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Trial registered on ANZCTR


Registration number
ACTRN12614000306617
Ethics application status
Approved
Date submitted
13/03/2014
Date registered
24/03/2014
Date last updated
1/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
The Dynamic Patterns of Thinking in Attention-Deficit/Hyperactivity Disorder (ADHD): Diagnostic accuracy of Euclidean, multifractal and lacunarity measures
Scientific title
In a group of Children with Attention-Deficit/Hyperactivity Disorder (ADHD) do Euclidean, multifractal and lacunarity measures have any diagnostic value to distinguish them from a control group (i.e., is the Receiver Operator Curve [ROC] area [AUC] > 0.5? )
Secondary ID [1] 284265 0
None
Universal Trial Number (UTN)
U1111-1146-3085
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Attention-Deficit/Hyperactivity Disorder (ADHD) 291392 0
Condition category
Condition code
Mental Health 291754 291754 0 0
Other mental health disorders
Public Health 291786 291786 0 0
Epidemiology

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Procedures:

The present study will be performed in two clinical interviews for each child.

Physical and neurological examinations (including handedness) and clinical
history will be obtained for each child in the first interview.

The child will be evaluated using the reference standard, i.e., Conners 3rd Edition(TM) and DSM-IV-TR diagnosis of ADHD. If as a result of the routinely assessment the child is diagnosed with ADHD combined type, he will be invited to voluntary participate in the study and have a second clinical interview to receive a detailed information and discuss the research.

After receiving a comprehensive description of the study, written informed ascent/consent will be obtained from the children and parents.

The child will be presented with a problem-solving task, i.e., the Battleship Game.
The inference problem-solving task is a standardised computer version of the battleship boardgame: Battleship 5.0, that has been developed for this research using Lazarus IDE 1.02 for the open source Pascal compiler, Free Pascal (FPC) 2.6.0 to be executed under Linux Slackware 14.0.
The full task includes eight individual games, each one defined by a standard template with the position of the ships.
Each participant will be seated (beside the interviewer), in front of a computer screen running the computer game Battleship 5.0.

Following the APA guidelines and prior to beginning each trial the interviewer will initialise the computer game session with a case identification number and the current date for each participant. Afterwards they will read a standardised version of the instructions and demonstrate to the children how to play the game. The child will be requested to verbalise the coordinated (letter-number) of his shots and simultaneously clicking the mouse pointer in
the correspondent position in the board game screen. The tasks will be preceded by a short practise trial with some general examples.
During the task completion the child will receive visual feedback (in the computer screen) about the number of shots already performed, time passed, and their ongoing performance (amount of sunk ships).
At the end of each game the child will be asked if he or she would like to play another game.
The total testing duration will be approximately 20-40 min; including one break after the fourth game.
After finishing the interview an archive file will be created for each participant containing the data coming from the computer game Battleship 5.0 .

A graph representing the inferential dynamics will be build using the (x,y) shots coordinates with GNUPLOT Version 4.4 patchlevel 3 and stored as a graphic file in PNG format. The graphic file is a binary image of 2048x2048 pixels, without borders with black background and the graph in white pixels.
A FORTRAN code developed for this research and compiled with gfortran under Linux Slackware-64, 14.0 will be used to calculate Euclidean and dynamics measures from (x,y) shots coordinates i.e., geometric distance between shots,
cumulative distance, instantaneous speed and average speed.
Multifractal, Lacunarity and Entropy measures are going to be calculated from the graphic PNG files using QM-2.01_alpha_2013_02_27 (Interactive Quantitative Morphology).
MF (Multifractal & Regression Java Tools) and FRACLAC V2.5wb126 for IMAGEJ 1.47m will be used to get alternative replicated measurements from the same graphic PNG files.
The Outcome Measures are: Total number of shots performed to solve the problem, their (x,y) coordinates and time between shots. A graph will be generated with the sequence of (x,y) coordinates of each shot fired to solve the problem; Multifractal and Lacunarity spectrum along with other geometrical measures (biomarkers) will be estimated from the resulting graph.
Intervention code [1] 288975 0
Diagnosis / Prognosis
Intervention code [2] 288999 0
Other interventions
Comparator / control treatment
The reference standard used for this study is a combination of methods to establish the presence of the target condition, i.e., Conners 3rd Edition(TM) and DSM-IV-TR diagnosis of ADHD.
Control group
Active

Outcomes
Primary outcome [1] 291690 0
The set of Cartesian coordinates (x,y) representing the shot sequence fired by each subject to solve the problem.
Including:
The total number of shots performed to solve the problem and the time between shots.
Timepoint [1] 291690 0
Immediately after completion of interview and problem-solving task by each participant
Primary outcome [2] 291714 0
Result of ADHD diagnostic coming from: Conners 3rd edition and DSM-IV-TR.
Timepoint [2] 291714 0
Immediately after completion of interview and problem-solving task by each participant
Primary outcome [3] 291715 0
A multivariate outcome vector composed of the geometric measures estimated from the graph of each game which include:
Multifractal spectrum of Generalised or Renyi dimensions for q integer values from 0 to10, including: Box-counting, nformation and Correlation dimensions.

Lacunarity spectrum for e integer values from 1 to10 and Entropy measures.

Geometrical and kinematic measures: i.e., geometric distance between shots, Cumulative distance, Instantaneous speed and Average speed.
Timepoint [3] 291715 0
Immediately after completion of interview and problem-solving task by each participant
Secondary outcome [1] 307291 0
The clinical history. including physical and neurological assessment and handedness.
Timepoint [1] 307291 0
Immediately after completion of interview and problem-solving task by each participant

Eligibility
Key inclusion criteria
Inclusion criteria for cases:

A full DSM-IV-TR diagnosis of ADHD combined type with associated impairment in at least two settings.

Conners’ Rating Scale (CPRS) hyperactivity rating greater than two s above age -and sex- specific means.

ADHD Patients totally drug-naive; that never used any psychoactive drug or received any psychoactive therapy.

Inclusion criteria for controls:

No DSM-IV-TR diagnosis of ADHD any type.

No Conners’ Parent Rating Scale (CPRS) hyperactivity rating greater than two s above age- and sex-specific means.
Minimum age
5 Years
Maximum age
12 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion criteria for cases:

Evidence of medical or neurological disorders, or any other Axis I psychiatric disorder.

Exclusion criteria for controls:

DSM-IV-TR diagnosis of ADHD any type.

Conners’ Parent Rating Scale (CPRS) hyperactivity rating greater than two s above age- and sex-specific means.

Evidence of medical or neurological disorders, or any other Axis I psychiatric disorder.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
This is an exploratory, prospective, phase (I) diagnostic of accuracy study with a case-control convenience sampling design; that consider statistic control (as co-variates) for the potential confounding factors: age, gender, instruction level and ethnicity (ethnicity will be collected using the NZ Census related question as a template). Measures of intelligence like IQ scores are not going to be included, due to the fact that strong logical, statistical and methodological arguments have been raised against this practise in studies of neurodevelopmental disorders, particularly in ADHD.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
31/03/2014
Actual
26/05/2014
Date of last participant enrolment
Anticipated
Actual
13/09/2017
Date of last data collection
Anticipated
Actual
13/09/2017
Sample size
Target
36
Accrual to date
Final
36
Recruitment outside Australia
Country [1] 5894 0
New Zealand
State/province [1] 5894 0
Nelson

Funding & Sponsors
Funding source category [1] 288890 0
Self funded/Unfunded
Name [1] 288890 0
Country [1] 288890 0
Primary sponsor type
Individual
Name
Fabian Labra-Sprohnle
Address
Dr Fabian Labra-Sprohnle
Paediatric Research Unit
Nelson Marlborough District Health Board
PO Box: 1144 Nelson 7040
Country
New Zealand
Secondary sponsor category [1] 287587 0
None
Name [1] 287587 0
Address [1] 287587 0
Country [1] 287587 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290719 0
The Central Health and Disability Ethics Committee
Ethics committee address [1] 290719 0
Health and Disability Ethics Committees
1 The Terrace
C/- MEDSAFE, Level 6, Deloitte House
10 Brandon Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 290719 0
New Zealand
Date submitted for ethics approval [1] 290719 0
Approval date [1] 290719 0
13/03/2014
Ethics approval number [1] 290719 0

Summary
Brief summary
Summary of proposed research

Attention-Deficit/Hyperactive Disorder (ADHD) is one of the most common childhood neurodevelopmental disorders. Despite this, no useful biomarker or “gold standard” diagnostic test exists. This research will test a new approach to identify biomarkers that may serve later research into diagnosis as well as in the therapy of ADHD. The proposed strategy is based on a diagrammatic representations of the dynamics of thought processes and its description by means of geometrical measures.

Hypothesis:

The dynamic patterns of thinking of children with ADHD are expected to be different when compared with their controls. It is postulated that some Euclidean and fractal descriptive measures (Cumulative distance, Generalized (Renyi) dimension and Lacunarity spectrum), have the ability to distinguish patients with ADHD from those without it, acting as diagnostic biomarkers.

Study Aims:

To describe the dynamic patterns of thinking of children with ADHD and their controls using standardised diagrams.

To estimate geometrical measures as biomarkers from the standardised diagrams.

To determine whether the geometrical measures (biomarkers) have any ability to distinguish patients with ADHD from those without ADHD.

To estimate the diagnostic accuracy of the geometrical measures (biomarkers) by evaluating sensitivity, specificity and the ROC curve area (AUC) (from traditional statistics classifiers and machine learning classifiers).

To adjust and optimise the problem-solving task, and the data collection for the following phase.

Designs and Methods:

This is an exploratory phase (I)study of diagnostic accuracy with a case-control design.

Inclusion criteria for cases:

A full DSM-IV-TR diagnosis of ADHD combined type with associated impairment in at least two settings.

Conners’ Rating Scale (CPRS) hyperactivity rating greater than two s above age -and sex- specific means.

ADHD Patients totally drug-naive; that have never used any psychoactive drug or received any psychoactive therapy.

Inclusion criteria for controls:

No DSM-IV-TR diagnosis of ADHD any type.

No Conners’ Parent Rating Scale (CPRS) hyperactivity rating greater than two s above age- and sex-specific means.

Exclusion criteria for cases:

Evidence of medical or neurological disorders, or any other Axis (I)psychiatric disorder.

Exclusion criteria for controls:

DSM-IV-TR diagnosis of ADHD any type.

Conners’ Parent Rating Scale (CPRS) hyperactivity rating greater than two s above age- and sex-specific means.

Evidence of medical or neurological disorders, or any other Axis (I) psychiatric disorder.

Procedures:

Each child will be interviewed, using the clinical method along with presenting them with a problem-solving task i.e, a computer version of the Battleship game developed for this research. A subsidiary routine of the same software will record the outcome measures from each game.

Outcome Measures:

Total number of shots performed to solve the problem, their (x,y) coordinates and time between shots. A graph will be generated with the sequence of (x,y) coordinates of each shot fired to solve the problem; Multifractal and Lacunarity spectrum along with other geometrical measures (biomarkers) will be estimated from the resulting graph.

Statistical Analysis:

Multilevel Logistic Regression and Machine Learning classification techniques. Sensitivity, Specificity and a Receiver Operating Characteristics (ROC) analysis.

Research Impact:

ADHD biomarkers could enable the early detection of ADHD, the monitoring of ongoing treatment, to make differential diagnosis, serve as a triage and to create a replacement test. From an epidemiological point of view, the most relevant use of ADHD biomarkers is the possibility to perform screening programs to estimate measures of the prevalence and incidence of ADHD.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 46946 0
Dr Fabian Labra-Sprohnle
Address 46946 0
Dr Fabian Labra-Sprohnle
Paediatric Research Unit
Nelson Marlborough District Health Board
PO Box: 1144 Nelson 7040
Country 46946 0
New Zealand
Phone 46946 0
Phone: (64)(3)5447866
Fax 46946 0
Email 46946 0
[email protected]
Contact person for public queries
Name 46947 0
Fabian Labra-Sprohnle
Address 46947 0
Dr Fabian Labra-Sprohnle
Paediatric Research Unit
Nelson Marlborough District Health Board
PO Box: 1144 Nelson 7040
Country 46947 0
New Zealand
Phone 46947 0
Phone: (64)(3)5447866
Fax 46947 0
Email 46947 0
[email protected]
Contact person for scientific queries
Name 46948 0
Fabian Labra-Sprohnle
Address 46948 0
Dr Fabian Labra-Sprohnle
Paediatric Research Unit
Nelson Marlborough District Health Board
PO Box: 1144 Nelson 7040
Country 46948 0
New Zealand
Phone 46948 0
Phone: (64)(3)5447866
Fax 46948 0
Email 46948 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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