and ODD symptoms in addition to their diagnosed PDD symptoms. The TABS is a questionnaire for evaluating screening and severity of PDD symptoms. However, Clinicians cannot decide what PDD symptom is a most severe symptom of the child using the TABS. Therefore, this study couldn't indicate that what PDD symptoms may correlate with the lowest QCD for boys and girls of the two age groups. Furthermore, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, allowed diagnosis of ADHD along with comorbid autism spectrum disorder . TherefoThe minor hypothesis that the QCD scores of males with PDD would be significantly lower compared with those of females was partly confirmed. The total QCD scores, “School” and “after school” subscores were significantly lower for males than that for females in the children with PDD for elementary school students. The parents having children with PDD in elementary school expressed more concerns for males than that for females. Furthermore, “School” and “after school” subscores indicate that females could engage in school and after-school activities. The parents having children with PDD in junior high school expressed concerns regardless of gender.This study has some limitations that must be considered. The PDD diagnosis was made after two or three examinations, and further examinations may have led to changes in diagnoses. In addition, the accuracy of all four measures may be subject to recall bias, subjective reporting, and other types of response errors. Another limitation is the presence of differences between case and control populations. Controls were recruited from the general population of a single district, whereas children with PDD were recruited from a national center in Japan. Although the national center was located in the same district, outpatients at the center belonged to different districts. In addition, controls did not undergo any psychiatric evaluation; therefore, we cannot exclude the presence of mental disorders in these children. The last limitation is that this study compared cases and controls evenly in puberty age. Participants were divided into a PDD group (cases) and a community group (controls) for elementary and junior high school students, respectively. We thought the age difference between the cases (13.3 ± 1.00) and controls (13.1 ± 0.92) for junior high school students (p<0.05 and effect size 0.21) may not influence the results of the QCD, TABS ADHD-RS and ODBI scores in each of the groups differently. But this study did not consider the changes of puberty like adolescent rebellious behavior. Puberty age is a time impulse control is difficult. Parents might evaluate adolescent rebellious behavior as ADHD and ODD symptoms of ADHD-RS and ODBI.In summary, this study determined that children with PDD experience more difficulties in daily functioning compared with a community sample of children. These difficulties differ for gender and vary over the day. The use of QCD in children with PDD enables clinicians to elucidate problems in their daily life during specific time periods of the day. QCD has three important characteristics: the ability to evaluate life function, the capacity to evaluate behavior throughout the day, and ease of use in daily practice. However, several factors need further consideration before determining reference values and cutoff scores. Finally, care should be taken when generalizing current results to wider populations because future studies including participants from a cross-section of districts are required.S1 AppendixTo prevent misinterpretation and biases, two Japanese psychiatrists with a good command of English, who understood the background and objectives of the evaluation scale, independently carried out forward translation of the QCD into English. Then, the two translators discussed and integrated the two translated versions into one. Another psychiatrist did back translation to Japanese, the original language. The back-translated version was examined by the author of the original version and it was confirmed that the intent of the author was accurately translated. After the final proofreading, construction of the QCD English version was completed.(PDF)Click here for additional data file.