Running head: ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
Attention Deficit Hyperactivity Disorder and its causal relationship with the SNAP 25 gene a
systematic review study.
By
Jacqulyne Taylor
BS, Concordia University, 2015
Thesis Submitted in Partial Fulfillment
Of the Requirements for the
Master's Degree in Public Health
Concordia University
June, 2015
1
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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Abstract
Over the past fifty years Attention-Deficit/Hyperactivity Disorder (ADHD) has been one
of the most studied childhood neurodevelopmental disorders. Attention-Deficit/Hyperactivity
Disorder (ADHD) is growing in numbers every year and can cause many debilitating issues. A
few of these symptoms are: having a hard time resisting temptation, having trouble taking turns,
and have difficulty getting along with others. To this day there is still not any concrete ways to
test for this condition other than subjective data. My research project delves into the possibility
that there is a relationship between the SNAP-25 gene mutation and AttentionDeficit/Hyperactivity Disorder (ADHD). The importance of this research project is that if
science can find a cause for this condition then tests can be developed to diagnose children at a
much earlier age. If a diagnosis can be made earlier, then non-pharmacological interventions can
be created to help aid in adaptation. The primary research question is whether there is an
association between the SNAP-25 gene. This study utilized a systematic review method to
compare relevant studies.
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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Table of Contents
Chapter
Page
1. Introduction
5
Statement of the Problem
5
Purpose and Significance of the Study
6
Research Questions and Associated Hypothesis
7
2. Literature Review
7
Search Strategy
7
Theoretical Foundation
8
Literature Review Related to Key Variables or Concepts
8
Conclusion
10
3. Methods
10
Methods
10
Inclusion and Exclusion criteria
11
Data Analysis Plan
12
4. Results
12
Data Collection
13
Results
15
5. Conclusions
16
Interpretation of the Findings
16
Limitations of the Study
17
Recommendations
18
Implications for Social Change
18
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
Conclusion
References
4
18
19
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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Introduction
Over the past fifty years there has been an increased interest in research into the
possibility of genetic causative factors in relation to Attention-Deficit/Hyperactivity Disorder
(ADHD). This continued interest has found some inconsistent findings in terms of what gene is
associated, but studies have indicated definitely that genetic influences play a part in the etiology
of ADHD. A study conducted looked into the genetic and environmental influence on the clinical
diagnosis of ADHD (Larson, Chang, D'Onofrio, & Lichtenstein, 2014). The study found that
ADHD had a high heritability with, and environmental effects were insignificant. Another study
also examined the possibility of genetics and ADHD (Asherson et al, 2004). This study found
that the SNAP-25 gene is associated with ADHD but the precise causal functional variant is still
undecided. The next puzzle is to figure out what specific genes are the cause.
Today’s society is plagued with a multitude of different psychiatric conditions, one of
them is Attention-Deficit/Hyperactivity Disorder (ADHD). ADHD was first described by Sir
George Still in 1902 (ADHD history, n.d.). The condition never really received any notice until
1997 when there was the first formal survey on ADHD diagnoses in the U.S. (Centers for
Disease Control and Prevention [CDC], 1997). This survey’s results showed a much larger
number than anticipated, thus research boomed. Since that year there has been a constant upward
trend with ADHD diagnoses (CDC, 2015). ADHD is a brain disorder found in childhood that
can persist into adolescence and adulthood. ADHD symptoms can include but are not limited to:
hyperactive behavior, difficult controlling impulses, having difficulty concentrating, and trouble
with peer relationships (Learning Disabilities, 2015). Another issue with ADHD is that often the
diagnosis is accompanied by other issues, such as oppositional defiant disorder (Learning
Disabilities, 2015). ADHD can have serious impacts on a child’s emotional and physical
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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wellbeing. Many times symptoms are present in young as infants. (National Institute of Mental
Health, 2012).The current estimate for today is around 11 percent of our children in the United
States have ADHD, and that is an alarming rate (CDC, 2015). If a particular cause of ADHD can
be nailed down, then a diagnosis can be made much earlier and intervention programs can be
formed.
A study conducted by Rasmussen and colleagues (2004) found that twins who had
inattentive and combined types of ADHD both had the same familial gene cluster, thus showing
a direct correlation in ADHD and heredity. Medical professionals do not always consider
heredity a cause of ADHD because no definitive genes have been labeled as such (Rasmussen,
Neuman, Heath, Levy, Hay, & Todd, 2004). To this date it is believed ADHD may have many
causes, but none have been solidified. In order to set up early best practice intervention programs
we need to have more concrete causes.
Purpose and Significance of the Study
The purpose of this systematic review is to take a closer look at the different studies on
familial causes for ADHD, specifically genomes. The systematic review will help to look for a
common trend in the studies completed to help add to the research on ADHD specific genes. The
studies out there have found some conflicting results and this would be a good way to look for a
trend. Studies have shown that children who are diagnosed early in their youth with ADHD learn
to cope more effectively with the symptoms (Voeller, 2004). When there is a way to clinically
diagnose a young child with ADHD, other than a rating scale, individualized programs can be
created to help today’s youth cope with this issue. ADHD is here to stay no matter what the
cause is and it is prudent for us to start looking into the exact cause in order to move forward.
The public health implications for early diagnosis and treatment are important. Childhood self-
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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esteem, productivity, and learning all would benefit with any new findings. Children with
undiagnosed ADHD often have low self-esteem due to always being in trouble and the outcast.
Children with low self-esteem do not focus on growth but just on not making mistakes (Simply
Psychology, 2012).
Research Questions and Associated Hypothesis
In regards to my research topic I have one main question:
Is the SNAP -25 gene associated with the etiology of Attention-Deficit/Hyperactivity Disorder
(ADHD)? My hope is that if a gene can be associated with a diagnosis then much earlier
detection can be made for this condition. Early detection would mean the creating of evidence
based programs to help facilitate the teaching of coping mechanisms with associated symptoms
and help reduce the use of medications.
Null hypothesis: There is not an association between SNAP 25 gene and ADHD.
Research hypothesis: There is an association between SNAP 25 gene and ADHD.
Background Literature Review
Search strategy
In terms of my search strategy my inclusion criteria included: Search Engines: Academic
Search Premier and CINAHL PLUS with TEXT. The search terms utilized were: ADHD and
Familial, ADHD studies, ADHD and causes, Molecular Psychiatry and ADHD, American
Journal of Pharmaco Genomics and ADHD. The exclusion criteria was: Non peer reviewed
articles, older than 1998, phenomenological studies, and non-relevant studies.
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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Theoretical Foundation
The Organizational Change Theory (OCT) theory is based on the processes and
strategies can help increase the chances that health programs and policies will be adapted
(Riverside, n.d.). The origin for this theory is hard to place but most likely is an adaptation from
Kirkpatrick’s ‘Four Levels of Learning Evaluation Model’ (Theories of Change, n.d.).
Organizational Change Theory has been utilized to help guide implementation in many different
health programs. If one major cause of ADHD can be proven to be inherited then early
intervention programs can be tailored to families who are expecting and have history with
ADHD. Many parents see the signs early on but ignore them and blame it on teachers, situations,
or others. According to a study, at least 40% of children who have ADHD showed symptoms
before the age of four; this shows that there is a lot of room for intervention programs to make a
difference (Krieger, 2012). The theoretical foundation works by laying out future goals then
working back to see what needs to happen in order for those goals to be met. Many studies have
adapted this model because of its easy to use step process in terms of results. The steps for this
theory are: awareness of the problem, decision to adopt the innovation, implementation, and then
making the implementation a part of the culture (University of Pennsylvania, n.d.). This theory is
a good fit because in terms of ADHD we need to work backwards in order to find a cause. Once
a cause is identified then earlier diagnosis and programs can be created and incorporated into
medical practice.
Literature Review Related to Key Variables or Concepts
Today’s society is plagued with a multitude of different psychiatric conditions,
one of them is Attention-Deficit/Hyperactivity Disorder (ADHD). ADHD can affect people at all
age ranges and can be mild to very debilitating. A few symptoms of ADHD are:
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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•daydream a lot;
•forget or lose things a lot;
•squirm or fidget;
•talk too much;
•make careless mistakes or take unnecessary risks;
•have a hard time resisting temptation; and
•have trouble taking turns (CDC, 2015).
According to the Centers for Disease Control and Prevention (CDC), 11 percent of children
under the age of 18 suffer from this condition and the number is growing. ADHD is one of the
most common neurodevelopmental disorders of childhood (CDC, 2015). Medical professionals
still do not consistently relate heredity to a concrete causes in terms of ADHD and primary
diagnostic tool is a questionnaire (Rasmussen, et al., 2004).
The studies completed on ADHD specific type of genomes to date, have some
inconsistent findings but all studies agree that some type of genome is the cause. This systematic
review will help to look for a common trend in the studies completed to solidify ADHD and
heredity genes/causes. To this date it is believed ADHD may have many causes, but none have
been solidified. In order to set up early best practice intervention programs we need to have
more concrete causes. One study looking into the SNAP-25 gene association with ADHD did not
find any concrete relationship between the two and felt further studies are warranted (Laurin,
Feng, Ickowicz, Pathare, Malone, Tannock, Schachar, Kennedy& Barr, 2007). Another study
conducted also looked into the relationship between the SNAP-25 gene and ADHD and found a
correlation, which shows the inconsistent results (Brophy, Hawi, Kirley, Fitzgerald & Gill,
2002).
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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This study examines the conflicting research on the SNAP-25 gene looking for any
positive or negative trends. The rationale for this study is that there is a desperate need for an
accurate earlier diagnosis of this condition so behavioral therapies and programs can be
implemented earlier in life. There has been many genes studied with this condition but the
SNAP-25 gene appears to be the most common theme with varying results.
Conclusion
As this condition and its association with gene mutation is a fairly new studied area the
literature review definitely shows the gaps for inconsistent findings. Hopefully a systematic
review can combine the relevant studies looking for that common thread. A commonly agreed
upon theme among medical professionals is that there is genetic cause, but the uncertainty is
which one. ADHD affect more and more children every day, and while stimulant medication is
the current go to treatment, medication does not teach coping skills and lifelong changes, this
comes from early intervention. Early identification and treatment need to occur such as blood
tests and pre-natal testing. If early treatment happens high probability child will not need
medication, or for only brief periods in their life. With early identification schools can also have
evidence based programs to help facilitate normal development.
Methods
I applied a systematic review design to explore the possible relationship between
Attention Deficit Hyperactive Disorder (ADHD) and the Synaptosomal-associated protein 25
(SNAP 25) gene. The systematic review supported me in addressing my research question on the
relationship between ADHD and the SNAP 25 gene. This design type combined sample sizes
and effects to help clarify the relationship to determine whether there is a correlation or not.
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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At the beginning of this year I searched for electronic articles and studies on Google
Scholar, PubMed, CINAHL Plus, and MEDLINE. The keywords used in the search included
ADHD and familial associations, genes, possible causes, and twins. I went through the reference
lists from the compiled articles to also help identify articles for inclusion. After excluding
articles that did not correspond with the criteria, the remaining articles were organized into a
chart.
I searched for original research articles that included gene association that focused on the
SNAP 25 gene. Studies that researched other gene associations were only included if they
contained the SNAP 25 gene in it.
Inclusion and Exclusion criteria
In this study the first priority was to include studies that scanned the gene association
with ADHD. The studies were also scanned to be primarily in English to assure material is not
lost in translation. The included studies must contain the SNAP 25 gene with no age restrictions
on its participants. All included studies were less than 15 years old to ensure relevant data are
used. For the inclusion and exclusion criteria and studies/articles screened please refer to Table 1
and Figure 1.
Table 1
Inclusion and Exclusion Criteria
Inclusion Criteria
-Published after year 2000
-Contained the SNAP 25
gene
-Peer reviewed articles
-ADHD causes
- Quantitative studies
Exclusion Criteria
-Older than year 2000.
-Does not study SNAP 25
gene
-None peer reviewed
- No ADHD causes
- Phenomenological studies
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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After using the inclusion and exclusion criteria, I determined there were three peer-reviewed
studies I would include in this systematic review. The number of findings is from the process of
elimination presented in figure 1.
Studies included
(28)
Studies excluded
(20)
Final
(3)
Figure 1: Results of Inclusion and Exclusion Criteria
Data analysis plan
I used a systematic review method to combine and analyze results from individual
studies. In this analysis I combined the effects from the included studies. The analysis included
sample sizes, and tests associated with genetic disease markers. A few of these tests are: the
extended transmission disequilibrium test (ETDT), and the haplotype-based haplotype relative
risk test (HHRR) (Mill, Richards, Knight, Curran, & Asherson, 2004).
Table 2
Effects and Exposures to be measured
Type of Variable
(Effect or
Exposure)
Description
Level of
Measurement
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
Effect- ETDT
screening study
Effect-HHRR
screening study
SNAP 25 allele mutation
Quantitative
SNAP 25 allele mutation
Quantitative
Results
Data Collection
A flow chart representing the sequence of the selection process of studies for this systematic
review are in Figure 1.
48 studies identified in the initial
survey
20 excluded
20 low quality studies
excluded
28 met inclusion criteria
3 with methodology score of 2
included in final analysis.
13
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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Figure 1: Process to select studies for inclusion in the systematic review.
The figure above represents the process results when completing the literature review.
There is the possibility for data discrepancies as the utilized studies did conduct different types
of genomic testing and different genetic markers.
Table 1
Characteristics of Included Studies
Study
(Authors
name)
Brophy et
al, 2002
Setting
Study
Design
n
Population
Interventio
n
Clinics and
Schools
Observatio
nal study
93
Ages 4-14
ethnically
Irish with
ADHD or
UADD
DNA
amplificati
on and
WenderUtah rating
scale for
parents
Barr et al,
2007
Toronto
based
Observatio
nal study
266
Primary
Outcomes
Score
Found
2
increased
preferential
transmissio
n of SNAP25/DdeI
allele to
ADHD
cases.
Nuclear
Transmissi No clear
2
families in on/disequili pattern of
the Toronto brium
transmissio
area
test (TDT) n of risk
analysis,
alleles
dependent
on the sex
of the
transmittin
g parent
was
observed
across the
markers
tested in
our sample
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
Nelson at
al, 2003
UCLA
School of
Medicine
Observatio
nal study
202
Families
with
children
who have
ADHD and
who does
not have
ADHD.
Genomic
DNA was
isolated
using the
Puregene
Kit and
Using the
transmissio
n
Disequilibr
ium test
(TDT).
15
We provide 2
additional
evidence of
linkage
disequilibri
um
of
haplotypes
in SNAP25 and
ADHD
with new
evidence
supporting
a paternal,
rather than
maternal,
haplotype
transmissio
n bias
Table 1 provides a short description of each study included in my systematic review.
Due to the wide variety of tools used to measure SNAP 25 allele relationship to ADHD, a
systematic review was an appropriate design for synthesizing and analyzing relevant literature
for the presence of relationships between the SNAP-25 gene allele and ADHD. The variables
analyzed included HHRR analysis of SNAP-25, HHRR analysis of parental transmission of
SNAP-25, TDT analysis of SNAP-25, and TDT analysis of parental transmission of SNAP-25.
Results
Data analysis included study sample size, outcome variables, and statistical significance
after analyzing the included studies in the systematic review. The reported outcome was there
SNAP 25 allele association with ADHD.
Table 2
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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Additional characteristics of studies to include statistical significance
Author
Score
Brophy et
al, 2002
2
Barr et al,
2007
Nelson at
2
2
Control (if
applicable)
DSM-IV
ADHD
criteria
n/a
n/a
al, 2003
Intervention Measures
Results
Interview,
Genotyping
P=0.671
IBD allele
sharing
between
affected sib
pairs.
Transmission P=0.05of the TC
maternal)
haplotype
P= 0.027paterna
Genotyping SNAP25
P=1.0
(MnlII)
SNAP25
P=0.004
(9806)
Genotyping Transmission P=0.011of the 30
paternal
UTR SNAP- P= 0.05 25
maternal
Stat.
Significant?
No
No
Yes
No
Yes
Yes
Yes
The study conducted by Brophy et al, 2002 concluded that there was found increased
preferential transmission of SNAP-25/DdeI allele to ADHD cases. The actual statistical results
do not show significance which is surprising. The second study by Barr et al, 2007 concluded
that there is a possible neurodevelopmental etiology responsible for ADHD, but feel it is
premature to state if there is preferential transmission. The third study conducted by Nelson et
al, 2003 found a statistical significance in “additional evidence of linkage disequilibrium of
haplotypes in SNAP-25 and ADHD with new evidence supporting a paternal, rather than
maternal, haplotype transmission bias”, pg. 312.
Conclusions
Interpretation of the Findings
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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This study was a systematic review on ADHD and its’ association with the SNAP-25
gene. Previous studies results are conflicting, thus I wanted to try and fill in those gaps. My
findings confirm that there is an association between the SNAP-25 gene and ADHD to include a
link with paternal transmission. The conceptual framework used in this study was Organizational
Change Theory (OCT) , this theory is often the basis of newly implemented testing or teaching
programs which would be a perfect fit for the SNAP-25 gene testing and program start-up. The
findings will be analyzed with the change theory’s foundation that it is more about the change
versus the new process.
Limitations of the Study
The first limitation of this study is the number of studies utilized for the systematic
review. There are not many published studies testing the allele of the SNAP-25 gene. This is a
limitation because the results are a small snapshot of the ADHD community. This also raises the
possible issue of publication bias. It’s possible that there have been studies that tested the SNAP25 gene, but were not published. All three studies utilized genome testing that was validated
through program such as Mathematica (Wolfram Research Inc., IL, and USA).
Another limitation is that the studies utilized did not all use the same testing on the allele.
This is a limitation because the results are a small snapshot of the ADHD community and may
not be entirely representative of all testing of ADHD and the SNAP-25 gene, which would
reduce the generalizability of my results. My conclusion definitely supports the need for more
research to be done. The only way to have avoided this limitation would have been to broaden
the research topic. The fact that there were three studies included may have had a small impact
on my results and conclusions.
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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Recommendations
ADHD is a growing concern every day and needs to be addressed with more passion. As
evidenced by this systematic review, there is a potential for a genetic cause of ADHD that is
linked with paternal transmission. Existing research is not robust enough to demonstrate a cause
an effect relationship, so further research is warranted. Some of these issues include: not enough
studies conducted on the association of the SNAP-25 gene and ADHD; the small sample sizes
used in research; and the future studies need to test the gene by replicating the research
techniques used.
I recommend further research be conducted on testing the allele of the SNAP-25 gene by
replicating the tests used in these studies such as haplotype-based haplotype relative risk
(HHRR) and transmission disequilibrium test (TDT) . There is a strong connection between
these studies, but the limitations of this study mean that further research is needed to validate
these findings.
Implications for Social Change
If researchers can find a definitive link between the SNAP-25 gene and ADHD this opens
a window for non-subjective tests to confirm a diagnosis. Once a test is created then this will
lead to age appropriate programs and interventions starting at birth to aid with this issue. ADHD
is a growing concern with over 6% of our kids with ADHD taking medication some as early as
four years of age (CDC, 2015). The current treatment recommendation for those under age five
is behavioral therapy and most do not receive it. (CDC, 2015).
Conclusion
ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)
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Like it or not ADHD is here to stay and is affecting around 11% of today’s youth (CDC,
2015). There is no single way to “test” a child for ADHD and a diagnosis depends on subjective
data. Children with ADHD have an uphill struggle most of their youth which can include:
difficulty with learning, making friends, controlling impulse, and hyperactivity (NIH, 2012). As
these children grow into teens and adults many are prone to depression, drug use, and suicide
(Voeller, 2004). The need is there to pursue a definitive cause so we can move forward helping
our children.
References
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Brophy, Hawi, Fitzgerald Gill, & Kirley. (2002). Synaptosomal-associated protein 25 (SNAP-
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association in the Irish population. Molecular Psychiatry, 7, 913–917.
Centers for Disease Control and Prevention. (March 18, 2015). ADHD Timeline, to include
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from: http://www.cdc.gov/ncbddd/adhd/data.html.
Center for Theory of Change. (n.d.). Theories of Change Origins. Retrieved from:
http://www.theoryofchange.org/what-is-theory-of-change/toc-background/toc-origins/
Kustanovich, V., Merriman, B., McGough, J., McCracken, J. T., Smalley, S. L., & Nelson, S. F.
(2003).Biased paternal transmission of SNAP-25 risk alleles in attention-deficit
hyperactivity disorder. Molecular Psychiatry, 8(3), 309
Krieger, K. (June 28, 2012). Is it ADHD or Typical Toddler Behavior? Ten Early Signs of ADHD
Risk in Preschool Age Children. Retrieved from:
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Larsson, H., Chang, Z., D'Onofrio, B. M., & Lichtenstein, P. (2014). The heritability of clinically
diagnosed attention deficit hyperactivity disorder across the lifespan. Psychological
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Laurin, N., Feng, Y., Ickowicz, A., Pathare, T., Malone, M., Tannock, R., & ... Barr, C. L.
(2007). No preferential transmission of paternal alleles at risk genes in attention-deficit
hyperactivity disorder. Molecular Psychiatry, 12(3), 226-229.
doi:10.1038/sj.mp.4001936
Learning Disabilities. (2015). Other Disorders That Sometimes Accompany ADHD. Retrieved
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from: http://www.ldonline.org/adhdbasics/other
Mill, J., Richards, S., Knight, J., Curran, S., Taylor, E., & Asherson, P. (2004). Haplotype
analysis of SNAP-25 suggests a role in the etiology of ADHD. Molecular Psychiatry,
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National Institute Health. (2012).What is attention deficit hyperactivity disorder? Retrieved
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Rasmussen, E., Neuman, R., Heath, A., Levy, F., Hay, D., & Todd, R. (2004). Familial
clustering of latent class and DSM-IV defined attention-deficit/hyperactivity disorder
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University of Pennsylvania. (n.d.). Stage Theory of Organizational Change. Retrieved from:
http://www.med.upenn.edu/hbhe4/part4-ch15-stage-theory-of-organizationalchange.shtml
Voeller, K. S. (2004). Attention-Deficit Hyperactivity Disorder (ADHD). Journal Of Child
Neurology, 19(10), 798-814.