Patent Application: US-201515113757-A

Abstract:
the present invention relates to the field of biomarkers and in particular to their utilisation in treatment . embodiments of the invention have been particularly developed as biomarkers enabling optimisation of treatment regimes and as uses of the biomarkers in tests for the prediction of optimised treatments and treatment outcomes in the treatment of attention - deficit / hyperactivity disorder in children and adolescents . the invention will be described hereinafter with reference to this application . however , it will be appreciated that the invention is not limited to this particular field of use .

Description:
in one preferred embodiment the present invention relates to a method of identifying a predictor of treatment outcome in attention - deficit / hyperactivity disorder ( adhd ). adhd is diagnosed using the adhd - rs iv and the mini international neuropsychiatric interview for children and adolescents ( mini - kid ; sheehan d v , et al . reliability and validity of the mini international neuropsychiatric interview for children and adolescents ( mini - kid ). j clin psychiatry 2010 ; 71 ( 3 ): 313 - 326 ) was used to identify other current and lifetime psychiatric co - morbidities . adhd symptom severity was assessed using the adhd - rs iv ( clinician rated ) and the conners &# 39 ; parent rating scale — revised : long version ( cprs - r : l ). adhd - rs iv and cprs - r : l scores are collected at baseline ( i . e . before treatment ) and after a predetermined period of treatment with mph , for example after 6 weeks . in some embodiments , the symptom scores are collected at baseline and after 6 weeks . the adhd - rs iv and cprs - r : l scores provide a measure of the degree of adhd in a subject based on the adhd symptom severity determined . the scores obtained in the above - mentioned symptom reporting scales are referred to herein as “ symptom scores ”. symptom response by week 6 was defined a priori as a reduction in symptom scores on the adhd - rs - iv scale of 25 % or greater . the comparison of the symptom scores measured before and after treatment with mph provides a measure of treatment outcome for each patient . the skilled reader will , of course , understand that such symptom scores can be measured by any applicable diagnostic method for determining the degree of adhd known in the art and that the statistical comparison of the scores can also be performed by methods commonly known in the art . once the baseline symptom scores have been collected , and before any treatment with mph has commenced , further baseline parameters are established for each of the subjects with adhd as well as for subjects of a matched control group who do not suffer from adhd . the parameters assessed in one embodiment are , for example , the subjects &# 39 ; general cognitive and emotional cognitive performance . again , the skilled addressee will appreciate that the above - described parameters are listed as examples only and that the present invention can be performed by assessing other parameters relevant to adhd . 336 children and adolescents aged between 6 and 17 participated in the current study . enrolment and screening criteria are summarized in table 1 , broad inclusion and minimal exclusion criteria were used to recruit a representative sample of the general adhd population who typically receive mph in routine practice . the study was conducted in accordance with the principles of the “ declaration of helsinki 2008 ” ( world medical association ( 2008 ). “ world medical association declaration of helsinki ethical principles for medical research involving human subjects .” 59 th wma general assembly , seoul , october 2008 . retrieved 22 jul . 2013 , from http :// www . wma . net / en / 30publications / 10policies / b3 / 17c . pdf ) or the international conference on harmonization ( ich ) guidelines ( retrieved 22 jul . 2013 from http :// www . ich . org / fileadmin / public_web_site / news_room / c_publications / ich_20_anniversary_value_benefits_of_ichfor_regulators . pdf ) and / or in accordance with the laws and regulations of the country in which the research is conducted , including the principles of “ good clinical practice ” as outlined in the us code of federal regulations . institutional review board ( irb )/ independent ethics committee ( iec ) approval is obtained prior to participant enrolment at each site . of the starting sample of 336 subjects ( mean age = 11 . 9 ; 72 . 9 % male ), 284 returned for a follow - up session at week 6 ( mean age = 11 . 98 ; 73 . 2 % male ). of these , 62 % ( n = 176 ) showed a response to treatment at week 6 . adhd participants were either treatment naïve or washed out before baseline . adhd participants were prescribed open - label mph by their treating paediatrician . the open - label treatment design was intended to maximize participant safety , and is consistent with the study &# 39 ; s naturalistic methodology . participants continued treatment with mph until week 6 ( for a minimum duration of 4 weeks ), while refraining from any other adhd treatments , including other stimulants , non - stimulant adhd drugs and non - pharmacological adhd therapies such as counselling or behaviour therapies . demographic variables were assessed at screening , and clinical and cognitive measures were evaluated at baseline ( week 0 ) and week 6 ( post - treatment ). as indicated above , adhd diagnosis was assessed using the adhd - rs iv and the mini kid was used to identify other current and lifetime psychiatric co - morbidities . adhd symptom severity was assessed using the adhd - rs iv and the cprs - r : l . both scales were administered at baseline and at week 6 . inter - rater reliability training for administration of the adhd - rs - iv was provided by the global trial manager to all principal investigators and research staff performing assessments . participating clinicians received training and were assessed using videorecordings of a simulated consultation between a clinician and a parent describing a child &# 39 ; s symptoms . symptom response by week 6 was defined a priori as a reduction in symptoms on the adhd - rs - iv of 25 % or greater . ten cognitive tasks , summarized in table 2 , were administered to participants at baseline and at the study endpoint ( week 6 ) using the validated computer - based , touch - screen cognitive test battery , “ integneuro ™” ( brain resource ltd . ; see williams et al ., pediatr neurol 2010 ; 42 ( 2 ): 118 - 126 , for a detailed description ). standardized , pre - recorded task instructions will be concurrently presented visually on the screen and audibly through headphones . memory recall tested immediate and delayed recall scores ( i . e ., the number of words correctly recalled across the learning trials and the delayed trial ), assessing verbal learning , memory recall , and verbal self - monitoring ( crossen , 1994 ). digit span evaluated immediate recall and assessed the ability to hold , retain and manipulate new verbal information online ( groth - marnat and baker , 2003 ). verbal interference ( word , colour ) measured the ability to inhibit inappropriate , well - learned , impulsive , automatic responses ( sacks , 1991 ). switching of attention ( digits + letters ) evaluated the ability to sustain and control the direction of attention and switch attention from one over - learned task to another ( o &# 39 ; donnell et al ., 1994 ). continuous performance test ( n - back ) assessed the ability to maintain sustained attention and inhibit impulsive responding over an extended period . additionally , the task assessed target detection , and the ability to update information held in short term memory ( borgaro , 2003 ). go / no - go assessed executive functioning and cognitive inhibition , or the ability to suppress well - learned , automatic responses ( logan et al ., 1984 ). maze task measured how quickly a participant learned the route through the maze and their ability to remember that route . this task involves : executive functioning and planning ; the ability to choose , try , reject and adapt alternative courses of thought and action ; visuospatial learning and memory ( bowden , 1989 ). emotion identification measured emotional recognition and discrimination between emotions ( mathersul et al . 2009 ; williams et al . 2009 ). a total of 48 individual measures derived from these ten tasks were included in the current analysis , using standardized z - scores for each task measure , derived from the normative population scores that form part of the test . the primary outcome variable was non - response , based on change scores from baseline to week 6 on the adhd - rs iv . participants who had less than 25 % reduction in baseline adhd - rs total score were deemed to be non - responders . roc analyses , based on signal detection methods ( kraemer et al ., 1999 ) were used to identify which variables , and at what level or score , optimally discriminate non - responders and responders . in this recursive partitioning procedure , cut - points on tests are identified that discriminate non - responders from responders at p & lt ; 0 . 01 . a kappa statistic is calculated for each cut - point , and the largest kappa coefficients correspond to cut - points with maximum sensitivity and specificity ( kraemer et al ., 1999 ; qroc freeware available at mirecc . stanford . edu ). this recursive partitioning method uses the patients &# 39 ; cognitive test results to identify subgroups with significantly increased or decreased probability of mph response . this process is repeated in a classification tree approach , until no further significant partitions can be achieved or until subgroup size reduces to 10 subjects , up to a maximum of 3 times for each progressive tree branch , resulting in a maximum of 8 potential final subgroups at the bottom of the classification tree . for subgroups at the end of each branch of the classification tree , in which the proportion of responders differed from the response rate observed in the overall sample ( 62 %) by at least 10 percentage points either direction ( i . e ., 72 % or greater = elevated response likelihood ; 52 % or lower = decreased response likelihood ), these subgroups are considered to represent “ high ” and “ low ” response groups , respectively . to evaluate the predictive utility of the cognitive test battery , each of the subgroups representing high and low response were combined and further descriptive statistics were provided . sensitivity , specificity , positive predicted value , and negative predicted value were calculated to evaluate the predictive utility of the cognitive test battery . participants were included if they had missing data on any of the cognitive tests but were excluded if they did not have observed outcome data on the adhd - rs - iv . descriptive statistics of the study sample ( n = 336 ) shown in table 3 . of the total sample who completed the week 6 follow - up assessment ( n = 284 ), 62 % ( n = 176 ) met the criterion for response to methylphenidate ( i . e ., ≧ 25 % reduction in baseline adhd - rs iv scores by week 6 endpoint assessment ). details for those participants who did not complete the follow - up assessment are provided in fig1 . among all participants , 57 % reported prior ( lifetime ) use of stimulant medication to treat adhd ( although washed out at baseline if they had been recently using stimulant mediation ). previous use of stimulant medication was not related to response status at week 6 ( χ 2 = 1 . 8 , df = 1 , p & gt ; 0 . 05 ). of the 10 tasks ( 48 scores ) in the cognitive test battery and 2 demographic measures of gender and age , 5 cognitive tasks were identified in the roc tree of fig2 as significant discriminators of responders and non - responders : as shown in fig2 , a total of seven subgroups of patients were identified in the roc analysis varying in their response to mph treatment . among three groups of patients shown as gray boxes with dashed outlines in fig2 ( n = 28 ; n = 25 ; and n = 20 ; grouped based on assessment using the above - described cognitive test battery ) the proportions of responders to mph were significantly lower ( 18 %, 44 %, and 40 %) relative to the overall response rate of 62 % ( see fig2 ). among two groups of patients shown as gray boxes with bolded outlines ( n = 20 and n = 70 ; grouped based on assessment using the above - described cognitive test battery ) the proportions of responders to mph were significantly higher ( 85 % and 83 %) than the overall response rate ( see fig2 ). two groups of patients ( n = 13 and n = 78 ; shown as white boxes in the lowest panel of fig2 ) were identified that had responder rates comparable to the overall sample ( 69 % and 60 %). based on assessment scores at baseline ( patient responses to the 45 - minute cognitive battery ), roc classifications identified three groups of children and adolescents with specific pre - treatment cognitive assessment profiles ( n = 28 , n = 25 and n = 20 ), who have a significantly reduced response rate to mph compared to the overall adhd group response rate (“ significantly ” here refers to being “ beyond the clinically significant cut - off point of 10 percentage points below the overall group response rate level of 62 %”. one of these groups consisted of patients with poor accuracy in switching of attention ( their normative scores in the switching of attention accuracy test were below the 22nd percentile ), who were younger than 10 years old and also had poor planning implementation ( i . e . maze scores below the 14 th percentile for the time taken to complete the first error - free path ). this group of younger patients contributed the lowest proportion of responders with a response rate of only 18 %. the second group of patients identified as less likely to respond to mph also had poor switching of attention scores ( i . e . below the 22 nd percentile ) but were 10 years of age or older and also scored in the normal to high range on the verbal interference task . these patients had verbal interference reaction times above or equal to the 34 th percentile relative to the normative population ( n = 25 ) and had a response rate of only 44 %. a third group of patients was identified using the scores on the continuous performance test ( cpt ), a measure of sustained attention . of the patients with normal or high switching of attention accuracy ( in or above the 22 nd percentile ; see fig2 , right side ), those with very low sustained attention reaction time scores ( n = 20 ; cpt scores & lt ; 0 . 5 th percentile ), only 40 % qualified as responders to mph . these three distinct cognitive pre - treatment profiles which identified three groups of patients with a reduced response rate to mph ( compared to the overall adhd group response rate ) are shown in gray boxes with dashed outlines in fig2 . roc signal detection also identified two groups of children and adolescents with distinct cognitive pre - treatment profiles in which these profiles correlated with a significantly increased response to mph compared to the overall adhd group response rate . eighty - five percent ( 85 %) of participants responded to mph if they were 10 years of age or older , and showed low cognitive flexibility as measured by the switching of attention test accuracy scores (& lt ; 22 nd percentile ) and poor verbal interference reaction times (& lt ; 34 th percentile ; a measure of impulsivity ) at baseline . a second pre - treatment profile corresponding with a high response rate ( 83 %): was identified . specifically , among participants with normal to above - normal switching of attention accuracy scores (& gt ;= 22 nd percentile ), and not having extremely slow continuous performance test reaction time scores (& gt ;= 0 . 5th percentile ) and normal to above - average scores on the digit span task (& gt ;= 46 th percentile ). among these patients ( n = 70 ), being accurate , fast , and having good working memory was associated with high response to mph . the resulting roc classification tree comprised five group of patients with pre - treatment profiles that were associated with either significantly increased treatment response rates ( two groups , together comprising 32 % of the sample : 98 / 284 ) or significantly decreased treatment response rates ( three groups together comprising 24 % of the sample : 73 / 284 ). using the using the percentile cut - off points identified by each roc analysis to identify these groups of patients , the specificity of these classifications was 77 % and had a negative predictive value of 67 %, reflecting good utility for accurately identifying non - responders . in addition , these classifications yielded a sensitivity value of 76 % and positive predictive value of 83 %, reflecting good utility for accurately identifying responders . table 4 compares the low response groups and high response groups in relation to other parameters measured in the present study . groups were found to statistically differ in age , which is expected since age forms part of the classification tree . groups did not significantly differ with respect to : gender ; baseline levels of overall adhd symptom severity ( as measured by the clinician rated adhd - rs - iv , or parent rated cprs - r : l ); the dosage of mph at the time of post - treatment assessment ( week 6 ); baseline levels of overall adhd symptom severity ( as measured by the clinician rated adhd - rs - iv , or parent rated cprs - r : l ); or proportions of the clinical combined or hyperactive adhd sub - types , or the inattentive adhd subtype . showing that these criteria are not indicators for the above - described clinical or demographic features defining the patient groups identified . a low responders = children and adolescents with response rates 10 % or less than the base response rate ( 62 %); high responders = children and adolescents with response rates 10 % or higher than the base response rate ( 62 %) in this large effectiveness study of the effects of methylphenidate on adhd symptoms , the response to mph was 62 %, which is comparable with the literature ( kooij et al ., 2010 ). signal detection methods and roc analyses were chosen for this planned hypothesis - generation that will guide subsequent , formal hypothesis testing . specifically , baseline responses to a computerized cognitive test battery comprising 10 tests yielding 48 scores were evaluated for their ability to differentiate responders and non - responders at 6 weeks of mph treatment . for the purpose of hypothesis - generation , baseline scores from an initial cohort were analysed using signal detection methods . responses to the tasks of switching of attention , continuous performance test , verbal interference , and maze significantly predicted whether children and adolescents experienced a subsequent reduction of adhd symptoms after receiving mph , i . e . were useful biomarkers in the methods of the present invention . specifically , the proportion of responders among those with the roc - defined non - responder profiles was 33 %, and the proportion of responders among the children with responder profiles was 83 %. the effect size seen for utility of the test in roc tree analyses shows that the algorithm derived from the cognitive tests is useful in clinical practice . non - responders had compromised cognition , including switching of attention , sustained attention , planning , and impulsivity . responders showed intact cognition , particularly in speed and accuracy , switching of attention , sustained attention , and working memory . response profiles yielded response rates ranging from 18 % to 85 %. altogether , more than half of the sample could be placed into the much more or much less likely to respond groups defined a priori as entailing an effect size ( number needed to treat ) of 10 or less . four of the most common findings in previous adhd research in relation to adhd symptom severity have included : a ) deficits in sustained attention , measured herein using the continuous performance test ( barkley 1997 ; williams et al ., 2010 ); b ) deficits in working memory ( via digit span ) ( barkley 1997 ); c ) increased impulsivity ( reflected in verbal interference reaction times ) ( lansbergen 2007 ; williams et al ., 2010 ); and d ) frontal executive inefficiencies ( barkley 1997 ), exemplified by maze errors and well as switching of attention inaccuracies . notwithstanding , the skilled reader will appreciate that neither of these cognitive parameters alone , or in combination , has previously been suggested or disclosed as being useful in patient - specific , cognitive pre - treatment profiles , i . e . as useful biomarkers , for establishing a cognitive pre - treatment profile allowing the prediction of mph treatment outcome in children and adolescents suffering from adhd , as is one embodiment of the present invention . the switching of attention task , which was the first variable identified in the present study to discriminate mph treatment responders and non - responders , requires holding “ on - line ” 2 sets of information at the same time and alternately switching between them , utilizing abilities of cognitive flexibility and executive function , both of which are deficits associated with adhd . greater errors on this task reflect a deficit in this ability , reflecting the continuation of using the same set of information , instead of switching to the alternate set of information . the continuous performance ( n - back ) task assesses the capacity to sustain attention over a prolonged period of time , and requires watching a series of letters appear on the screen , remembering each time what the previous letter was , in order to be able to respond when the same letter appears twice in a row . poor performance in the continuous performance ( n - back ) task is often seen in adhd patients ( williams et al ., 2010 ). lower accuracy and slower response times reflect poorer attention skills . however , the use of this cognitive parameter in a multi - parameter cognitive pre - treatment profile , i . e . as a useful biomarker , for the prediction of mph treatment outcome in children and adolescents suffering from adhd , as described here for one embodiment of the present invention , has not previously been suggested or disclosed . the verbal interference task assesses controlled attention similar to the stroop test ( sacks , 1991 ). it requires the reading of a colour name word , but responding with the name of the font colour the word is written in . as will be understood , answering correctly requires the test subject to inhibit the automatic response of reading out word written . lower accuracy and slower response times in this task indicate a patient &# 39 ; s difficulty in inhibiting automatic responses . inhibiting automatic behaviour is a core deficit in adhd . notwithstanding , the use of this cognitive parameter in a multi - parameter cognitive pre - treatment profile , i . e . as a useful biomarker , for the prediction of mph treatment outcome in children and adolescents suffering from adhd , as described here for one embodiment of the present invention , has not previously been suggested or disclosed . higher scores obtained in the maze test are indicative of the extended time periods required for successfully completing a maze and suggest a deficit in executive functioning and planning skills . executive functioning and planning skills are cognitive functions that are not generally known to be particularly stimulant - responsive . further , higher scores indicate a person &# 39 ; s greater difficulty in choosing , trying , rejecting , and adapting to alternative courses of thought and action . in addition to the obvious social and academic consequences of such problems , the current study , for the first time , suggests that children and adolescents suffering from adhd and obtaining higher maze test scores are markedly less likely to respond adequately to mph treatment — the current mainstay treatment for adhd . while previous adhd research demonstrated deficits in executive functions . the correlation between maze test scores and non - response to mph treatment in children and adolescents suffering from adhd , as described here for one embodiment of the present invention , has not previously been suggested or disclosed . in the current study , signal detection methods and roc analyses were chosen for transparent hypothesis - generation . for the optimal classification of non - responders and responders to mph treatment in a group of children and adolescents suffering from adhd , multiple roc tests were conducted inflating type 1 error risk ( i . e . evaluation of 48 measures at each level of the classification tree ) the use of alpha = 0 . 01 for each test provided some , albeit limited protection , from this concern . furthermore , the present study includes the application of roc analysis rather than standard analytical tools such as general linear models , or logistic regression . the inventor realised that , as roc analysis is not mathematically compromised by issues such as multi - collinearity ( i . e ., highly correlated predictor variables ) or the distributions of the residuals ( kiernan et al ., 2001 ), and as it is roc analysis can be applied when evaluating a large number of potential predictors of any binary outcome such as treatment response / no treatment response , it was particularly useful to analyse the 48 variables tested in each participant of the present study . as will be appreciated , the surprising findings of the present study , for the first time , have allowed for the provision of low - cost , short and easily conducted tests to identify children and adolescents who are markedly less likely to have a positive treatment response to stimulant medication . the benefits of identifying children and adolescents with adhd who will not respond adequately to stimulant medication will be manyfold but , predominantly , will serve to reduce the occurrence of unnecessary side effects of stimulant medication where therapeutic benefit is achieved while facilitating an earlier exploration of alternative treatments to benefit the patients and their families . polanczyk g , de lima m s , horta b l , biederman j , rohde l a : the worldwide prevalence of adhd : a systematic review and metaregression analysis . am j psychiatry 2007 , 164 : 942 - 948 kooij s j , bejerot s , blackwell a , caci h , casas - brugue m , carpentier p j , edvinsson d , fayyad j , foeken k , fitzgerald m , gaillac v , ginsberg y , henry c , krause j , lensing m b , manor i , niederhofer h , nunes - filipe c , ohlmeier m d , oswald p , pallanti s , pehlivanidis a , ramos - 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