Clinical utility of the standardized observation tool Autism Behavior Coding System for early intervention research in autism spectrum disorder.

The Autism Behavior Coding System (ABCS) was developed to help evaluating the effectiveness of early intensive interventions in children with autism spectrum disorder (ASD). The video-based ABCS assesses eight core autistic behavioral variables during therapist-child interaction using standardized quantitative criteria, four behaviors according to their frequency of occurrence, four according to their duration. The present study focuses (1) on the correspondence of ABCS scores with scores on two standard clinical instruments (the ADOS-2 and an ASD-adaptation of the Children's Global Assessment Scale, DD-CGAS), (2) on the sensitivity to change of ABCS scores by the end of an intensive 18 days intervention period (EIP) and (c) on the predictability of short- and longer-term changes in social and repetitive behaviors from ABCS scores at baseline and EIP. Data from 51 children (42 M, 9 F; median age 45 months) followed over 1 year were available. There were significant correlations at baseline between several ABCS scores and ADOS-2 as well as DD-CGAS scores. Correlations at EIP between some ABCS and DD-CGAS scores were highly significant. Four ABCS scores reflected significant changes from baseline to EIP. Several baseline ABCS scores were predictive of DD-CGAS and ADOS-2 scores at EIP and Year 1. However, associations between ABCS score changes from baseline to EIP and the clinical scale changes by Year 1 were not significant. It is concluded that several ABCS scores have adequate clinical validity and sensitivity to change. The short-term changes in ABCS scores and their relationship to longer-term clinical changes need further study.

Using historical data to facilitate clinical prevention trials in Alzheimer disease? An analysis of longitudinal MCI (mild cognitive impairment) data sets.

BACKGROUND: The Placebo Group Simulation Approach (PGSA) aims at partially replacing randomized placebo-controlled trials (RPCTs), making use of data from historical control groups in order to decrease the needed number of study participants exposed to lengthy placebo treatment. PGSA algorithms to create virtual control groups were originally derived from mild cognitive impairment (MCI) data of the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. To produce more generalizable algorithms, we aimed to compile five different MCI databases in a heuristic manner to create a "standard control algorithm" for use in future clinical trials. METHODS: We compared data from two North American cohort studies (n=395 and 4328, respectively), one company-sponsored international clinical drug trial (n=831) and two convenience patient samples, one from Germany (n=726), and one from Switzerland (n=1558). RESULTS: Despite differences between the five MCI samples regarding inclusion and exclusion criteria, their baseline demographic and cognitive performance data varied less than expected. However, the five samples differed markedly with regard to their subsequent cognitive performance and clinical development: (1) MCI patients from the drug trial did not deteriorate on verbal fluency over 3 years, whereas patients in the other samples did; (2) relatively few patients from the drug trial progressed from MCI to dementia (about 10% after 4 years), in contrast to the other four samples with progression rates over 30%. CONCLUSION: Conventional MCI criteria were insufficient to allow for the creation of well-defined and internationally comparable samples of MCI patients. More recently published criteria for MCI or "MCI due to AD" are unlikely to remedy this situation. The Alzheimer scientific community needs to agree on a standard set of neuropsychological tests including appropriate selection criteria to make MCI a scientifically more useful concept. Patient data from different sources would then be comparable, and the scientific merits of algorithm-based study designs such as the PGSA could be properly assessed.

Short-Term and Highly Intensive Early Intervention FIAS: Two-Year Outcome Results and Factors of Influence.

BACKGROUND: Comprehensive behaviorally or developmentally based early intervention programs have been shown to be effective in improving cognitive, social communicative, and adaptive skills of children with autism spectrum disorder (ASD). Besides the definition of relevant outcome predictors, the question of whether early intensive intervention positively changes core autism symptoms in children, as well as their long-term outcome, is an important issue for current research. The primary objective of the current study was to examine whether symptomatic and behavioral changes in children up to 4.5 years with ASD were sustained one and two years after an initial 18 days of intensive FIAS (Frühintervention bei autistischen Störungen) intervention. METHODS: We analyzed the data of 32 young children with moderately severe to severe ASD who had been treated at the FIAS center between January 2011 and July 2017 and who had completed their 2-year follow-up in summer 2019. RESULTS: ADOS total scores decreased significantly from baseline to the 1-year follow-up and from baseline to the 2-year follow-up (p < 0.01), with the most prominent change being from baseline to 2-year follow-up. The DD-C-GAS, a global scale used to assess four areas of everyday functioning, showed highly significant improvements on all subdomains. We found mostly significant correlations between results on both rating instruments at all time points, yet mostly no meaningful correlation between their changes over time. There was a close and statistically significant relationship between parents' treatment adherence and ADOS scores, indicating that the better parents' treatment adherence, the lower the children scored on the ADOS at 1- and 2-year follow-up. Overall, improvement on both scales was virtually independent of age and autism symptom severity at baseline, suggesting that older (>43 months) and more severely affected children (ADOS total score >20) may benefit from the FIAS intervention to the same extent as younger children do. CONCLUSIONS: The results of the study indicate that the FIAS approach of providing an initial highly intensive 18-day intervention period, followed by 2 years of less intensive follow-up care had an impact on the core autism symptoms as well as the adaptive functioning of children with ASD.

Process research in early intensive intervention in autism spectrum disorder: Sensitivity to change of the autism behavior coding system.

The development of sensitive measures to capture changes in core autism symptoms is crucial in early intervention research. The study examines the sensitivity to change of the Autism Behavior Coding System (ABCS), a video-based instrument to assess core autism symptoms during therapist-child interaction. Video sequences of 40 young children treated in the Frühintervention bei Autistischen Störungen center were analyzed with regard to the question of whether short-term changes during an 18 day period of early intervention could be captured, and whether these results are reflected in an independent clinical assessment (Developmental Disorders-Child-Global Assessment Scale [DD-C-GAS]). ABCS results showed statistically significant improvements on behavioral domains such as "expression of wishes" and "social cooperative behavior" (P < 0.01), less pronounced on "eye contact." Improvements on the DD-C-GAS were highly significant on all subdomains. Both scales showed high correlations within their subdomains, yet no significant correlations between the changes in both instruments' scores were found. An additional analysis between the DD-C-GAS scores at day 18 and the changes in the ABCS scores showed statistically significant associations in the expected direction between the changes in the variable "eye contact" and all DD-C-GAS subdomains. The correspondence of the two levels of assessment is low, but the specifics of this relationship deserve further study. The ABCS may prove useful in addition to standard assessment tools, especially in early intervention research settings, as it allows reliable analysis of core behavioral elements in young children with autism. Autism Res 2019, 12: 1817-1828. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: The study examined the sensitivity of an autism-specific video coding system (ABCS) in assessing changes after an 18 day period of intensive early intervention. Video sequences of therapist-child-interaction of 40 young children with autism spectrum disorder (ASD) were analyzed. Children's behavior improved in expression of wishes, social cooperativity and eye contact. A therapist-based global assessment scale also showed important improvement after 18 days, yet both assessment instruments showed weak correlations between their respective changes. We showed that the ABCS may prove useful in capturing short-term changes in autism-related behaviors, especially in early intervention research.

Assessing symptoms during comprehensive interventions for young children with autism spectrum disorder: Development and preliminary analysis of the Autism Behaviour Coding System (ABCS).

The aims of this paper are to present the Autism Behaviour Coding System (ABCS), a novel, video-based observational instrument for assessing core autism symptoms during intensive early interventions in autism spectrum disorder (ASD), to provide preliminary data on its psychometric characteristics and to discuss its clinical utility. Video recordings of child-therapist interactions during the 'Frühintervention bei autistischen Störungen' (FIAS) were coded by treatment-independent raters who were blind with respect to the temporal order of the sequences. We assessed inter-rater reliability using intra-class correlations (ICCs). Mean ICCs ranged from 0.85 to 0.90. We analysed the sensitivity of the ABCS to change by comparing the change in ABCS scores with the change in a validated external measure of level of functioning (Developmental Disorder-Child-Global Assessment of functioning Scale, DD-C-GAS) in a sample of 15 children who received intensive treatment. Both the ABCS and DD-C-GAS indicated that the intervention improved symptoms. The ABCS has promise as a research instrument and has good to excellent inter-rater agreement and sensitivity to intervention-related changes. This pilot study suggests that the ABCS may be useful as an objective method of assessing the proximal effects of therapy in young children with ASD.

Become Related: FIAS, an Intensive Early Intervention for Young Children with Autism Spectrum Disorders.

BACKGROUND: In autism spectrum disorders (ASDs), impairments in fundamental social abilities and a lack of interest in social stimuli become apparent early in life. These impairments are thought to negatively affect further brain and behavioural development. Early intensive interventions can help to attenuate social-development and other risk factors and, thus, to ameliorate the deficits associated with ASDs. We present FIAS, an intensive early intervention approach for young children with ASD, which aims at developing children's social motivation. During 18 days, therapists work continuously for 6 h a day with the affected child, involving the whole family in a day care setting. Follow-up care at home over 1 year as well as fresh-up interventions and inclusion in kindergarten or a play group should stabilise the effects and help to respond to further challenges. MATERIAL AND METHODS: Here, we present observations from the first 12 patients (25-48 months of age) treated according to the FIAS approach. We evaluated changes in core autistic symptoms and level of functioning after the 18 days of intensive intervention. Beyond standardised assessment, two innovative video-based instruments (Autism Behaviour Coding System and Evaluationsfragebogen) have been developed to assess autistic symptoms and interaction parameters during intervention. RESULTS: Improvements were noted in most core autistic symptom domains, with the highest effect sizes in domains like eye contact, communication, repetitive behaviour, imitation, motivation and reciprocity. In addition, the level of functioning significantly improved. CONCLUSIONS: The first evaluation of the FIAS approach shows promising results, as the FIAS intervention appears to improve core autistic symptom domains as well as the level of everyday functioning. Limitations of this study are the small sample size and the lack of a control group. A more comprehensive and longitudinal evaluation is in progress; this will focus on the stability of the observed effects and will attempt to identify potential predictors of treatment response. © 2015 S. Karger AG, Basel.

Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review.

INTRODUCTION: There is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia. METHODS: The databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review. RESULTS: In 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer's disease and healthy controls. CONCLUSION: IADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer.

Modeling the course of Alzheimer's disease to improve clinical trials: symposium report.

In a symposium held at the Clinical Trials in Alzheimer's Disease conference in Monte Carlo, Monaco (29 to 31 October 2012) three different, not mutually exclusive approaches to improve and facilitate clinical trials with anti-dementia drugs were presented and discussed. All three approaches are summarized in this manuscript. Core suggestions are: stratification of trial participants at the outset of studies, using cognitive and disease-course characteristics available at baseline; creating new composite cognitive scores for optimizing responsiveness to decline in early and very early Alzheimer's disease; and replacing some of the conventional long-term placebo-controlled trials in advanced stages of drug development, using the placebo group simulation approach. Future efforts should focus on incorporating, where appropriate, the suggestions provided at the symposium into clinical trials now being planned.

For debate: substituting placebo controls in long-term Alzheimer's prevention trials.

INTRODUCTION: Novel compounds with potential to attenuate or stop the progression of Alzheimer's disease (AD) from its presymptomatic stage to dementia are being tested in man. The study design commonly used is the long-term randomized, placebo-controlled trial (RPCT), meaning that many patients will receive placebo for 18 months or longer. It is ethically problematic to expose presymptomatic AD patients, who by definition are at risk of developing dementia, to prolonged placebo treatment. As an alternative to long-term RPCTs we propose a novel clinical study design, termed the placebo group simulation approach (PGSA), using mathematical models to forecast outcomes of presymptomatic AD patients from their own baseline data. Forecasted outcomes are compared with outcomes observed on candidate drugs, thus replacing a concomitant placebo group. METHODS: First models were constructed using mild cognitive impairment (MCI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. One outcome is the Alzheimer Disease Assessment Scale - cognitive subscale (ADAScog) score after 24 months, predicted in a linear regression model; the other is the trajectory over 36 months of a composite neuropsychological test score (Neuro-Psychological Battery (NP-Batt)), using a mixed model. Demographics and clinical, biological and neuropsychological baseline values were tested as potential predictors in both models. RESULTS: ADAScog scores after 24 months are predicted from gender, obesity, Functional Assessment Questionnaire (FAQ) and baseline scores of Mini-Mental State Examination, ADAScog and NP-Batt with an R2 of 0.63 and a residual standard deviation of 0.67, allowing reasonably precise estimates of sample means. The model of the NP-Batt trajectory has random intercepts and slopes and fixed effects for body mass index, time, apolipoprotein E4, age, FAQ, baseline scores of ADAScog and NP-Batt, and four interaction terms. Estimates of the residual standard deviation range from 0.3 to 0.5 on a standard normal scale. If novel drug candidates are expected to diminish the negative slope of scores with time, a change of 0.04 per year could be detected in samples of 400 with a power of about 80%. CONCLUSIONS: First PGSA models derived from ADNI MCI data allow prediction of cognitive endpoints and trajectories that correspond well with real observed values. Corroboration of these models with data from other observational studies is ongoing. It is suggested that the PGSA may complement RPCT designs in forthcoming long-term drug studies with presymptomatic AD individuals.

Norms for change in episodic memory as a prerequisite for the diagnosis of mild cognitive impairment (MCI).

The new diagnostic criteria for mild cognitive impairment (MCI) from the International Working Group on Mild Cognitive Impairment (Winblad et al., 2004, p. 243) list "evidence of decline over time in objective cognitive tasks" as one diagnostic sign, implying the repeated neuropsychological testing. This study aimed to compare different assessment methods of longitudinal change based on the performances of 366 cognitively healthy participants (237 men, 129 women) examined with a German version of the California Verbal Learning Test (Delis, Kramer, Kaplan, & Ober, 1987) at baseline and 2 years later. Age, education, gender, and baseline performance were taken into account. Results revealed marked practice effects after 2 years. Normal ranges for change that controls for practice effects and regression to the mean proved to be superior to other reliable change indexes. This new method allows for more valid interpretation of change in neuropsychological functioning and thus diagnosis of MCI.

Impact of APOE status on cognitive maintenance in healthy elderly persons.

OBJECTIVE: The epsilon4 allele, a variant of the apolipoprotein E (ApoE) gene, is the most prominent genetic risk factor for sporadic, non-familial Alzheimer's disease (AD) currently known. We investigated the impact of the ApoE-epsilon4 status on cognitive performance at repeated test administration in elderly non-symptomatic persons, with a specific focus on practice effects. METHODS: Three hundred and fifty-five physically and mentally healthy participants of the Basel Study on the Elderly (119 F, 236 M; age 68.3 +/- 7.6; years of education 12.7 +/- 3.1; Mini-Mental State scores 29.0 +/- 1.0) were grouped into ApoE epsilon4 carriers and ApoE epsilon4 non-carriers (36.9% and 63.1% of the sample, respectively). Participants were assessed at the beginning of the longitudinal study and on average two years later by means of the California Verbal Learning Test (CVLT) and the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (CERAD-NAB), a multidimensional cognitive test battery. Baseline and change scores were analyzed with multiple regression procedures and adjusted for age, education and gender; change scores were also adjusted for baseline performance. RESULTS: The ApoE epsilon4 non-carriers showed slightly better performance with regard to most cognitive parameters at baseline. Mean practice effects of the ApoE epsilon4 non-carriers in 12 out of 13 CVLT variables and in five out of the nine main CERAD-NAB variables were above the 50th percentile, while those of the ApoE epsilon4 carriers were below the 50th percentile in the respective distributions of test-retest change scores. CONCLUSIONS: The epsilon4 allele of the ApoE gene has a negative impact on cognitive performance, notably on episodic memory functions, in physically and mentally healthy aged persons. Practice effects seen in carriers of the ApoE epsilon4 were inferior in most areas tested to the effects seen in ApoE epsilon4 non-carriers. Further follow-up of these subjects will help to determine the clinical significance of these findings.

Lack of practice effects on neuropsychological tests as early cognitive markers of Alzheimer disease?

Reliable assessment of change from previous cognitive functioning is a prerequisite for determining the possible presence of neurodegenerative diseases such as Alzheimer's disease (AD). We investigated whether standardized change scores on the German version of the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (CERAD-NAB) could be used for early diagnosis of AD and whether change scores on the CERAD-NAB are superior in this respect to scores recorded on 1 occasion only. Three hundred seventy-four normal control subjects were assessed twice. Data from 95 patients with mostly mild probable AD were collected at their first entry to a memory clinic and an average of 1.1 +/- 0.24 years later. It is concluded that repeated testing with the CERAD-NAB does not generally add to improved diagnostic accuracy for mild and very mild AD and cannot, therefore, be recommended as a routine clinical procedure.

Retrospective evaluation of an intensive method of treatment for children with pervasive developmental disorder.

The objective of this preliminary study was to evaluate a novel intensive therapy program in young children with pervasive developmental disorder (PDD). Twenty-three children treated at the Mifne Institute in Israel between 1997 and 1999 were assessed. Videos taken before coming to Mifne and after intensive treatment at the institute and before and after another 6 months of continued treatment at children's homes were coded and blind rated by trained personnel using the Childhood Autism Rating Scale (CARS) and the Social Behavior Rating Scale (SBRS). Total scores on both scales improved significantly after 3 weeks and after 6 months. There were some significant improvements at item level although the magnitude of the changes was modest. Despite the small number of participants, the modest increase in test scores, and the retrospective study design, these preliminary results are promising. There is a case for performing a full prospective, comparative investigation of this treatment approach.

Assessment of everyday behavior in Alzheimer's disease patients: its significance for diagnostics and prediction of disease progression.

In addition to cognitive decline, current diagnostic criteria for Alzheimer's disease (AD) require evidence of impaired social and/or occupational functioning. The Nurses' Observation Scale for Geriatric Patients (NOSGER) is used to rate the frequency of disturbances in everyday behaviors and, although not specifically developed for this purpose, is often applied for diagnostic purposes. The NOSGER assesses six dimensions: Memory, Instrumental Activities of Daily Living (IADLs), Self-Care (ADL), Mood, Social Behavior, and Disturbing Behavior. The goals of this study were 1) to establish normative data for the NOSGER as a function of demographic variables (i.e., age, years of education, and gender) in healthy elderly subjects; 2) to obtain cutoff values distinguishing healthy elderly subjects from probable AD patients with mild dementia; and 3) to describe the natural course of behavioral changes occurring in mild AD according to the NOSGER dimensions. NOSGER data of 445 normal controls [NCs, 376 men, 69 women; Mini-Mental Status Examination (MMSE) = 28.8 +/- 1.17] and 217 probable AD patients with mild dementia (97 men, 120 women; MMSE = 26.1 +/- 1.59) from the Memory Clinic of Basel, Switzerland, were analyzed. Cutoff scores for distinguishing between average NCs and mildly demented AD patients ranged between 7 and 9 for different NOSGER dimensions. Formulae to obtain demographically adjusted and z-transformed NOSGER dimension and MMSE scores for assessment of individual cases were determined. NCs were best distinguished from patients in the NOSGER dimension Mood, followed by Memory, ADLs, Social Behavior, and Disturbing Behavior. Linear courses of behavioral deterioration were found-in four NOSGER dimensions (Memory, IADLs, Mood, and Social Behavior) in these mildly demented patients. No quadratic course was found for any of the NOSGER dimensions. The NOSGER revealed good discriminatory power in those behavioral dimensions affected in early stages of AD and is suitable for monitoring behavioral changes as a function of disease progression. Its use in combination with the MMSE for dementia screening purposes is recommended.

Disease stage in Alzheimer disease and treatment effects of rivastigmine.

The efficacy and tolerability of the cholinesterase inhibitor rivastigmine in the treatment of Alzheimer disease (AD) have been demonstrated in several clinical trials, which included patients with a wide range of dementia severities. To investigate the association between severity of disease and treatment response, the combined data from three large randomized, placebo-controlled trials were analyzed. The pooled patient population was stratified into three cohorts showing moderately severe (Mini-Mental State Examination score [MMSE] < or = 15), moderate (MMSE 16-22), and mild (MMSE > or = 22) dementia. In each cohort, the effects of rivastigmine 6 to 12 mg/day versus placebo were evaluated using the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog) and the Progressive Deterioration Scale. Rivastigmine 6 to 12 mg/day maintained ADAS-cog scores at or above placebo levels in all cohorts, while cognitive deterioration with placebo was progressive and severity dependent. Activities of daily living showed statistically significant benefits with rivastigmine across all severity cohorts.

Rivastigmine in Alzheimer disease: efficacy over two years.

OBJECTIVE: Beyond 6 to 9 months of treatment with cholinesterase inhibitors (ChE-Is), there is a notable increase in the rate of cognitive decline in Alzheimer disease (AD) patients, and there are few longer-term studies to evaluate this finding. The authors examined whether the ChE-I rivastigmine continued to be therapeutically effective after up to 2 years of treatment in 2,010 patients with probable AD. METHODS: The clinical course of AD patients treated with rivastigmine was compared with a prediction of their course derived by a baseline-dependent historical model of disease progression developed from data in untreated AD patients. Rivastigmine efficacy data came from four 6-month, placebo-controlled, randomized, controlled trials (RCTs) and two open-label extension studies. Cognitive performance was assessed by various clinician- and caregiver-rated measures. RESULTS: After 2 years on rivastigmine, there was less cognitive deterioration than in historical-control subjects. These effects of rivastigmine on cognitive performance were considered clinically meaningful relative to expected global decline. Treatment-emergent adverse events were the commonly-seen side effects of ChEIs and were similar in frequency to those seen in patients assigned to shorter-term rivastigmine therapy. CONCLUSION: Rivastigmine had a beneficial effect on cognitive performance for up to 2 years in patients with AD, versus no treatment or placebo treatment in historical-control subjects. Caregiver and clinician assessments indicated that the cognitive performance findings were of a magnitude relevant to global patient functioning. Rivastigmine remained safe over this 2-year treatment period.

The influence of anxiety and pain sensitivity on experimental pain in man.

A study was made of a number of factors that might be responsible for the unreliable results obtained in experimentally induced pain in man. In a randomised, double-blind, cross-over study on 32 healthy, male volunteers, the ischaemic pain test [14] and several psychological tests were performed. The influence of the following factors on the pain test results were examined: (a) ingestion of single, oral doses of 1000 mg aspirin (ASA) and placebo, (b) practice effect, (c) initial pain sensitivity, (d) anxiety, coping behaviour, attitude to the experiment and personality factors. The analgesic activity of ASA could not be demonstrated. An interaction between primary pain sensitivity and the sequence of drug administration was found. Furthermore, anxiety had a marked influence on the test results. Using experimental pain models reliable results are not to be expected as anxiety fluctuates intra- and interindividually in an unpredictable and uncontrollable manner.