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1.  Inborn errors in the metabolism of glutathione 
Glutathione is a tripeptide composed of glutamate, cysteine and glycine. Glutathione is present in millimolar concentrations in most mammalian cells and it is involved in several fundamental biological functions, including free radical scavenging, detoxification of xenobiotics and carcinogens, redox reactions, biosynthesis of DNA, proteins and leukotrienes, as well as neurotransmission/neuromodulation. Glutathione is metabolised via the gamma-glutamyl cycle, which is catalyzed by six enzymes. In man, hereditary deficiencies have been found in five of the six enzymes. Glutathione synthetase deficiency is the most frequently recognized disorder and, in its severe form, it is associated with hemolytic anemia, metabolic acidosis, 5-oxoprolinuria, central nervous system (CNS) damage and recurrent bacterial infections. Gamma-glutamylcysteine synthetase deficiency is also associated with hemolytic anemia, and some patients with this disorder show defects of neuromuscular function and generalized aminoaciduria. Gamma-glutamyl transpeptidase deficiency has been found in patients with CNS involvement and glutathionuria. 5-Oxoprolinase deficiency is associated with 5-oxoprolinuria but without a clear association with other symptoms. Dipeptidase deficiency has been described in one patient. All disorders are very rare and inherited in an autosomal recessive manner. Most of the mutations are leaky so that many patients have residual enzyme activity. Diagnosis is made by measuring the concentration of different metabolites in the gamma-glutamyl cycle, enzyme activity and in glutathione synthetase and gamma-glutamylcysteine synthetase deficiency, also by mutation analysis. Prenatal diagnosis has been preformed in glutathione synthetase deficiency. The prognosis is difficult to predict, as few patients are known, but seems to vary significantly between different patients. The aims of the treatment of glutathione synthesis defects are to avoid hemolytic crises and to increase the defense against reactive oxygen species. No treatment has been recommended for gamma-glutamyl transpeptidase, 5-oxoprolinase and dipeptidase deficiency.
doi:10.1186/1750-1172-2-16
PMCID: PMC1852094  PMID: 17397529
2.  Non-Specialist Psychosocial Interventions for Children and Adolescents with Intellectual Disability or Lower-Functioning Autism Spectrum Disorders: A Systematic Review 
PLoS Medicine  2013;10(12):e1001572.
In a systematic review, Brian Reichow and colleagues assess the evidence that non-specialist care providers in community settings can provide effective interventions for children and adolescents with intellectual disabilities or lower-functioning autism spectrum disorders.
Please see later in the article for the Editors' Summary
Background
The development of effective treatments for use by non-specialists is listed among the top research priorities for improving the lives of people with mental illness worldwide. The purpose of this review is to appraise which interventions for children with intellectual disabilities or lower-functioning autism spectrum disorders delivered by non-specialist care providers in community settings produce benefits when compared to either a no-treatment control group or treatment-as-usual comparator.
Methods and Findings
We systematically searched electronic databases through 24 June 2013 to locate prospective controlled studies of psychosocial interventions delivered by non-specialist providers to children with intellectual disabilities or lower-functioning autism spectrum disorders. We screened 234 full papers, of which 34 articles describing 29 studies involving 1,305 participants were included. A majority of the studies included children exclusively with a diagnosis of lower-functioning autism spectrum disorders (15 of 29, 52%). Fifteen of twenty-nine studies (52%) were randomized controlled trials and just under half of all effect sizes (29 of 59, 49%) were greater than 0.50, of which 18 (62%) were statistically significant. For behavior analytic interventions, the best outcomes were shown for development and daily skills; cognitive rehabilitation, training, and support interventions were found to be most effective for improving developmental outcomes, and parent training interventions to be most effective for improving developmental, behavioral, and family outcomes. We also conducted additional subgroup analyses using harvest plots. Limitations include the studies' potential for performance bias and that few were conducted in lower- and middle-income countries.
Conclusions
The findings of this review support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or lower-functioning autism spectrum disorders. Given the scarcity of specialists in many low-resource settings, including many lower- and middle-income countries, these findings may provide guidance for scale-up efforts for improving outcomes for children with developmental disorders or lower-functioning autism spectrum disorders.
Protocol Registration
PROSPERO CRD42012002641
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Newborn babies are helpless, but over the first few years of life, they acquire motor (movement) skills, language (communication) skills, cognitive (thinking) skills, and social (interpersonal interaction) skills. Individual aspects of these skills are usually acquired at specific ages, but children with a development disorder such as an autism spectrum disorder (ASD) or intellectual disability (mental retardation) fail to reach these “milestones” because of impaired or delayed brain maturation. Autism, Asperger syndrome, and other ASDs (also called pervasive developmental disorders) affect about 1% of the UK and US populations and are characterized by abnormalities in interactions and communication with other people (reciprocal socio-communicative interactions; for example, some children with autism reject physical affection and fail to develop useful speech) and a restricted, stereotyped, repetitive repertoire of interests (for example, obsessive accumulation of facts about unusual topics). About half of individuals with an ASD also have an intellectual disability—a reduced overall level of intelligence characterized by impairment of the skills that are normally acquired during early life. Such individuals have what is called lower-functioning ASD.
Why Was This Study Done?
Most of the children affected by developmental disorders live in low- and middle-income countries where there are few services available to help them achieve their full potential and where little research has been done to identify the most effective treatments. The development of effective treatments for use by non-specialists (for example, teachers and parents) is necessary to improve the lives of people with mental illnesses worldwide, but particularly in resource-limited settings where psychiatrists, psychologists, and other specialists are scarce. In this systematic review, the researchers investigated which psychosocial interventions for children and adolescents with intellectual disabilities or lower-functioning ASDs delivered by non-specialist providers in community settings produce improvements in development, daily skills, school performance, behavior, or family outcomes when compared to usual care (the control condition). A systematic review identifies all the research on a given topic using predefined criteria; psychosocial interventions are defined as therapy, education, training, or support aimed at improving behavior, overall development, or specific life skills without the use of drugs.
What Did the Researchers Do and Find?
The researchers identified 29 controlled studies (investigations with an intervention group and a control group) that examined the effects of various psychosocial interventions delivered by non-specialist providers to children (under 18 years old) who had a lower-functioning ASD or intellectual disability. The researchers retrieved information on the participants, design and methods, findings, and intervention characteristics for each study, and calculated effect sizes—a measure of the effectiveness of a test intervention relative to a control intervention—for several outcomes for each intervention. Across the studies, three-quarters of the effect size estimates were positive, and nearly half were greater than 0.50; effect sizes of less than 0.2, 0.2–0.5, and greater than 0.5 indicate that an intervention has no, a small, or a medium-to-large effect, respectively. For behavior analytic interventions (which aim to improve socially significant behavior by systematically analyzing behavior), the largest effect sizes were seen for development and daily skills. Cognitive rehabilitation, training, and support (interventions that facilitates the relearning of lost or altered cognitive skills) produced good improvements in developmental outcomes such as standardized IQ tests in children aged 6–11 years old. Finally, parental training interventions (which teach parents how to provide therapy services for their child) had strong effects on developmental, behavioral, and family outcomes.
What Do These Findings Mean?
Because few of the studies included in this systematic review were undertaken in low- and middle-income countries, the review's findings may not be generalizable to children living in resource-limited settings. Moreover, other characteristics of the included studies may limit the accuracy of these findings. Nevertheless, these findings support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or a lower-functioning ASD, and indicate which interventions are likely to produce the largest improvements in developmental, behavioral, and family outcomes. Further studies are needed, particularly in low- and middle-income countries, to confirm these findings, but given that specialists are scarce in many resource-limited settings, these findings may help to inform the implementation of programs to improve outcomes for children with intellectual disabilities or lower-functioning ASDs in low- and middle-income countries.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001572.
This study is further discussed in a PLOS Medicine Perspective by Bello-Mojeed and Bakare
The US Centers for Disease Control and Prevention provides information (in English and Spanish) on developmental disabilities, including autism spectrum disorders and intellectual disability
The US National Institute of Mental Health also provides detailed information about autism spectrum disorders, including the publication “A Parent's Guide to Autism Spectrum Disorder”
Autism Speaks, a US non-profit organization, provides information about all aspects of autism spectrum disorders and includes information on the Autism Speaks Global Autism Public Health Initiative
The National Autistic Society, a UK charity, provides information about all aspects of autism spectrum disorders and includes personal stories about living with these conditions
The UK National Health Service Choices website has an interactive guide to child development and information about autism and Asperger syndrome, including personal stories, and about learning disabilities
The UK National Institute for Health and Care Excellence provides clinical guidelines for the management and support of children with autism spectrum disorders
The World Health Organization provides information on its Mental Health Gap Action Programme (mhGAP), which includes recommendations on the management of developmental disorders by non-specialist providers; the mhGAP Evidence Resource Center provides evidence reviews for parent skills training for management of children with intellectual disabilities and pervasive developmental disorders and interventions for management of children with intellectual disabilities
PROSPERO, an international prospective register of systematic reviews, provides more information about this systematic review
doi:10.1371/journal.pmed.1001572
PMCID: PMC3866092  PMID: 24358029
3.  Efficacy of Folic Acid Supplementation in Autistic Children Participating in Structured Teaching: An Open-Label Trial 
Nutrients  2016;8(6):337.
Autism spectrum disorders (ASD) are recognized as a major public health issue. Here, we evaluated the effects of folic acid intervention on methylation cycles and oxidative stress in autistic children enrolled in structured teaching. Sixty-six autistic children enrolled in this open-label trial and participated in three months of structured teaching. Forty-four children were treated with 400 μg folic acid (two times/daily) for a period of three months during their structured teaching (intervention group), while the remaining 22 children were not given any supplement for the duration of the study (control group). The Autism Treatment Evaluation Checklist (ATEC) and Psychoeducational Profile-third edition (PEP-3) were measured at the beginning and end of the treatment period. Folic acid, homocysteine, and glutathione metabolism in plasma were measured before and after treatment in 29 autistic children randomly selected from the intervention group and were compared with 29 age-matched unaffected children (typical developmental group). The results illustrated folic acid intervention improved autism symptoms towards sociability, cognitive verbal/preverbal, receptive language, and affective expression and communication. Furthermore, this treatment also improved the concentrations of folic acid, homocysteine, and normalized glutathione redox metabolism. Folic acid supplementation may have a certain role in the treatment of children with autism.
doi:10.3390/nu8060337
PMCID: PMC4924178  PMID: 27338456
autism; folic acid intervention; structured teaching; homocysteine; glutathione redox status
4.  Glutathione Redox Control of Asthma: From Molecular Mechanisms to Therapeutic Opportunities 
Antioxidants & Redox Signaling  2012;17(2):375-408.
Abstract
Asthma is a chronic inflammatory disorder of the airways associated with airway hyper-responsiveness and airflow limitation in response to specific triggers. Whereas inflammation is important for tissue regeneration and wound healing, the profound and sustained inflammatory response associated with asthma may result in airway remodeling that involves smooth muscle hypertrophy, epithelial goblet-cell hyperplasia, and permanent deposition of airway extracellular matrix proteins. Although the specific mechanisms responsible for asthma are still being unraveled, free radicals such as reactive oxygen species and reactive nitrogen species are important mediators of airway tissue damage that are increased in subjects with asthma. There is also a growing body of literature implicating disturbances in oxidation/reduction (redox) reactions and impaired antioxidant defenses as a risk factor for asthma development and asthma severity. Ultimately, these redox-related perturbations result in a vicious cycle of airway inflammation and injury that is not always amenable to current asthma therapy, particularly in cases of severe asthma. This review will discuss disruptions of redox signaling and control in asthma with a focus on the thiol, glutathione, and reduced (thiol) form (GSH). First, GSH synthesis, GSH distribution, and GSH function and homeostasis are discussed. We then review the literature related to GSH redox balance in health and asthma, with an emphasis on human studies. Finally, therapeutic opportunities to restore the GSH redox balance in subjects with asthma are discussed. Antioxid. Redox Signal. 17, 375–408.
I. Introduction and Conceptual Framework
II. Glutathione Synthesis
III. Distribution of Glutathione in the Body
IV. Glutathione Function and Homeostasis
A. Glutathione as a cysteine reservoir
B. Xenobiotic conjugation and detoxification
C. Free radical scavenging
D. Maintenance of thiol equilibrium
E. Protein S-glutathionylation
F. Regulation of cell surface proteins
G. Protection against nitrosative stress from RNS
V. Glutathione Redox Balance in Health
A. Intracellular glutathione redox status
B. Plasma glutathione redox status
C. Epithelial lining fluid glutathione redox status
VI. Glutathione Redox Balance in Asthma
A. Airway glutathione concentrations in asthma, measured invasively
B. Airway glutathione concentrations in asthma, measured noninvasively
C. Systemic glutathione concentrations in asthma
D. Glutathione redox balance in asthma: Effect of corticosteroids
VII. Other Glutathione-Related Proteins and Redox Systems in Asthma
A. Glutathione peroxidases
B. Glutathione reductases
C. Glutathione-S-transferases
D. Nitrosoglutathione
E. Thioredoxins
F. Glutaredoxins
G. Peroxiredoxins
VIII. Physiological and Biological Implications of Altered Glutathione Redox Balance in Asthma
IX. Altered Glutathione Redox Balance in Asthma: Therapeutic Opportunities
A. Glutathione and glutathione-ethyl esters
B. Cysteine precursors
C. Dietary interventions
1. Selenium
2. Whey protein
3. Sulfur amino acids
4. B vitamins
5. Glutamine and glycine
X. Clinical Implications and Future Directions
doi:10.1089/ars.2011.4198
PMCID: PMC3353819  PMID: 22304503
5.  Effectiveness of Methylcobalamin and Folinic Acid Treatment on Adaptive Behavior in Children with Autistic Disorder Is Related to Glutathione Redox Status 
Autism Research and Treatment  2013;2013:609705.
Treatments targeting metabolic abnormalities in children with autism are limited. Previously we reported that a nutritional treatment significantly improved glutathione metabolism in children with autistic disorder. In this study we evaluated changes in adaptive behaviors in this cohort and determined whether such changes are related to changes in glutathione metabolism. Thirty-seven children diagnosed with autistic disorder and abnormal glutathione and methylation metabolism were treated with twice weekly 75 µg/Kg methylcobalamin and twice daily 400 µg folinic acid for 3 months in an open-label fashion. The Vineland Adaptive Behavior Scale (VABS) and glutathione redox metabolites were measured at baseline and at the end of the treatment period. Over the treatment period, all VABS subscales significantly improved with an average effect size of 0.59, and an average improvement in skills of 7.7 months. A greater improvement in glutathione redox status was associated with a greater improvement in expressive communication, personal and domestic daily living skills, and interpersonal, play-leisure, and coping social skills. Age, gender, and history of regression did not influence treatment response. The significant behavioral improvements observed and the relationship between these improvements to glutathione redox status suggest that nutritional interventions targeting redox metabolism may benefit some children with autism.
doi:10.1155/2013/609705
PMCID: PMC3810468  PMID: 24224089
6.  Behavioural and skill-based early interventions in children with autism spectrum disorders 
Introduction
Autism spectrum disorders (ASD) comprise typical or infantile autism (Kanner syndrome), Asperger’s disorder and atypical autism or pervasive developmental disorder - not otherwise specified. The syndrome is characterized by deficits in (1) verbal and nonverbal communication, (2) reciprocal social interaction and (3) repetitive patterns of behaviour, interests and activities.
Early behavioural interventions are based on learning theory and behaviour therapy. They take into account specific deficits in perception, emotional reactions, social interaction and communication. In Germany, these comprehensive models are not widely evaluated and implemented.
Research questions
What are the clinical effectiveness and safety of early behavioural or skills-based early interventions in autism compared to other interventions or to treatment as usual?What are specific factors responsible for the effectiveness?What are the cost-effectiveness and cost consequences of different early interventions in autism?Which legal, social and ethical aspects are relevant with regard to the implementation of the respective interventions in persons with autism?
Methods
Following a systematic review of the literature, controlled studies on early behavioural or skills-based interventions published since 2000 in English or German with children until the age of twelve are included and critically appraised. Studies must have at least ten participants per intervention group.
Results
In total, 15 publications based on 14 studies, eight systematic reviews and one health economic study are included. Most studies evaluate early interventions based upon the Lovaas model (Early intensive behavioural treatment (EIBT), Applied behavioural analysis (ABA)). Other evaluate pragmatic interventions or interventions based on other theoretical models like specific parent interventions, responsive education and prelinguistic milieu teaching, joint attention, symbolic play, and picture exchange communication system. Behaviour analytic interventions referring to the Lovaas model remain the most empirically evaluated early interventions in autism. Preschool children with autism can achieve improvements in cognitive and functional domains when treated within behavioural interventions with a frequency of at least 20 hours per week. It is not clear which is the minimum duration of effective interventions, and which active components are necessary for the effectiveness. There was no high quality evidence for other comprehensive early interventions. The identified health economic study is not suitable to evaluate the cost-effectiveness or cost consequences of early interventions. No publications concerning legal, ethical or social aspects were identified. The financial situation of persons with autisms and their families will be improved through the implementation of the “Pflege-Weiterententwicklungsgesetz” (Pf-WG). Further questions concern the organisation of care and the legal representation of autistic patients. Ethical questions arise mainly in the context of the equal supply of care to each individual patient in all regions of the country and the situation of the caregivers.
Discussion
There are only a few studies with high methodology evaluating early interventions in children with autism. Most studies have a short duration with a lack of blinded outcome assessment in many cases. The lack of high quality comparative studies does not allow answering questions of comparative effectiveness of early interventions in autism. It can be concluded that interventions referring to the Lovaas model seem to have the highest effectiveness. This seems to be especially true when they are run clinic-based. However, there was no solid evidence with regard to factors responsible for the effectiveness of programms according to the ABA model. With regard to communication improvement, a systematic parent training seems to be superior to treatment as usual where a mixture of therapeutic elements is used. As well for clinical and health economic studies there is a substantial problem of generalisability into the German context. The identified health economic study is not suitable to evaluate the cost-effectiveness or cost consequences of early interventions.
Conclusion
Based on the available studies, there is no sufficient evidence for any of the evaluated behavioural early intervention programmes. Studies suggest that preschool children with autism in behavioural intervention programmes with a frequency of at least 20 hours per week can achieve improvements in cognitive and functional domains. There is no evidence that in a substantial portion of the children a normal development can be achieved by early interventions. Most research evidence is available for ABA. A minimal necessary intensity of interventions to achieve positive outcomes cannot be derived from literature. There are no valid statements possible as to cost-effectiveness or consequences of these interventions. Effective early interventions may reduce total autism costs in the long run. This may be achieved when the initial high treatment expenditures are more than compensated later if persons with this disorder have better social functioning.
doi:10.3205/hta000072
PMCID: PMC3011283  PMID: 21289897
7.  Novel metabolic biomarkers related to sulfur-dependent detoxification pathways in autistic patients of Saudi Arabia 
BMC Neurology  2011;11:139.
Background
Xenobiotics are neurotoxins that dramatically alter the health of the child. In addition, an inefficient detoxification system leads to oxidative stress, gut dysbiosis, and immune dysfunction. The consensus among physicians who treat autism with a biomedical approach is that those on the spectrum are burdened with oxidative stress and immune problems. In a trial to understand the role of detoxification in the etiology of autism, selected parameters related to sulfur-dependent detoxification mechanisms in plasma of autistic children from Saudi Arabia will be investigated compared to control subjects.
Methods
20 males autistic children aged 3-15 years and 20 age and gender matching healthy children as control group were included in this study. Levels of reduced glutathione (GSH), total (GSH+GSSG), glutathione status (GSH/GSSG), glutathione reductase (GR), glutathione- s-transferase (GST), thioredoxin (Trx), thioredoxin reductase (TrxR) and peroxidoxins (Prxs I and III) were determined.
Results
Reduced glutathione, total glutathione, GSH/GSSG and activity levels of GST were significantly lower, GR shows non-significant differences, while, Trx, TrxR and both Prx I and III recorded a remarkably higher values in autistics compared to control subjects.
Conclusion
The impaired glutathione status together with the elevated Trx and TrxR and the remarkable over expression of both Prx I and Prx III, could be used as diagnostic biomarkers of autism.
doi:10.1186/1471-2377-11-139
PMCID: PMC3217885  PMID: 22051046
8.  Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity 
Background
The relationship between relative metabolic disturbances and developmental disorders is an emerging research focus. This study compares the nutritional and metabolic status of children with autism with that of neurotypical children and investigates the possible association of autism severity with biomarkers.
Method
Participants were children ages 5-16 years in Arizona with Autistic Spectrum Disorder (n = 55) compared with non-sibling, neurotypical controls (n = 44) of similar age, gender and geographical distribution. Neither group had taken any vitamin/mineral supplements in the two months prior to sample collection. Autism severity was assessed using the Pervasive Development Disorder Behavior Inventory (PDD-BI), Autism Treatment Evaluation Checklist (ATEC), and Severity of Autism Scale (SAS). Study measurements included: vitamins, biomarkers of vitamin status, minerals, plasma amino acids, plasma glutathione, and biomarkers of oxidative stress, methylation, sulfation and energy production.
Results
Biomarkers of children with autism compared to those of controls using a t-test or Wilcoxon test found the following statistically significant differences (p < 0.001): Low levels of biotin, plasma glutathione, RBC SAM, plasma uridine, plasma ATP, RBC NADH, RBC NADPH, plasma sulfate (free and total), and plasma tryptophan; also high levels of oxidative stress markers and plasma glutamate. Levels of biomarkers for the neurotypical controls were in good agreement with accessed published reference ranges. In the Autism group, mean levels of vitamins, minerals, and most amino acids commonly measured in clinical care were within published reference ranges.
A stepwise, multiple linear regression analysis demonstrated significant associations between several groups of biomarkers with all three autism severity scales, including vitamins (adjusted R2 of 0.25-0.57), minerals (adj. R2 of 0.22-0.38), and plasma amino acids (adj. R2 of 0.22-0.39).
Conclusion
The autism group had many statistically significant differences in their nutritional and metabolic status, including biomarkers indicative of vitamin insufficiency, increased oxidative stress, reduced capacity for energy transport, sulfation and detoxification. Several of the biomarker groups were significantly associated with variations in the severity of autism. These nutritional and metabolic differences are generally in agreement with other published results and are likely amenable to nutritional supplementation. Research investigating treatment and its relationship to the co-morbidities and etiology of autism is warranted.
doi:10.1186/1743-7075-8-34
PMCID: PMC3135510  PMID: 21651783
9.  Human genome meeting 2016 
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Human Genomics  2016;10(Suppl 1):12.
Table of contents
O1 The metabolomics approach to autism: identification of biomarkers for early detection of autism spectrum disorder
A. K. Srivastava, Y. Wang, R. Huang, C. Skinner, T. Thompson, L. Pollard, T. Wood, F. Luo, R. Stevenson
O2 Phenome-wide association study for smoking- and drinking-associated genes in 26,394 American women with African, Asian, European, and Hispanic descents
R. Polimanti, J. Gelernter
O3 Effects of prenatal environment, genotype and DNA methylation on birth weight and subsequent postnatal outcomes: findings from GUSTO, an Asian birth cohort
X. Lin, I. Y. Lim, Y. Wu, A. L. Teh, L. Chen, I. M. Aris, S. E. Soh, M. T. Tint, J. L. MacIsaac, F. Yap, K. Kwek, S. M. Saw, M. S. Kobor, M. J. Meaney, K. M. Godfrey, Y. S. Chong, J. D. Holbrook, Y. S. Lee, P. D. Gluckman, N. Karnani, GUSTO study group
O4 High-throughput identification of specific qt interval modulating enhancers at the SCN5A locus
A. Kapoor, D. Lee, A. Chakravarti
O5 Identification of extracellular matrix components inducing cancer cell migration in the supernatant of cultivated mesenchymal stem cells
C. Maercker, F. Graf, M. Boutros
O6 Single cell allele specific expression (ASE) IN T21 and common trisomies: a novel approach to understand DOWN syndrome and other aneuploidies
G. Stamoulis, F. Santoni, P. Makrythanasis, A. Letourneau, M. Guipponi, N. Panousis, M. Garieri, P. Ribaux, E. Falconnet, C. Borel, S. E. Antonarakis
O7 Role of microRNA in LCL to IPSC reprogramming
S. Kumar, J. Curran, J. Blangero
O8 Multiple enhancer variants disrupt gene regulatory network in Hirschsprung disease
S. Chatterjee, A. Kapoor, J. Akiyama, D. Auer, C. Berrios, L. Pennacchio, A. Chakravarti
O9 Metabolomic profiling for the diagnosis of neurometabolic disorders
T. R. Donti, G. Cappuccio, M. Miller, P. Atwal, A. Kennedy, A. Cardon, C. Bacino, L. Emrick, J. Hertecant, F. Baumer, B. Porter, M. Bainbridge, P. Bonnen, B. Graham, R. Sutton, Q. Sun, S. Elsea
O10 A novel causal methylation network approach to Alzheimer’s disease
Z. Hu, P. Wang, Y. Zhu, J. Zhao, M. Xiong, David A Bennett
O11 A microRNA signature identifies subtypes of triple-negative breast cancer and reveals MIR-342-3P as regulator of a lactate metabolic pathway
A. Hidalgo-Miranda, S. Romero-Cordoba, S. Rodriguez-Cuevas, R. Rebollar-Vega, E. Tagliabue, M. Iorio, E. D’Ippolito, S. Baroni
O12 Transcriptome analysis identifies genes, enhancer RNAs and repetitive elements that are recurrently deregulated across multiple cancer types
B. Kaczkowski, Y. Tanaka, H. Kawaji, A. Sandelin, R. Andersson, M. Itoh, T. Lassmann, the FANTOM5 consortium, Y. Hayashizaki, P. Carninci, A. R. R. Forrest
O13 Elevated mutation and widespread loss of constraint at regulatory and architectural binding sites across 11 tumour types
C. A. Semple
O14 Exome sequencing provides evidence of pathogenicity for genes implicated in colorectal cancer
E. A. Rosenthal, B. Shirts, L. Amendola, C. Gallego, M. Horike-Pyne, A. Burt, P. Robertson, P. Beyers, C. Nefcy, D. Veenstra, F. Hisama, R. Bennett, M. Dorschner, D. Nickerson, J. Smith, K. Patterson, D. Crosslin, R. Nassir, N. Zubair, T. Harrison, U. Peters, G. Jarvik, NHLBI GO Exome Sequencing Project
O15 The tandem duplicator phenotype as a distinct genomic configuration in cancer
F. Menghi, K. Inaki, X. Woo, P. Kumar, K. Grzeda, A. Malhotra, H. Kim, D. Ucar, P. Shreckengast, K. Karuturi, J. Keck, J. Chuang, E. T. Liu
O16 Modeling genetic interactions associated with molecular subtypes of breast cancer
B. Ji, A. Tyler, G. Ananda, G. Carter
O17 Recurrent somatic mutation in the MYC associated factor X in brain tumors
H. Nikbakht, M. Montagne, M. Zeinieh, A. Harutyunyan, M. Mcconechy, N. Jabado, P. Lavigne, J. Majewski
O18 Predictive biomarkers to metastatic pancreatic cancer treatment
J. B. Goldstein, M. Overman, G. Varadhachary, R. Shroff, R. Wolff, M. Javle, A. Futreal, D. Fogelman
O19 DDIT4 gene expression as a prognostic marker in several malignant tumors
L. Bravo, W. Fajardo, H. Gomez, C. Castaneda, C. Rolfo, J. A. Pinto
O20 Spatial organization of the genome and genomic alterations in human cancers
K. C. Akdemir, L. Chin, A. Futreal, ICGC PCAWG Structural Alterations Group
O21 Landscape of targeted therapies in solid tumors
S. Patterson, C. Statz, S. Mockus
O22 Genomic analysis reveals novel drivers and progression pathways in skin basal cell carcinoma
S. N. Nikolaev, X. I. Bonilla, L. Parmentier, B. King, F. Bezrukov, G. Kaya, V. Zoete, V. Seplyarskiy, H. Sharpe, T. McKee, A. Letourneau, P. Ribaux, K. Popadin, N. Basset-Seguin, R. Ben Chaabene, F. Santoni, M. Andrianova, M. Guipponi, M. Garieri, C. Verdan, K. Grosdemange, O. Sumara, M. Eilers, I. Aifantis, O. Michielin, F. de Sauvage, S. Antonarakis
O23 Identification of differential biomarkers of hepatocellular carcinoma and cholangiocarcinoma via transcriptome microarray meta-analysis
S. Likhitrattanapisal
O24 Clinical validity and actionability of multigene tests for hereditary cancers in a large multi-center study
S. Lincoln, A. Kurian, A. Desmond, S. Yang, Y. Kobayashi, J. Ford, L. Ellisen
O25 Correlation with tumor ploidy status is essential for correct determination of genome-wide copy number changes by SNP array
T. L. Peters, K. R. Alvarez, E. F. Hollingsworth, D. H. Lopez-Terrada
O26 Nanochannel based next-generation mapping for interrogation of clinically relevant structural variation
A. Hastie, Z. Dzakula, A. W. Pang, E. T. Lam, T. Anantharaman, M. Saghbini, H. Cao, BioNano Genomics
O27 Mutation spectrum in a pulmonary arterial hypertension (PAH) cohort and identification of associated truncating mutations in TBX4
C. Gonzaga-Jauregui, L. Ma, A. King, E. Berman Rosenzweig, U. Krishnan, J. G. Reid, J. D. Overton, F. Dewey, W. K. Chung
O28 NORTH CAROLINA macular dystrophy (MCDR1): mutations found affecting PRDM13
K. Small, A. DeLuca, F. Cremers, R. A. Lewis, V. Puech, B. Bakall, R. Silva-Garcia, K. Rohrschneider, M. Leys, F. S. Shaya, E. Stone
O29 PhenoDB and genematcher, solving unsolved whole exome sequencing data
N. L. Sobreira, F. Schiettecatte, H. Ling, E. Pugh, D. Witmer, K. Hetrick, P. Zhang, K. Doheny, D. Valle, A. Hamosh
O30 Baylor-Johns Hopkins Center for Mendelian genomics: a four year review
S. N. Jhangiani, Z. Coban Akdemir, M. N. Bainbridge, W. Charng, W. Wiszniewski, T. Gambin, E. Karaca, Y. Bayram, M. K. Eldomery, J. Posey, H. Doddapaneni, J. Hu, V. R. Sutton, D. M. Muzny, E. A. Boerwinkle, D. Valle, J. R. Lupski, R. A. Gibbs
O31 Using read overlap assembly to accurately identify structural genetic differences in an ashkenazi jewish trio
S. Shekar, W. Salerno, A. English, A. Mangubat, J. Bruestle
O32 Legal interoperability: a sine qua non for international data sharing
A. Thorogood, B. M. Knoppers, Global Alliance for Genomics and Health - Regulatory and Ethics Working Group
O33 High throughput screening platform of competent sineups: that can enhance translation activities of therapeutic target
H. Takahashi, K. R. Nitta, A. Kozhuharova, A. M. Suzuki, H. Sharma, D. Cotella, C. Santoro, S. Zucchelli, S. Gustincich, P. Carninci
O34 The undiagnosed diseases network international (UDNI): clinical and laboratory research to meet patient needs
J. J. Mulvihill, G. Baynam, W. Gahl, S. C. Groft, K. Kosaki, P. Lasko, B. Melegh, D. Taruscio
O36 Performance of computational algorithms in pathogenicity predictions for activating variants in oncogenes versus loss of function mutations in tumor suppressor genes
R. Ghosh, S. Plon
O37 Identification and electronic health record incorporation of clinically actionable pharmacogenomic variants using prospective targeted sequencing
S. Scherer, X. Qin, R. Sanghvi, K. Walker, T. Chiang, D. Muzny, L. Wang, J. Black, E. Boerwinkle, R. Weinshilboum, R. Gibbs
O38 Melanoma reprogramming state correlates with response to CTLA-4 blockade in metastatic melanoma
T. Karpinets, T. Calderone, K. Wani, X. Yu, C. Creasy, C. Haymaker, M. Forget, V. Nanda, J. Roszik, J. Wargo, L. Haydu, X. Song, A. Lazar, J. Gershenwald, M. Davies, C. Bernatchez, J. Zhang, A. Futreal, S. Woodman
O39 Data-driven refinement of complex disease classification from integration of heterogeneous functional genomics data in GeneWeaver
E. J. Chesler, T. Reynolds, J. A. Bubier, C. Phillips, M. A. Langston, E. J. Baker
O40 A general statistic framework for genome-based disease risk prediction
M. Xiong, L. Ma, N. Lin, C. Amos
O41 Integrative large-scale causal network analysis of imaging and genomic data and its application in schizophrenia studies
N. Lin, P. Wang, Y. Zhu, J. Zhao, V. Calhoun, M. Xiong
O42 Big data and NGS data analysis: the cloud to the rescue
O. Dobretsberger, M. Egger, F. Leimgruber
O43 Cpipe: a convergent clinical exome pipeline specialised for targeted sequencing
S. Sadedin, A. Oshlack, Melbourne Genomics Health Alliance
O44 A Bayesian classification of biomedical images using feature extraction from deep neural networks implemented on lung cancer data
V. A. A. Antonio, N. Ono, Clark Kendrick C. Go
O45 MAV-SEQ: an interactive platform for the Management, Analysis, and Visualization of sequence data
Z. Ahmed, M. Bolisetty, S. Zeeshan, E. Anguiano, D. Ucar
O47 Allele specific enhancer in EPAS1 intronic regions may contribute to high altitude adaptation of Tibetans
C. Zeng, J. Shao
O48 Nanochannel based next-generation mapping for structural variation detection and comparison in trios and populations
H. Cao, A. Hastie, A. W. Pang, E. T. Lam, T. Liang, K. Pham, M. Saghbini, Z. Dzakula
O49 Archaic introgression in indigenous populations of Malaysia revealed by whole genome sequencing
Y. Chee-Wei, L. Dongsheng, W. Lai-Ping, D. Lian, R. O. Twee Hee, Y. Yunus, F. Aghakhanian, S. S. Mokhtar, C. V. Lok-Yung, J. Bhak, M. Phipps, X. Shuhua, T. Yik-Ying, V. Kumar, H. Boon-Peng
O50 Breast and ovarian cancer prevention: is it time for population-based mutation screening of high risk genes?
I. Campbell, M.-A. Young, P. James, Lifepool
O53 Comprehensive coverage from low DNA input using novel NGS library preparation methods for WGS and WGBS
C. Schumacher, S. Sandhu, T. Harkins, V. Makarov
O54 Methods for large scale construction of robust PCR-free libraries for sequencing on Illumina HiSeqX platform
H. DoddapaneniR. Glenn, Z. Momin, B. Dilrukshi, H. Chao, Q. Meng, B. Gudenkauf, R. Kshitij, J. Jayaseelan, C. Nessner, S. Lee, K. Blankenberg, L. Lewis, J. Hu, Y. Han, H. Dinh, S. Jireh, K. Walker, E. Boerwinkle, D. Muzny, R. Gibbs
O55 Rapid capture methods for clinical sequencing
J. Hu, K. Walker, C. Buhay, X. Liu, Q. Wang, R. Sanghvi, H. Doddapaneni, Y. Ding, N. Veeraraghavan, Y. Yang, E. Boerwinkle, A. L. Beaudet, C. M. Eng, D. M. Muzny, R. A. Gibbs
O56 A diploid personal human genome model for better genomes from diverse sequence data
K. C. C. Worley, Y. Liu, D. S. T. Hughes, S. C. Murali, R. A. Harris, A. C. English, X. Qin, O. A. Hampton, P. Larsen, C. Beck, Y. Han, M. Wang, H. Doddapaneni, C. L. Kovar, W. J. Salerno, A. Yoder, S. Richards, J. Rogers, J. R. Lupski, D. M. Muzny, R. A. Gibbs
O57 Development of PacBio long range capture for detection of pathogenic structural variants
Q. Meng, M. Bainbridge, M. Wang, H. Doddapaneni, Y. Han, D. Muzny, R. Gibbs
O58 Rhesus macaques exhibit more non-synonymous variation but greater impact of purifying selection than humans
R. A. Harris, M. Raveenedran, C. Xue, M. Dahdouli, L. Cox, G. Fan, B. Ferguson, J. Hovarth, Z. Johnson, S. Kanthaswamy, M. Kubisch, M. Platt, D. Smith, E. Vallender, R. Wiseman, X. Liu, J. Below, D. Muzny, R. Gibbs, F. Yu, J. Rogers
O59 Assessing RNA structure disruption induced by single-nucleotide variation
J. Lin, Y. Zhang, Z. Ouyang
P1 A meta-analysis of genome-wide association studies of mitochondrial dna copy number
A. Moore, Z. Wang, J. Hofmann, M. Purdue, R. Stolzenberg-Solomon, S. Weinstein, D. Albanes, C.-S. Liu, W.-L. Cheng, T.-T. Lin, Q. Lan, N. Rothman, S. Berndt
P2 Missense polymorphic genetic combinations underlying down syndrome susceptibility
E. S. Chen
P4 The evaluation of alteration of ELAM-1 expression in the endometriosis patients
H. Bahrami, A. Khoshzaban, S. Heidari Keshal
P5 Obesity and the incidence of apolipoprotein E polymorphisms in an assorted population from Saudi Arabia population
K. K. R. Alharbi
P6 Genome-associated personalized antithrombotical therapy for patients with high risk of thrombosis and bleeding
M. Zhalbinova, A. Akilzhanova, S. Rakhimova, M. Bekbosynova, S. Myrzakhmetova
P7 Frequency of Xmn1 polymorphism among sickle cell carrier cases in UAE population
M. Matar
P8 Differentiating inflammatory bowel diseases by using genomic data: dimension of the problem and network organization
N. Mili, R. Molinari, Y. Ma, S. Guerrier
P9 Vulnerability of genetic variants to the risk of autism among Saudi children
N. Elhawary, M. Tayeb, N. Bogari, N. Qotb
P10 Chromatin profiles from ex vivo purified dopaminergic neurons establish a promising model to support studies of neurological function and dysfunction
S. A. McClymont, P. W. Hook, L. A. Goff, A. McCallion
P11 Utilization of a sensitized chemical mutagenesis screen to identify genetic modifiers of retinal dysplasia in homozygous Nr2e3rd7 mice
Y. Kong, J. R. Charette, W. L. Hicks, J. K. Naggert, L. Zhao, P. M. Nishina
P12 Ion torrent next generation sequencing of recessive polycystic kidney disease in Saudi patients
B. M. Edrees, M. Athar, F. A. Al-Allaf, M. M. Taher, W. Khan, A. Bouazzaoui, N. A. Harbi, R. Safar, H. Al-Edressi, A. Anazi, N. Altayeb, M. A. Ahmed, K. Alansary, Z. Abduljaleel
P13 Digital expression profiling of Purkinje neurons and dendrites in different subcellular compartments
A. Kratz, P. Beguin, S. Poulain, M. Kaneko, C. Takahiko, A. Matsunaga, S. Kato, A. M. Suzuki, N. Bertin, T. Lassmann, R. Vigot, P. Carninci, C. Plessy, T. Launey
P14 The evolution of imperfection and imperfection of evolution: the functional and functionless fractions of the human genome
D. Graur
P16 Species-independent identification of known and novel recurrent genomic entities in multiple cancer patients
J. Friis-Nielsen, J. M. Izarzugaza, S. Brunak
P18 Discovery of active gene modules which are densely conserved across multiple cancer types reveal their prognostic power and mutually exclusive mutation patterns
B. S. Soibam
P19 Whole exome sequencing of dysplastic leukoplakia tissue indicates sequential accumulation of somatic mutations from oral precancer to cancer
D. Das, N. Biswas, S. Das, S. Sarkar, A. Maitra, C. Panda, P. Majumder
P21 Epigenetic mechanisms of carcinogensis by hereditary breast cancer genes
J. J. Gruber, N. Jaeger, M. Snyder
P22 RNA direct: a novel RNA enrichment strategy applied to transcripts associated with solid tumors
K. Patel, S. Bowman, T. Davis, D. Kraushaar, A. Emerman, S. Russello, N. Henig, C. Hendrickson
P23 RNA sequencing identifies gene mutations for neuroblastoma
K. Zhang
P24 Participation of SFRP1 in the modulation of TMPRSS2-ERG fusion gene in prostate cancer cell lines
M. Rodriguez-Dorantes, C. D. Cruz-Hernandez, C. D. P. Garcia-Tobilla, S. Solorzano-Rosales
P25 Targeted Methylation Sequencing of Prostate Cancer
N. Jäger, J. Chen, R. Haile, M. Hitchins, J. D. Brooks, M. Snyder
P26 Mutant TPMT alleles in children with acute lymphoblastic leukemia from México City and Yucatán, Mexico
S. Jiménez-Morales, M. Ramírez, J. Nuñez, V. Bekker, Y. Leal, E. Jiménez, A. Medina, A. Hidalgo, J. Mejía
P28 Genetic modifiers of Alström syndrome
J. Naggert, G. B. Collin, K. DeMauro, R. Hanusek, P. M. Nishina
P31 Association of genomic variants with the occurrence of angiotensin-converting-enzyme inhibitor (ACEI)-induced coughing among Filipinos
E. M. Cutiongco De La Paz, R. Sy, J. Nevado, P. Reganit, L. Santos, J. D. Magno, F. E. Punzalan , D. Ona , E. Llanes, R. L. Santos-Cortes , R. Tiongco, J. Aherrera, L. Abrahan, P. Pagauitan-Alan; Philippine Cardiogenomics Study Group
P32 The use of “humanized” mouse models to validate disease association of a de novo GARS variant and to test a novel gene therapy strategy for Charcot-Marie-Tooth disease type 2D
K. H. Morelli, J. S. Domire, N. Pyne, S. Harper, R. Burgess
P34 Molecular regulation of chondrogenic human induced pluripotent stem cells
M. A. Gari, A. Dallol, H. Alsehli, A. Gari, M. Gari, A. Abuzenadah
P35 Molecular profiling of hematologic malignancies: implementation of a variant assessment algorithm for next generation sequencing data analysis and clinical reporting
M. Thomas, M. Sukhai, S. Garg, M. Misyura, T. Zhang, A. Schuh, T. Stockley, S. Kamel-Reid
P36 Accessing genomic evidence for clinical variants at NCBI
S. Sherry, C. Xiao, D. Slotta, K. Rodarmer, M. Feolo, M. Kimelman, G. Godynskiy, C. O’Sullivan, E. Yaschenko
P37 NGS-SWIFT: a cloud-based variant analysis framework using control-accessed sequencing data from DBGAP/SRA
C. Xiao, E. Yaschenko, S. Sherry
P38 Computational assessment of drug induced hepatotoxicity through gene expression profiling
C. Rangel-Escareño, H. Rueda-Zarate
P40 Flowr: robust and efficient pipelines using a simple language-agnostic approach;ultraseq; fast modular pipeline for somatic variation calling using flowr
S. Seth, S. Amin, X. Song, X. Mao, H. Sun, R. G. Verhaak, A. Futreal, J. Zhang
P41 Applying “Big data” technologies to the rapid analysis of heterogenous large cohort data
S. J. Whiite, T. Chiang, A. English, J. Farek, Z. Kahn, W. Salerno, N. Veeraraghavan, E. Boerwinkle, R. Gibbs
P42 FANTOM5 web resource for the large-scale genome-wide transcription start site activity profiles of wide-range of mammalian cells
T. Kasukawa, M. Lizio, J. Harshbarger, S. Hisashi, J. Severin, A. Imad, S. Sahin, T. C. Freeman, K. Baillie, A. Sandelin, P. Carninci, A. R. R. Forrest, H. Kawaji, The FANTOM Consortium
P43 Rapid and scalable typing of structural variants for disease cohorts
W. Salerno, A. English, S. N. Shekar, A. Mangubat, J. Bruestle, E. Boerwinkle, R. A. Gibbs
P44 Polymorphism of glutathione S-transferases and sulphotransferases genes in an Arab population
A. H. Salem, M. Ali, A. Ibrahim, M. Ibrahim
P46 Genetic divergence of CYP3A5*3 pharmacogenomic marker for native and admixed Mexican populations
J. C. Fernandez-Lopez, V. Bonifaz-Peña, C. Rangel-Escareño, A. Hidalgo-Miranda, A. V. Contreras
P47 Whole exome sequence meta-analysis of 13 white blood cell, red blood cell, and platelet traits
L. Polfus, CHARGE and NHLBI Exome Sequence Project Working Groups
P48 Association of adipoq gene with type 2 diabetes and related phenotypes in african american men and women: The jackson heart study
S. Davis, R. Xu, S. Gebeab, P Riestra, A Gaye, R. Khan, J. Wilson, A. Bidulescu
P49 Common variants in casr gene are associated with serum calcium levels in koreans
S. H. Jung, N. Vinayagamoorthy, S. H. Yim, Y. J. Chung
P50 Inference of multiple-wave population admixture by modeling decay of linkage disequilibrium with multiple exponential functions
Y. Zhou, S. Xu
P51 A Bayesian framework for generalized linear mixed models in genome-wide association studies
X. Wang, V. Philip, G. Carter
P52 Targeted sequencing approach for the identification of the genetic causes of hereditary hearing impairment
A. A. Abuzenadah, M. Gari, R. Turki, A. Dallol
P53 Identification of enhancer sequences by ATAC-seq open chromatin profiling
A. Uyar, A. Kaygun, S. Zaman, E. Marquez, J. George, D. Ucar
P54 Direct enrichment for the rapid preparation of targeted NGS libraries
C. L. Hendrickson, A. Emerman, D. Kraushaar, S. Bowman, N. Henig, T. Davis, S. Russello, K. Patel
P56 Performance of the Agilent D5000 and High Sensitivity D5000 ScreenTape assays for the Agilent 4200 Tapestation System
R. Nitsche, L. Prieto-Lafuente
P57 ClinVar: a multi-source archive for variant interpretation
M. Landrum, J. Lee, W. Rubinstein, D. Maglott
P59 Association of functional variants and protein physical interactions of human MUTY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome
Z. Abduljaleel, W. Khan, F. A. Al-Allaf, M. Athar , M. M. Taher, N. Shahzad
P60 Modification of the microbiom constitution in the gut using chicken IgY antibodies resulted in a reduction of acute graft-versus-host disease after experimental bone marrow transplantation
A. Bouazzaoui, E. Huber, A. Dan, F. A. Al-Allaf, W. Herr, G. Sprotte, J. Köstler, A. Hiergeist, A. Gessner, R. Andreesen, E. Holler
P61 Compound heterozygous mutation in the LDLR gene in Saudi patients suffering severe hypercholesterolemia
F. Al-Allaf, A. Alashwal, Z. Abduljaleel, M. Taher, A. Bouazzaoui, H. Abalkhail, A. Al-Allaf, R. Bamardadh, M. Athar
doi:10.1186/s40246-016-0063-5
PMCID: PMC4896275  PMID: 27294413
10.  Nutritional and Metabolic Biomarkers in Autism Spectrum Disorders: An Exploratory Study 
Context
Autism spectrum disorder (ASD) is currently on the rise, now affecting approximately 1 in 68 children in the United States according to a 2010 surveillance summary from the Centers for Disease Control and Prevention (CDC). This figure is an estimated increase of 78% from the figure in 2002. The CDC suggests that more investigation is needed to understand this astounding increase in autism in such a short period.
Objective
The aim of this pilot study was to determine whether a group of children with ASD exhibited similar variations in a broad array of potential correlates, including medical histories, symptoms, genetics, and multiple nutritional and metabolic biomarkers.
Design
This study was a retrospective, descriptive chart review.
Setting
The study took place at the University of Kansas Medical Center (KUMC).
Participants
Participants were 7 children with ASD who had sought treatment at the Integrative Medicine Clinic at the medical center.
Results
A majority of the children exhibited an elevated copper:zinc ratio and abnormal vitamin D levels. Children also demonstrated abnormal levels of the essential fatty acids: (1) α-linolenic acid (ALA)— C13:3W3, and (2) linoleic acid (LA)—C18:2W6; high levels of docosahexaenoic acid (DHA); and an elevated ω-6:ω-3 ratio. Three of 7 children demonstrated abnormal manganese levels. Children did not demonstrate elevated urine pyruvate or lactate but did have abnormal detoxification markers. Three of 7 patients demonstrated abnormalities in citric acid metabolites, bacterial metabolism, and fatty acid oxidation markers. A majority demonstrated elevated serum immunoglobulin G (IgG) antibodies to casein, egg whites, egg yolks, and peanuts. A majority had absent glutathione S-transferase (GSTM) at the 1p13.3 location, and 3 of 7 children were heterozygous for the glutathione S-transferase I105V (GSTP1). A majority also exhibited genetic polymorphism of the mitochondrial gene superoxide dismutase A16V (SOD2).
Conclusions
The findings from this small group of children with ASD points to the existence of nutritional, metabolic, and genetic correlates of ASD. These factors appear to be important potential abnormalities that warrant a case control study to evaluate their reliability and validity as markers of ASD.
PMCID: PMC4566479  PMID: 26770138
11.  One carbon metabolism disturbances and the C677T MTHFR gene polymorphism in children with autism spectrum disorders 
Autism spectrum disorders (ASDs), which include the prototypic autistic disorder (AD), Asperger’s syndrome (AS) and pervasive developmental disorders not otherwise specified (PDD-NOS), are complex neurodevelopmental conditions of unknown aetiology. The current study investigated the metabolites in the methionine cycle, the transsulphuration pathway, folate, vitamin B12 and the C677T polymorphism of the MTHFR gene in three groups of children diagnosed with AD (n= 15), AS (n= 5) and PDD-NOS (n= 19) and their age- and sex-matched controls (n= 25). No metabolic disturbances were seen in the AS patients, while in the AD and PDD-NOS groups, lower plasma levels of methionine (P= 0.01 and P= 0.03, respectively) and α-aminobutyrate were observed (P= 0.01 and P= 0.001, respectively). Only in the AD group, plasma cysteine (P= 0.02) and total blood glutathione (P= 0.02) were found to be reduced. Although there was a trend towards lower levels of serine, glycine, N, N-dimethylglycine in AD patients, the plasma levels of these metabolites as well as the levels of homocysteine and cystathionine were not statistically different in any of the ASDs groups. The serum levels of vitamin B12 and folate were in the normal range. The results of the MTHFR gene analysis showed a normal distribution of the C677T polymorphism in children with ASDs, but the frequency of the 677T allele was slightly more prevalent in AD patients. Our study indicates a possible role for the alterations in one carbon metabolism in the pathophysiology of ASDs and provides, for the first time, preliminary evidence for metabolic and genetic differences between clinical subtypes of ASDs.
doi:10.1111/j.1582-4934.2008.00463.x
PMCID: PMC4496129  PMID: 19267885
autism; methionine cycle; transsulphuration; vitamins; MTHFR
12.  Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism 
Autism is a behaviorally-defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G>A), transcobalamin II (TCN2 776G>C), catechol-O-methyltransferase (COMT 472G>A), methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C), and GST M1. We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism.
doi:10.1002/ajmg.b.30366
PMCID: PMC2610366  PMID: 16917939
autism; oxidative stress; genotype; glutathione; methionine
13.  Age-Dependent Brain Gene Expression and Copy Number Anomalies in Autism Suggest Distinct Pathological Processes at Young Versus Mature Ages 
PLoS Genetics  2012;8(3):e1002592.
Autism is a highly heritable neurodevelopmental disorder, yet the genetic underpinnings of the disorder are largely unknown. Aberrant brain overgrowth is a well-replicated observation in the autism literature; but association, linkage, and expression studies have not identified genetic factors that explain this trajectory. Few studies have had sufficient statistical power to investigate whole-genome gene expression and genotypic variation in the autistic brain, especially in regions that display the greatest growth abnormality. Previous functional genomic studies have identified possible alterations in transcript levels of genes related to neurodevelopment and immune function. Thus, there is a need for genetic studies involving key brain regions to replicate these findings and solidify the role of particular functional pathways in autism pathogenesis. We therefore sought to identify abnormal brain gene expression patterns via whole-genome analysis of mRNA levels and copy number variations (CNVs) in autistic and control postmortem brain samples. We focused on prefrontal cortex tissue where excess neuron numbers and cortical overgrowth are pronounced in the majority of autism cases. We found evidence for dysregulation in pathways governing cell number, cortical patterning, and differentiation in young autistic prefrontal cortex. In contrast, adult autistic prefrontal cortex showed dysregulation of signaling and repair pathways. Genes regulating cell cycle also exhibited autism-specific CNVs in DNA derived from prefrontal cortex, and these genes were significantly associated with autism in genome-wide association study datasets. Our results suggest that CNVs and age-dependent gene expression changes in autism may reflect distinct pathological processes in the developing versus the mature autistic prefrontal cortex. Our results raise the hypothesis that genetic dysregulation in the developing brain leads to abnormal regional patterning, excess prefrontal neurons, cortical overgrowth, and neural dysfunction in autism.
Author Summary
Autism is a disorder characterized by aberrant social, communication, and restricted and repetitive behaviors. It develops clinically in the first years of life. Toddlers and children with autism often exhibit early brain enlargement and excess neuron numbers in the prefrontal cortex. Adults with autism generally do not display enlargement but instead may have a smaller brain size. Thus, we investigated DNA and mRNA patterns in prefrontal cortex from young versus adult postmortem individuals with autism to identify age-related gene expression differences as well as possible genetic correlates of abnormal brain enlargement, excess neuron numbers, and abnormal functioning in this disorder. We found abnormalities in genetic pathways governing cell number, neurodevelopment, and cortical lateralization in autism. We also found that the key pathways associated with autism are different between younger and older autistic individuals. These findings suggest that dysregulated gene pathways in the early stages of neurodevelopment could lead to later behavioral and cognitive deficits associated with autism.
doi:10.1371/journal.pgen.1002592
PMCID: PMC3310790  PMID: 22457638
14.  Redox metabolism abnormalities in autistic children associated with mitochondrial disease 
Translational Psychiatry  2013;3(6):e273-.
Research studies have uncovered several metabolic abnormalities associated with autism spectrum disorder (ASD), including mitochondrial disease (MD) and abnormal redox metabolism. Despite the close connection between mitochondrial dysfunction and oxidative stress, the relation between MD and oxidative stress in children with ASD has not been studied. Plasma markers of oxidative stress and measures of cognitive and language development and ASD behavior were obtained from 18 children diagnosed with ASD who met criteria for probable or definite MD per the Morava et al. criteria (ASD/MD) and 18 age and gender-matched ASD children without any biological markers or symptoms of MD (ASD/NoMD). Plasma measures of redox metabolism included reduced free glutathione (fGSH), oxidized glutathione (GSSG), the fGSH/GSSG ratio and 3-nitrotyrosine (3NT). In addition, a plasma measure of chronic immune activation, 3-chlorotyrosine (3CT), was also measured. Language was measured using the preschool language scale or the expressive one-word vocabulary test (depending on the age), adaptive behaviour was measured using the Vineland Adaptive Behavior Scale (VABS) and core autism symptoms were measured using the Autism Symptoms Questionnaire and the Social Responsiveness Scale. Children with ASD/MD were found to have lower scores on the communication and daily living skill subscales of the VABS despite having similar language and ASD symptoms. Children with ASD/MD demonstrated significantly higher levels of fGSH/GSSG and lower levels of GSSG as compared with children with ASD/NoMD, suggesting an overall more favourable glutathione redox status in the ASD/MD group. However, compare with controls, both ASD groups demonstrated lower fGSH and fGSH/GSSG, demonstrating that both groups suffer from redox abnormalities. Younger ASD/MD children had higher levels of 3CT than younger ASD/NoMD children because of an age-related effect in the ASD/MD group. Both ASD groups demonstrated significantly higher 3CT levels than control subjects, suggesting that chronic inflammation was present in both groups of children with ASD. Interestingly, 3NT was found to correlate positively with several measures of cognitive function, development and behavior for the ASD/MD group, but not the ASD/NoMD group, such that higher 3NT concentrations were associated with more favourable adaptive behaviour, language and ASD-related behavior. To determine whether difference in receiving medications and/or supplements could account for the differences in redox and inflammatory biomarkers across ASD groups, we examined differences in medication and supplements across groups and their effect of redox and inflammatory biomarkers. Overall, significantly more participants in the ASD/MD group were receiving folate, vitamin B12, carnitine, co-enzyme Q10, B vitamins and antioxidants. We then determined whether folate, carnitine, co-enzyme Q10, B vitamins and/or antioxidants influenced redox or inflammatory biomarkers. Antioxidant supplementation was associated with a significantly lower GSSG, whereas antioxidants, co-enzyme Q10 and B vitamins were associated with a higher fGSH/GSSG ratio. There was no relation between folate, carnitine, co-enzyme Q10, B vitamins and antioxidants with 3NT, 3CT or fGSH. Overall, our findings suggest that ASD/MD children with a more chronic oxidized microenvironment have better development. We interpret this finding in light of the fact that more active mitochondrial can create a greater oxidized microenvironment especially when dysfunctional. Thus, compensatory upregulation of mitochondria which are dysfunctional may both increase activity and function at the expense of a more oxidized microenvironment. Although more ASD/MD children were receiving certain supplements, the use of such supplements were not found to be related to the redox biomarkers that were related to cognitive development or behavior in the ASD/MD group but could possibly account for the difference in glutathione metabolism noted between groups. This study suggests that different subgroups of children with ASD have different redox abnormalities, which may arise from different sources. A better understanding of the relationship between mitochondrial dysfunction in ASD and oxidative stress, along with other factors that may contribute to oxidative stress, will be critical to understanding how to guide treatment and management of ASD children. This study also suggests that it is important to identify ASD/MD children as they may respond differently to specific treatments because of their specific metabolic profile.
doi:10.1038/tp.2013.51
PMCID: PMC3693408  PMID: 23778583
autism; inflammation; endophenotypes; mitochondrial disease; oxidative stress
15.  Data of multiple regressions analysis between selected biomarkers related to glutamate excitotoxicity and oxidative stress in Saudi autistic patients 
Data in Brief  2016;7:111-116.
This work demonstrates data of multiple regression analysis between nine biomarkers related to glutamate excitotoxicity and impaired detoxification as two mechanisms recently recorded as autism phenotypes. The presented data was obtained by measuring a panel of markers in 20 autistic patients aged 3–15 years and 20 age and gender matching healthy controls. Levels of GSH, glutathione status (GSH/GSSG), glutathione reductase (GR), glutathione-s-transferase (GST), thioredoxin (Trx), thioredoxin reductase (TrxR) and peroxidoxins (Prxs I and III), glutamate, glutamine, glutamate/glutamine ratio glutamate dehydrogenase (GDH) in plasma and mercury (Hg) in red blood cells were determined in both groups. In Multiple regression analysis, R2 values which describe the proportion or percentage of variance in the dependent variable attributed to the variance in the independent variables together were calculated. Moreover, β coefficients values which show the direction either positive or negative and the contribution of the independent variable relative to the other independent variables in explaining the variation of the dependent variable were determined. A panel of inter-related markers was recorded. This paper contains data related to and supporting research articles currently published entitled “Mechanism of nitrogen metabolism-related parameters and enzyme activities in the pathophysiology of autism” [1], “Novel metabolic biomarkers related to sulfur-dependent detoxification pathways in autistic patients of Saudi Arabia [2], and “A key role for an impaired detoxification mechanism in the etiology and severity of autism spectrum disorders” [3].
doi:10.1016/j.dib.2016.02.025
PMCID: PMC4764897  PMID: 26933667
Autism; Multiple Regression Analysis; Glutamate excitotoxicity; Oxidative stress; Detoxification; Glutathione status
16.  S-Glutathionylation: From Molecular Mechanisms to Health Outcomes 
Antioxidants & Redox Signaling  2011;15(1):233-270.
Abstract
Redox homeostasis governs a number of critical cellular processes. In turn, imbalances in pathways that control oxidative and reductive conditions have been linked to a number of human disease pathologies, particularly those associated with aging. Reduced glutathione is the most prevalent biological thiol and plays a crucial role in maintaining a reduced intracellular environment. Exposure to reactive oxygen or nitrogen species is causatively linked to the disease pathologies associated with redox imbalance. In particular, reactive oxygen species can differentially oxidize certain cysteine residues in target proteins and the reversible process of S-glutathionylation may mitigate or mediate the damage. This post-translational modification adds a tripeptide and a net negative charge that can lead to distinct structural and functional changes in the target protein. Because it is reversible, S-glutathionylation has the potential to act as a biological switch and to be integral in a number of critical oxidative signaling events. The present review provides a comprehensive account of how the S-glutathionylation cycle influences protein structure/function and cellular regulatory events, and how these may impact on human diseases. By understanding the components of this cycle, there should be opportunities to intervene in stress- and aging-related pathologies, perhaps through prevention and diagnostic and therapeutic platforms. Antioxid. Redox Signal. 15, 233–270.
I. Introduction
A. Glutathione homeostasis
B. Proximal donors for S-glutathionylation reactions
II. Detection of S-Glutathionylation
A. Antibody detection of S-glutathionylation
B. Analytical detection and quantification of P-SSG
III. Enzymes That Catalyze the S-Glutathionylation Cycle
A. Proteins with S-glutathionylase activity
1. Glutathione S-transferases
2. Gamma-glutamyl transpeptidase
3. Grx1 and Grx2
B. Proteins with deglutathionylase activity
IV. Redox Regulation of Kinase Signaling Pathways
A. S-glutathionylation and modulation of mitogenic signaling
1. Ras-MEK-ERK pathway
2. Protein tyrosine phosphatases
3. Protein kinase A
B. Phosphatidylinositol 3-kinase-Akt-p53 pathway
C. I kappa B kinase-nuclear factor kappa B pathway
D. JNK-c-Jun pathway
V. S-Glutathionylation and Modulation of Survival/Apoptosis
A. S-glutathionylation of death receptors
B. S-glutathionylation of caspases
VI. Redox Regulation of Calcium-Dependent Proteins
A. Protein kinase C
B. Sarco/ER calcium ATPase
C. Nitric oxide synthase
VII. S-Glutathionylation and Ubiquitin-Proteasome Pathway
VIII. S-Glutathionylation and Unfolded Protein Response
A. Signaling pathways in the unfolded protein response
B. Protein disulfide isomerase
IX. Redox Regulation of Cell Migration and Mobilization
A. S-glutathionylation of cytoskeletal proteins
B. Redox regulation of bone marrow mobilization
X. Cancer and Redox Homeostasis
A. Energy metabolism
B. S-glutathionylation and tumor metastasis
C. S100 proteins in cancer and leukocyte migration
1. S100B
2. S100A8 and S100A9
XI. Redox Dysregulation in Pathophysiology
A. Liver injury
B. Diabetes mellitus
C. Cardiovascular disease
D. Traumatic brain injury
XII. Neurological Diseases and Redox Pathways
A. Parkinson's disease
B. Alzheimer's disease
C. Huntington's disease
D. Friedreich's ataxia
E. Amylotrophic lateral sclerosis
XIII. Conclusions
doi:10.1089/ars.2010.3540
PMCID: PMC3110090  PMID: 21235352
17.  Glutathione is a Physiologic Reservoir of Neuronal Glutamate 
Glutamate, the principal excitatory neurotransmitter of the brain, participates in a multitude of physiologic and pathologic processes, including learning and memory. Glutathione, a tripeptide composed of the amino acids glutamate, cysteine, and glycine, serves important cofactor roles in antioxidant defense and drug detoxification, but glutathione deficits occur in multiple neuropsychiatric disorders. Glutathione synthesis and metabolism are governed by a cycle of enzymes, the γ-glutamyl cycle, which can achieve intracellular glutathione concentrations of 1-10 millimolar. Because of the considerable quantity of brain glutathione and its rapid turnover, we hypothesized that glutathione may serve as a reservoir of neural glutamate. We quantified glutamate in HT22 hippocampal neurons, PC12 cells and primary cortical neurons after treatment with molecular inhibitors targeting three different enzymes of the glutathione metabolic cycle. Inhibiting 5-oxoprolinase and γ-glutamyl transferase, enzymes that liberate glutamate from glutathione, leads to decreases in glutamate. In contrast, inhibition of γ-glutamyl cysteine ligase, which uses glutamate to synthesize glutathione, results in substantial glutamate accumulation. Increased glutamate levels following inhibition of glutathione synthesis temporally precede later effects upon oxidative stress.
doi:10.1016/j.bbrc.2011.04.087
PMCID: PMC3923312  PMID: 21539809
Glutathione; Glutamate; Neurons; Antioxidants; Glutamyl cycle; Neurotransmitter
18.  The effect of epilepsy on autistic symptom severity assessed by the social responsiveness scale in children with autism spectrum disorder 
Background
As the prevalence of autism spectrum disorders in people with epilepsy ranges from 15 to 47 % (Clarke et al. in Epilepsia 46:1970–1977, 2005), it is speculated that there is a special relationship between the two disorders, yet there has been a lack of systematic studies comparing the behavioral phenotype between autistic individuals and autistic individuals with epilepsy. This study aims to investigate how the co-occurrence of epilepsy and Autism Spectrum Disorder (ASD) affects autistic characteristics assessed by the Social Responsiveness Scale (SRS), which has been used as a measure of autism symptoms in previous studies. In this research we referred to all individuals with Autism or Autistic Disorder as individuals with ASD.
Methods
We reviewed the complete medical records of 182 participants who presented to a single tertiary care referral center from January 1, 2013 to July 28, 2015, and subsequently received complete child and adolescent psychiatric assessments. Of the 182 participants, 22 were diagnosed with Autism Spectrum Disorder and epilepsy. Types of epilepsy observed in these individuals included complex partial seizure, generalized tonic–clonic seizure, or infantile spasm. Using ‘Propensity Score Matching’ we selected 44 children, diagnosed with only Autism Spectrum Disorder, whose age, gender, and intelligence quotient (IQ) were closely matched with the 22 children diagnosed with Autism Spectrum Disorder and epilepsy. Social functioning of participants was assessed by the social responsiveness scale, which consists of five categories: social awareness, social cognition, social communication, social motivation, and autistic mannerisms. Bivariate analyses were conducted to compare the ASD participants with epilepsy group with the ASD-only group on demographic and clinical characteristics. Chi square and t test p values were calculated when appropriate.
Results
There was no significant difference in age (p = 0.172), gender (p > 0.999), IQ (FSIQ, p = 0.139; VIQ, p = 0.114; PIQ, p = 0.295) between the two groups. ASD participants with epilepsy were significantly more impaired than ASD participants on some measures of social functioning such as social awareness (p = 0.03) and social communication (p = 0.027). ASD participants with epilepsy also scored significantly higher on total SRS t-score than ASD participants (p = 0.023).
Conclusions
Understanding the relationship between ASD and epilepsy is critical for appropriate management (e.g. social skills training, seizure control) of ASD participants with co-occurring epilepsy. Results of this study suggest that mechanisms involved in producing epilepsy may play a role in producing or augmenting autistic features such as poor social functioning. Prospective study with larger sample sizes is warranted to further explore this association.
doi:10.1186/s12993-016-0105-0
PMCID: PMC4924297  PMID: 27350381
Autism spectrum disorder; Epilepsy; Autistic symptom severity; Social responsiveness scale
19.  Autism 
BMJ Clinical Evidence  2010;2010:0322.
Introduction
Evidence for the efficacy of treatments for autism has improved in recent years. In this systematic review the evidence for both drug and non-drug treatments is appraised and clinical guidance is provided for their use.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of early intensive multidisciplinary intervention programmes in children with autism? What are the effects of dietary interventions in children with autism? What are the effects of drug treatments in children with autism? What are the effects of non-drug treatments in children with autism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2009 (Clinical evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 30 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: applied behavioural analysis; auditory integration training; Autism Preschool Programme; casein-free diet; chelation; Child’s Talk programme; cognitive behavioural therapy; digestive enzymes; EarlyBird programme; facilitated communication; Floortime therapy; gluten-free diet; immunoglobulins; melatonin; memantine; methylphenidate; More Than Words programme; music therapy; olanzapine; omega-3 fish oil; picture exchange communication system; Portage scheme; probiotics; relationship development interventions; risperidone; secretin; selective serotonin reuptake inhibitors (SSRIs); sensory integration training; social stories; social skills training; Son-Rise programme; TEACCH; vitamin A; vitamin B6 (pyridoxine) plus magnesium; and vitamin C.
Key Points
Autism is one of a group of pervasive developmental disorders, and is characterised by qualitative impairments in communication and social interaction, and by repetitive and stereotyped behaviours and interests. Abnormal development is present before the age of 3 years. A quarter of affected children show developmental regression, with loss of previously acquired skills.One third of children with autism have epilepsy, and three quarters have mental retardation. Only 15% of adults with autism will lead independent lives.Twin and family studies suggest that most cases of autism occur because of a combination of genetic factors. Autism is not caused by perinatal factors or by the MMR vaccine.
It may be difficult to apply the results of research in practice, as improvements in outcomes assessed in RCTs using standardised assessment tools may not correlate with improvements in function in a particular child with autism.
Some interventions are administered by (or in conjunction with) parents, and may be carried out in the home. Consideration of the direct financial costs, indirect costs (through possible lost earnings), and the impact on relationships within the family (to siblings or spouse) must be balanced against likely and possible improvements in outcome for the child with autism.
There is a lack of good-quality evidence on the effectiveness of early multidisciplinary intervention programmes, or for other treatments for children with autism. There is consensus, supported by a systematic review, that early intensive behavioural interventions are likely to be beneficial in children with autism.Attendance at a "More Than Words" training course for parents may improve communication between parents and children, as may participation in Child's Talk. There is consensus that the Autism Preschool Programme and TEACCH may be effective, although no RCTs or cohort studies evaluating these interventions have been found.We don't know whether early intervention using the EarlyBird programme, the Portage scheme, Relationship-Development Intervention, Social stories, music therapy, CBT, facilitated communication or Son-Rise are beneficial in children with autism.
Methylphenidate may reduce hyperactivity in children with autism. Methylphenidate may increase social withdrawal and irritability. Growth and blood pressure monitoring are required.
Risperidone may improve behaviour in children with autism compared with placebo, but its use is limited by adverse effects such as weight gain, drowsiness, prolactinaemia, and tremors.
There is consensus that selective serotonin reuptake inhibitors (SSRIs) improve symptoms in children with autism, although no RCTs have been found. The adverse effects of SSRIs, including possible increases in agitation, hostility, and suicidal ideation, are well documented.
We don't know whether auditory integration training, sensory integration training, chelation, a gluten- and casein-free diet, digestive enzymes, omega-3 fish oil, secretin, vitamin A, vitamin B6 plus magnesium, melatonin, olanzapine, or vitamin C are beneficial for treating children with autism, as few studies have been found.
PMCID: PMC2907623  PMID: 21729335
20.  Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science 
Lewis, Cara | Darnell, Doyanne | Kerns, Suzanne | Monroe-DeVita, Maria | Landes, Sara J. | Lyon, Aaron R. | Stanick, Cameo | Dorsey, Shannon | Locke, Jill | Marriott, Brigid | Puspitasari, Ajeng | Dorsey, Caitlin | Hendricks, Karin | Pierson, Andria | Fizur, Phil | Comtois, Katherine A. | Palinkas, Lawrence A. | Chamberlain, Patricia | Aarons, Gregory A. | Green, Amy E. | Ehrhart, Mark. G. | Trott, Elise M. | Willging, Cathleen E. | Fernandez, Maria E. | Woolf, Nicholas H. | Liang, Shuting Lily | Heredia, Natalia I. | Kegler, Michelle | Risendal, Betsy | Dwyer, Andrea | Young, Vicki | Campbell, Dayna | Carvalho, Michelle | Kellar-Guenther, Yvonne | Damschroder, Laura J. | Lowery, Julie C. | Ono, Sarah S. | Carlson, Kathleen F. | Cottrell, Erika K. | O’Neil, Maya E. | Lovejoy, Travis L. | Arch, Joanna J. | Mitchell, Jill L. | Lewis, Cara C. | Marriott, Brigid R. | Scott, Kelli | Coldiron, Jennifer Schurer | Bruns, Eric J. | Hook, Alyssa N. | Graham, Benjamin C. | Jordan, Katelin | Hanson, Rochelle F. | Moreland, Angela | Saunders, Benjamin E. | Resnick, Heidi S. | Stirman, Shannon Wiltsey | Gutner, Cassidy A. | Gamarra, Jennifer | Vogt, Dawne | Suvak, Michael | Wachen, Jennifer Schuster | Dondanville, Katherine | Yarvis, Jeffrey S. | Mintz, Jim | Peterson, Alan L. | Borah, Elisa V. | Litz, Brett T. | Molino, Alma | McCaughan, Stacey Young | Resick, Patricia A. | Pandhi, Nancy | Jacobson, Nora | Serrano, Neftali | Hernandez, Armando | Schreiter, Elizabeth Zeidler- | Wietfeldt, Natalie | Karp, Zaher | Pullmann, Michael D. | Lucenko, Barbara | Pavelle, Bridget | Uomoto, Jacqueline A. | Negrete, Andrea | Cevasco, Molly | Kerns, Suzanne E. U. | Franks, Robert P. | Bory, Christopher | Miech, Edward J. | Damush, Teresa M. | Satterfield, Jason | Satre, Derek | Wamsley, Maria | Yuan, Patrick | O’Sullivan, Patricia | Best, Helen | Velasquez, Susan | Barnett, Miya | Brookman-Frazee, Lauren | Regan, Jennifer | Stadnick, Nicole | Hamilton, Alison | Lau, Anna | Regan, Jennifer | Hamilton, Alison | Stadnick, Nicole | Barnett, Miya | Lau, Anna | Brookman-Frazee, Lauren | Stadnick, Nicole | Lau, Anna | Barnett, Miya | Regan, Jennifer | Roesch, Scott | Brookman-Frazee, Lauren | Powell, Byron J. | Waltz, Thomas J. | Chinman, Matthew J. | Damschroder, Laura | Smith, Jeffrey L. | Matthieu, Monica M. | Proctor, Enola K. | Kirchner, JoAnn E. | Waltz, Thomas J. | Powell, Byron J. | Chinman, Matthew J. | Damschroder, Laura J. | Smith, Jeffrey L. | Matthieu, Monica J. | Proctor, Enola K. | Kirchner, JoAnn E. | Matthieu, Monica M. | Rosen, Craig S. | Waltz, Thomas J. | Powell, Byron J. | Chinman, Matthew J. | Damschroder, Laura J. | Smith, Jeffrey L. | Proctor, Enola K. | Kirchner, JoAnn E. | Walker, Sarah C. | Bishop, Asia S. | Lockhart, Mariko | Rodriguez, Allison L. | Manfredi, Luisa | Nevedal, Andrea | Rosenthal, Joel | Blonigen, Daniel M. | Mauricio, Anne M. | Dishion, Thomas D. | Rudo-Stern, Jenna | Smith, Justin D. | Locke, Jill | Wolk, Courtney Benjamin | Harker, Colleen | Olsen, Anne | Shingledecker, Travis | Barg, Frances | Mandell, David | Beidas, Rinad S. | Hansen, Marissa C. | Aranda, Maria P. | Torres-Vigil, Isabel | Hartzler, Bryan | Steinfeld, Bradley | Gildred, Tory | Harlin, Zandrea | Shephard, Fredric | Ditty, Matthew S. | Doyle, Andrea | Bickel, John A. | Cristaudo, Katharine | Fox, Dan | Combs, Sonia | Lischner, David H. | Van Dorn, Richard A. | Tueller, Stephen J. | Hinde, Jesse M. | Karuntzos, Georgia T. | Monroe-DeVita, Maria | Peterson, Roselyn | Darnell, Doyanne | Berliner, Lucy | Dorsey, Shannon | Murray, Laura K. | Botanov, Yevgeny | Kikuta, Beverly | Chen, Tianying | Navarro-Haro, Marivi | DuBose, Anthony | Korslund, Kathryn E. | Linehan, Marsha M. | Harker, Colleen M. | Karp, Elizabeth A. | Edmunds, Sarah R. | Ibañez, Lisa V. | Stone, Wendy L. | Andrews, Jack H. | Johnides, Benjamin D. | Hausman, Estee M. | Hawley, Kristin M. | Prusaczyk, Beth | Ramsey, Alex | Baumann, Ana | Colditz, Graham | Proctor, Enola K. | Botanov, Yevgeny | Kikuta, Beverly | Chen, Tianying | Navarro-Haro, Marivi | DuBose, Anthony | Korslund, Kathryn E. | Linehan, Marsha M. | Harker, Colleen M. | Karp, Elizabeth A. | Edmunds, Sarah R. | Ibañez, Lisa V. | Stone, Wendy L. | Choy-Brown, Mimi | Andrews, Jack H. | Johnides, Benjamin D. | Hausman, Estee M. | Hawley, Kristin M. | Prusaczyk, Beth | Ramsey, Alex | Baumann, Ana | Colditz, Graham | Proctor, Enola K. | Meza, Rosemary D. | Dorsey, Shannon | Wiltsey-Stirman, Shannon | Sedlar, Georganna | Lucid, Leah | Dorsey, Caitlin | Marriott, Brigid | Zounlome, Nelson | Lewis, Cara | Gutner, Cassidy A. | Monson, Candice M. | Shields, Norman | Mastlej, Marta | Landy, Meredith SH | Lane, Jeanine | Stirman, Shannon Wiltsey | Finn, Natalie K. | Torres, Elisa M. | Ehrhart, Mark. G. | Aarons, Gregory A. | Malte, Carol A. | Lott, Aline | Saxon, Andrew J. | Boyd, Meredith | Scott, Kelli | Lewis, Cara C. | Pierce, Jennifer D. | Lorthios-Guilledroit, Agathe | Richard, Lucie | Filiatrault, Johanne | Hallgren, Kevin | Crotwell, Shirley | Muñoz, Rosa | Gius, Becky | Ladd, Benjamin | McCrady, Barbara | Epstein, Elizabeth | Clapp, John D. | Ruderman, Danielle E. | Barwick, Melanie | Barac, Raluca | Zlotkin, Stanley | Salim, Laila | Davidson, Marnie | Bunger, Alicia C. | Powell, Byron J. | Robertson, Hillary A. | Botsko, Christopher | Landes, Sara J. | Smith, Brandy N. | Rodriguez, Allison L. | Trent, Lindsay R. | Matthieu, Monica M. | Powell, Byron J. | Proctor, Enola K. | Harned, Melanie S. | Navarro-Haro, Marivi | Korslund, Kathryn E. | Chen, Tianying | DuBose, Anthony | Ivanoff, André | Linehan, Marsha M. | Garcia, Antonio R. | Kim, Minseop | Palinkas, Lawrence A. | Snowden, Lonnie | Landsverk, John | Sweetland, Annika C. | Fernandes, Maria Jose | Santos, Edilson | Duarte, Cristiane | Kritski, Afrânio | Krawczyk, Noa | Nelligan, Caitlin | Wainberg, Milton L. | Aarons, Gregory A. | Sommerfeld, David H. | Chi, Benjamin | Ezeanolue, Echezona | Sturke, Rachel | Kline, Lydia | Guay, Laura | Siberry, George | Bennett, Ian M. | Beidas, Rinad | Gold, Rachel | Mao, Johnny | Powers, Diane | Vredevoogd, Mindy | Unutzer, Jurgen | Schroeder, Jennifer | Volpe, Lane | Steffen, Julie | Dorsey, Shannon | Pullmann, Michael D | Kerns, Suzanne E. U. | Jungbluth, Nathaniel | Berliner, Lucy | Thompson, Kelly | Segell, Eliza | McGee-Vincent, Pearl | Liu, Nancy | Walser, Robyn | Runnals, Jennifer | Shaw, R. Keith | Landes, Sara J. | Rosen, Craig | Schmidt, Janet | Calhoun, Patrick | Varkovitzky, Ruth L. | Landes, Sara J. | Drahota, Amy | Martinez, Jonathan I. | Brikho, Brigitte | Meza, Rosemary | Stahmer, Aubyn C. | Aarons, Gregory A. | Williamson, Anna | Rubin, Ronnie M. | Powell, Byron J. | Hurford, Matthew O. | Weaver, Shawna L. | Beidas, Rinad S. | Mandell, David S. | Evans, Arthur C. | Powell, Byron J. | Beidas, Rinad S. | Rubin, Ronnie M. | Stewart, Rebecca E. | Wolk, Courtney Benjamin | Matlin, Samantha L. | Weaver, Shawna | Hurford, Matthew O. | Evans, Arthur C. | Hadley, Trevor R. | Mandell, David S. | Gerke, Donald R. | Prusaczyk, Beth | Baumann, Ana | Lewis, Ericka M. | Proctor, Enola K. | McWilliam, Jenna | Brown, Jacquie | Tucker, Michelle | Conte, Kathleen P | Lyon, Aaron R. | Boyd, Meredith | Melvin, Abigail | Lewis, Cara C. | Liu, Freda | Jungbluth, Nathaniel | Kotte, Amelia | Hill, Kaitlin A. | Mah, Albert C. | Korathu-Larson, Priya A. | Au, Janelle R. | Izmirian, Sonia | Keir, Scott | Nakamura, Brad J. | Higa-McMillan, Charmaine K. | Cooper, Brittany Rhoades | Funaiole, Angie | Dizon, Eleanor | Hawkins, Eric J. | Malte, Carol A. | Hagedorn, Hildi J. | Berger, Douglas | Frank, Anissa | Lott, Aline | Achtmeyer, Carol E. | Mariano, Anthony J. | Saxon, Andrew J. | Wolitzky-Taylor, Kate | Rawson, Richard | Ries, Richard | Roy-Byrne, Peter | Craske, Michelle | Simmons, Dena | Torrente, Catalina | Nathanson, Lori | Carroll, Grace | Smith, Justin D. | Brown, Kimbree | Ramos, Karina | Thornton, Nicole | Dishion, Thomas J. | Stormshak, Elizabeth A. | Shaw, Daniel S. | Wilson, Melvin N. | Choy-Brown, Mimi | Tiderington, Emmy | Smith, Bikki Tran | Padgett, Deborah K. | Rubin, Ronnie M. | Ray, Marilyn L. | Wandersman, Abraham | Lamont, Andrea | Hannah, Gordon | Alia, Kassandra A. | Hurford, Matthew O. | Evans, Arthur C. | Saldana, Lisa | Schaper, Holle | Campbell, Mark | Chamberlain, Patricia | Shapiro, Valerie B. | Kim, B.K. Elizabeth | Fleming, Jennifer L. | LeBuffe, Paul A. | Landes, Sara J. | Lewis, Cara C. | Rodriguez, Allison L. | Marriott, Brigid R. | Comtois, Katherine Anne | Lewis, Cara C. | Stanick, Cameo | Weiner, Bryan J. | Halko, Heather | Dorsey, Caitlin
Implementation Science : IS  2016;11(Suppl 1):85.
Table of contents
Introduction to the 3rd Biennial Conference of the Society for Implementation Research Collaboration: advancing efficient methodologies through team science and community partnerships
Cara Lewis, Doyanne Darnell, Suzanne Kerns, Maria Monroe-DeVita, Sara J. Landes, Aaron R. Lyon, Cameo Stanick, Shannon Dorsey, Jill Locke, Brigid Marriott, Ajeng Puspitasari, Caitlin Dorsey, Karin Hendricks, Andria Pierson, Phil Fizur, Katherine A. Comtois
A1: A behavioral economic perspective on adoption, implementation, and sustainment of evidence-based interventions
Lawrence A. Palinkas
A2: Towards making scale up of evidence-based practices in child welfare systems more efficient and affordable
Patricia Chamberlain
A3: Mixed method examination of strategic leadership for evidence-based practice implementation
Gregory A. Aarons, Amy E. Green, Mark. G. Ehrhart, Elise M. Trott, Cathleen E. Willging
A4: Implementing practice change in Federally Qualified Health Centers: Learning from leaders’ experiences
Maria E. Fernandez, Nicholas H. Woolf, Shuting (Lily) Liang, Natalia I. Heredia, Michelle Kegler, Betsy Risendal, Andrea Dwyer, Vicki Young, Dayna Campbell, Michelle Carvalho, Yvonne Kellar-Guenther
A3: Mixed method examination of strategic leadership for evidence-based practice implementation
Gregory A. Aarons, Amy E. Green, Mark. G. Ehrhart, Elise M. Trott, Cathleen E. Willging
A4: Implementing practice change in Federally Qualified Health Centers: Learning from leaders’ experiences
Maria E. Fernandez, Nicholas H. Woolf, Shuting (Lily) Liang, Natalia I. Heredia, Michelle Kegler, Betsy Risendal, Andrea Dwyer, Vicki Young, Dayna Campbell, Michelle Carvalho, Yvonne Kellar-Guenther
A5: Efficient synthesis: Using qualitative comparative analysis and the Consolidated Framework for Implementation Research across diverse studies
Laura J. Damschroder, Julie C. Lowery
A6: Establishing a veterans engagement group to empower patients and inform Veterans Affairs (VA) health services research
Sarah S. Ono, Kathleen F. Carlson, Erika K. Cottrell, Maya E. O’Neil, Travis L. Lovejoy
A7: Building patient-practitioner partnerships in community oncology settings to implement behavioral interventions for anxious and depressed cancer survivors
Joanna J. Arch, Jill L. Mitchell
A8: Tailoring a Cognitive Behavioral Therapy implementation protocol using mixed methods, conjoint analysis, and implementation teams
Cara C. Lewis, Brigid R. Marriott, Kelli Scott
A9: Wraparound Structured Assessment and Review (WrapSTAR): An efficient, yet comprehensive approach to Wraparound implementation evaluation
Jennifer Schurer Coldiron, Eric J. Bruns, Alyssa N. Hook
A10: Improving the efficiency of standardized patient assessment of clinician fidelity: A comparison of automated actor-based and manual clinician-based ratings
Benjamin C. Graham, Katelin Jordan
A11: Measuring fidelity on the cheap
Rochelle F. Hanson, Angela Moreland, Benjamin E. Saunders, Heidi S. Resnick
A12: Leveraging routine clinical materials to assess fidelity to an evidence-based psychotherapy
Shannon Wiltsey Stirman, Cassidy A. Gutner, Jennifer Gamarra, Dawne Vogt, Michael Suvak, Jennifer Schuster Wachen, Katherine Dondanville, Jeffrey S. Yarvis, Jim Mintz, Alan L. Peterson, Elisa V. Borah, Brett T. Litz, Alma Molino, Stacey Young McCaughanPatricia A. Resick
A13: The video vignette survey: An efficient process for gathering diverse community opinions to inform an intervention
Nancy Pandhi, Nora Jacobson, Neftali Serrano, Armando Hernandez, Elizabeth Zeidler- Schreiter, Natalie Wietfeldt, Zaher Karp
A14: Using integrated administrative data to evaluate implementation of a behavioral health and trauma screening for children and youth in foster care
Michael D. Pullmann, Barbara Lucenko, Bridget Pavelle, Jacqueline A. Uomoto, Andrea Negrete, Molly Cevasco, Suzanne E. U. Kerns
A15: Intermediary organizations as a vehicle to promote efficiency and speed of implementation
Robert P. Franks, Christopher Bory
A16: Applying the Consolidated Framework for Implementation Research constructs directly to qualitative data: The power of implementation science in action
Edward J. Miech, Teresa M. Damush
A17: Efficient and effective scaling-up, screening, brief interventions, and referrals to treatment (SBIRT) training: a snowball implementation model
Jason Satterfield, Derek Satre, Maria Wamsley, Patrick Yuan, Patricia O’Sullivan
A18: Matching models of implementation to system needs and capacities: addressing the human factor
Helen Best, Susan Velasquez
A19: Agency characteristics that facilitate efficient and successful implementation efforts
Miya Barnett, Lauren Brookman-Frazee, Jennifer Regan, Nicole Stadnick, Alison Hamilton, Anna Lau
A20: Rapid assessment process: Application to the Prevention and Early Intervention transformation in Los Angeles County
Jennifer Regan, Alison Hamilton, Nicole Stadnick, Miya Barnett, Anna Lau, Lauren Brookman-Frazee
A21: The development of the Evidence-Based Practice-Concordant Care Assessment: An assessment tool to examine treatment strategies across practices
Nicole Stadnick, Anna Lau, Miya Barnett, Jennifer Regan, Scott Roesch, Lauren Brookman-Frazee
A22: Refining a compilation of discrete implementation strategies and determining their importance and feasibility
Byron J. Powell, Thomas J. Waltz, Matthew J. Chinman, Laura Damschroder, Jeffrey L. Smith, Monica M. Matthieu, Enola K. Proctor, JoAnn E. Kirchner
A23: Structuring complex recommendations: Methods and general findings
Thomas J. Waltz, Byron J. Powell, Matthew J. Chinman, Laura J. Damschroder, Jeffrey L. Smith, Monica J. Matthieu, Enola K. Proctor, JoAnn E. Kirchner
A24: Implementing prolonged exposure for post-traumatic stress disorder in the Department of Veterans Affairs: Expert recommendations from the Expert Recommendations for Implementing Change (ERIC) project
Monica M. Matthieu, Craig S. Rosen, Thomas J. Waltz, Byron J. Powell, Matthew J. Chinman, Laura J. Damschroder, Jeffrey L. Smith, Enola K. Proctor, JoAnn E. Kirchner
A25: When readiness is a luxury: Co-designing a risk assessment and quality assurance process with violence prevention frontline workers in Seattle, WA
Sarah C. Walker, Asia S. Bishop, Mariko Lockhart
A26: Implementation potential of structured recidivism risk assessments with justice- involved veterans: Qualitative perspectives from providers
Allison L. Rodriguez, Luisa Manfredi, Andrea Nevedal, Joel Rosenthal, Daniel M. Blonigen
A27: Developing empirically informed readiness measures for providers and agencies for the Family Check-Up using a mixed methods approach
Anne M. Mauricio, Thomas D. Dishion, Jenna Rudo-Stern, Justin D. Smith
A28: Pebbles, rocks, and boulders: The implementation of a school-based social engagement intervention for children with autism
Jill Locke, Courtney Benjamin Wolk, Colleen Harker, Anne Olsen, Travis Shingledecker, Frances Barg, David Mandell, Rinad S. Beidas
A29: Problem Solving Teletherapy (PST.Net): A stakeholder analysis examining the feasibility and acceptability of teletherapy in community based aging services
Marissa C. Hansen, Maria P. Aranda, Isabel Torres-Vigil
A30: A case of collaborative intervention design eventuating in behavior therapy sustainment and diffusion
Bryan Hartzler
A31: Implementation of suicide risk prevention in an integrated delivery system: Mental health specialty services
Bradley Steinfeld, Tory Gildred, Zandrea Harlin, Fredric Shephard
A32: Implementation team, checklist, evaluation, and feedback (ICED): A step-by-step approach to Dialectical Behavior Therapy program implementation
Matthew S. Ditty, Andrea Doyle, John A. Bickel III, Katharine Cristaudo
A33: The challenges in implementing muliple evidence-based practices in a community mental health setting
Dan Fox, Sonia Combs
A34: Using electronic health record technology to promote and support evidence-based practice assessment and treatment intervention
David H. Lischner
A35: Are existing frameworks adequate for measuring implementation outcomes? Results from a new simulation methodology
Richard A. Van Dorn, Stephen J. Tueller, Jesse M. Hinde, Georgia T. Karuntzos
A36: Taking global local: Evaluating training of Washington State clinicians in a modularized cogntive behavioral therapy approach designed for low-resource settings
Maria Monroe-DeVita, Roselyn Peterson, Doyanne Darnell, Lucy Berliner, Shannon Dorsey, Laura K. Murray
A37: Attitudes toward evidence-based practices across therapeutic orientations
Yevgeny Botanov, Beverly Kikuta, Tianying Chen, Marivi Navarro-Haro, Anthony DuBose, Kathryn E. Korslund, Marsha M. Linehan
A38: Predicting the use of an evidence-based intervention for autism in birth-to-three programs
Colleen M. Harker, Elizabeth A. Karp, Sarah R. Edmunds, Lisa V. Ibañez, Wendy L. Stone
A39: Supervision practices and improved fidelity across evidence-based practices: A literature review
Mimi Choy-Brown
A40: Beyond symptom tracking: clinician perceptions of a hybrid measurement feedback system for monitoring treatment fidelity and client progress
Jack H. Andrews, Benjamin D. Johnides, Estee M. Hausman, Kristin M. Hawley
A41: A guideline decision support tool: From creation to implementation
Beth Prusaczyk, Alex Ramsey, Ana Baumann, Graham Colditz, Enola K. Proctor
A42: Dabblers, bedazzlers, or total makeovers: Clinician modification of a common elements cognitive behavioral therapy approach
Rosemary D. Meza, Shannon Dorsey, Shannon Wiltsey-Stirman, Georganna Sedlar, Leah Lucid
A43: Characterization of context and its role in implementation: The impact of structure, infrastructure, and metastructure
Caitlin Dorsey, Brigid Marriott, Nelson Zounlome, Cara Lewis
A44: Effects of consultation method on implementation of cognitive processing therapy for post-traumatic stress disorder
Cassidy A. Gutner, Candice M. Monson, Norman Shields, Marta Mastlej, Meredith SH Landy, Jeanine Lane, Shannon Wiltsey Stirman
A45: Cross-validation of the Implementation Leadership Scale factor structure in child welfare service organizations
Natalie K. Finn, Elisa M. Torres, Mark. G. Ehrhart, Gregory A. Aarons
A46: Sustainability of integrated smoking cessation care in Veterans Affairs posttraumatic stress disorder clinics: A qualitative analysis of focus group data from learning collaborative participants
Carol A. Malte, Aline Lott, Andrew J. Saxon
A47: Key characteristics of effective mental health trainers: The creation of the Measure of Effective Attributes of Trainers (MEAT)
Meredith Boyd, Kelli Scott, Cara C. Lewis
A48: Coaching to improve teacher implementation of evidence-based practices (EBPs)
Jennifer D. Pierce
A49: Factors influencing the implementation of peer-led health promotion programs targeting seniors: A literature review
Agathe Lorthios-Guilledroit, Lucie Richard, Johanne Filiatrault
A50: Developing treatment fidelity rating systems for psychotherapy research: Recommendations and lessons learned
Kevin Hallgren, Shirley Crotwell, Rosa Muñoz, Becky Gius, Benjamin Ladd, Barbara McCrady, Elizabeth Epstein
A51: Rapid translation of alcohol prevention science
John D. Clapp, Danielle E. Ruderman
A52: Factors implicated in successful implementation: evidence to inform improved implementation from high and low-income countries
Melanie Barwick, Raluca Barac, Stanley Zlotkin, Laila Salim, Marnie
Davidson
A53: Tracking implementation strategies prospectively: A practical approach
Alicia C. Bunger, Byron J. Powell, Hillary A. Robertson
A54: Trained but not implementing: the need for effective implementation planning tools
Christopher Botsko
A55: Evidence, context, and facilitation variables related to implementation of Dialectical Behavior Therapy: Qualitative results from a mixed methods inquiry in the Department of Veterans Affairs
Sara J. Landes, Brandy N. Smith, Allison L. Rodriguez, Lindsay R. Trent, Monica M. Matthieu
A56: Learning from implementation as usual in children’s mental health
Byron J. Powell, Enola K. Proctor
A57: Rates and predictors of implementation after Dialectical Behavior Therapy Intensive Training
Melanie S. Harned, Marivi Navarro-Haro, Kathryn E. Korslund, Tianying Chen, Anthony DuBose, André Ivanoff, Marsha M. Linehan
A58: Socio-contextual determinants of research evidence use in public-youth systems of care
Antonio R. Garcia, Minseop Kim, Lawrence A. Palinkas, Lonnie Snowden, John Landsverk
A59: Community resource mapping to integrate evidence-based depression treatment in primary care in Brazil: A pilot project
Annika C. Sweetland, Maria Jose Fernandes, Edilson Santos, Cristiane Duarte, Afrânio Kritski, Noa Krawczyk, Caitlin Nelligan, Milton L. Wainberg
A60: The use of concept mapping to efficiently identify determinants of implementation in the National Institute of Health--President’s Emergent Plan for AIDS Relief Prevention of Mother to Child HIV Transmission Implementation Science Alliance
Gregory A. Aarons, David H. Sommerfeld, Benjamin Chi, Echezona Ezeanolue, Rachel Sturke, Lydia Kline, Laura Guay, George Siberry
A61: Longitudinal remote consultation for implementing collaborative care for depression
Ian M. Bennett, Rinad Beidas, Rachel Gold, Johnny Mao, Diane Powers, Mindy Vredevoogd, Jurgen Unutzer
A62: Integrating a peer coach model to support program implementation and ensure long- term sustainability of the Incredible Years in community-based settings
Jennifer Schroeder, Lane Volpe, Julie Steffen
A63: Efficient sustainability: Existing community based supervisors as evidence-based treatment supports
Shannon Dorsey, Michael D Pullmann, Suzanne E. U. Kerns, Nathaniel Jungbluth, Lucy Berliner, Kelly Thompson, Eliza Segell
A64: Establishment of a national practice-based implementation network to accelerate adoption of evidence-based and best practices
Pearl McGee-Vincent, Nancy Liu, Robyn Walser, Jennifer Runnals, R. Keith Shaw, Sara J. Landes, Craig Rosen, Janet Schmidt, Patrick Calhoun
A65: Facilitation as a mechanism of implementation in a practice-based implementation network: Improving care in a Department of Veterans Affairs post-traumatic stress disorder outpatient clinic
Ruth L. Varkovitzky, Sara J. Landes
A66: The ACT SMART Toolkit: An implementation strategy for community-based organizations providing services to children with autism spectrum disorder
Amy Drahota, Jonathan I. Martinez, Brigitte Brikho, Rosemary Meza, Aubyn C. Stahmer, Gregory A. Aarons
A67: Supporting Policy In Health with Research: An intervention trial (SPIRIT) - protocol and early findings
Anna Williamson
A68: From evidence based practice initiatives to infrastructure: Lessons learned from a public behavioral health system’s efforts to promote evidence based practices
Ronnie M. Rubin, Byron J. Powell, Matthew O. Hurford, Shawna L. Weaver, Rinad S. Beidas, David S. Mandell, Arthur C. Evans
A69: Applying the policy ecology model to Philadelphia’s behavioral health transformation efforts
Byron J. Powell, Rinad S. Beidas, Ronnie M. Rubin, Rebecca E. Stewart, Courtney Benjamin Wolk, Samantha L. Matlin, Shawna Weaver, Matthew O. Hurford, Arthur C. Evans, Trevor R. Hadley, David S. Mandell
A70: A model for providing methodological expertise to advance dissemination and implementation of health discoveries in Clinical and Translational Science Award institutions
Donald R. Gerke, Beth Prusaczyk, Ana Baumann, Ericka M. Lewis, Enola K. Proctor
A71: Establishing a research agenda for the Triple P Implementation Framework
Jenna McWilliam, Jacquie Brown, Michelle Tucker
A72: Cheap and fast, but what is “best?”: Examining implementation outcomes across sites in a state-wide scaled-up evidence-based walking program, Walk With Ease
Kathleen P Conte
A73: Measurement feedback systems in mental health: Initial review of capabilities and characteristics
Aaron R. Lyon, Meredith Boyd, Abigail Melvin, Cara C. Lewis, Freda Liu, Nathaniel Jungbluth
A74: A qualitative investigation of case managers’ attitudes toward implementation of a measurement feedback system in a public mental health system for youth
Amelia Kotte, Kaitlin A. Hill, Albert C. Mah, Priya A. Korathu-Larson, Janelle R. Au, Sonia Izmirian, Scott Keir, Brad J. Nakamura, Charmaine K. Higa-McMillan
A75: Multiple pathways to sustainability: Using Qualitative Comparative Analysis to uncover the necessary and sufficient conditions for successful community-based implementation
Brittany Rhoades Cooper, Angie Funaiole, Eleanor Dizon
A76: Prescribers’ perspectives on opioids and benzodiazepines and medication alerts to reduce co-prescribing of these medications
Eric J. Hawkins, Carol A. Malte, Hildi J. Hagedorn, Douglas Berger, Anissa Frank, Aline Lott, Carol E. Achtmeyer, Anthony J. Mariano, Andrew J. Saxon
A77: Adaptation of Coordinated Anxiety Learning and Management for comorbid anxiety and substance use disorders: Delivery of evidence-based treatment for anxiety in addictions treatment centers
Kate Wolitzky-Taylor, Richard Rawson, Richard Ries, Peter Roy-Byrne, Michelle Craske
A78: Opportunities and challenges of measuring program implementation with online surveys
Dena Simmons, Catalina Torrente, Lori Nathanson, Grace Carroll
A79: Observational assessment of fidelity to a family-centered prevention program: Effectiveness and efficiency
Justin D. Smith, Kimbree Brown, Karina Ramos, Nicole Thornton, Thomas J. Dishion, Elizabeth A. Stormshak, Daniel S. Shaw, Melvin N. Wilson
A80: Strategies and challenges in housing first fidelity: A multistate qualitative analysis
Mimi Choy-Brown, Emmy Tiderington, Bikki Tran Smith, Deborah K. Padgett
A81: Procurement and contracting as an implementation strategy: Getting To Outcomes® contracting
Ronnie M. Rubin, Marilyn L. Ray, Abraham Wandersman, Andrea Lamont, Gordon Hannah, Kassandra A. Alia, Matthew O. Hurford, Arthur C. Evans
A82: Web-based feedback to aid successful implementation: The interactive Stages of Implementation Completion (SIC)TM tool
Lisa Saldana, Holle Schaper, Mark Campbell, Patricia Chamberlain
A83: Efficient methodologies for monitoring fidelity in routine implementation: Lessons from the Allentown Social Emotional Learning Initiative
Valerie B. Shapiro, B.K. Elizabeth Kim, Jennifer L. Fleming, Paul A. LeBuffe
A84: The Society for Implementation Research Collaboration (SIRC) implementation development workshop: Results from a new methodology for enhancing implementation science proposals
Sara J. Landes, Cara C. Lewis, Allison L. Rodriguez, Brigid R. Marriott, Katherine Anne Comtois
A85: An update on the Society for Implementation Research Collaboration (SIRC) Instrument Review Project
doi:10.1186/s13012-016-0428-0
PMCID: PMC4928139  PMID: 27357964
21.  Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder 
Translational Psychiatry  2013;3(1):e220-.
Autism spectrum disorder (ASD) has been associated with mitochondrial disease (MD). Interestingly, most individuals with ASD and MD do not have a specific genetic mutation to explain the MD, raising the possibility of that MD may be acquired, at least in a subgroup of children with ASD. Acquired MD has been demonstrated in a rodent ASD model in which propionic acid (PPA), an enteric bacterial fermentation product of ASD-associated gut bacteria, is infused intracerebroventricularly. This animal model shows validity as it demonstrates many behavioral, metabolic, neuropathologic and neurophysiologic abnormalities associated with ASD. This animal model also demonstrates a unique pattern of elevations in short-chain and long-chain acyl-carnitines suggesting abnormalities in fatty-acid metabolism. To determine if the same pattern of biomarkers of abnormal fatty-acid metabolism are present in children with ASD, the laboratory results from a large cohort of children with ASD (n=213) who underwent screening for metabolic disorders, including mitochondrial and fatty-acid oxidation disorders, in a medically based autism clinic were reviewed. Acyl-carnitine panels were determined to be abnormal if three or more individual acyl-carnitine species were abnormal in the panel and these abnormalities were verified by repeated testing. Overall, 17% of individuals with ASD demonstrated consistently abnormal acyl-carnitine panels. Next, it was determined if specific acyl-carnitine species were consistently elevated across the individuals with consistently abnormal acyl-carnitine panels. Significant elevations in short-chain and long-chain, but not medium-chain, acyl-carnitines were found in the ASD individuals with consistently abnormal acyl-carnitine panels—a pattern consistent with the PPA rodent ASD model. Examination of electron transport chain function in muscle and fibroblast culture, histological and electron microscopy examination of muscle and other biomarkers of mitochondrial metabolism revealed a pattern consistent with the notion that PPA could be interfering with mitochondrial metabolism at the level of the tricarboxylic-acid cycle (TCAC). The function of the fatty-acid oxidation pathway in fibroblast cultures and biomarkers for abnormalities in non-mitochondrial fatty-acid metabolism were not consistently abnormal across the subgroup of ASD children, consistent with the notion that the abnormalities in fatty-acid metabolism found in this subgroup of children with ASD were secondary to TCAC abnormalities. Glutathione metabolism was abnormal in the subset of ASD individuals with consistent acyl-carnitine panel abnormalities in a pattern similar to glutathione abnormalities found in the PPA rodent model of ASD. These data suggest that there are similar pathological processes between a subset of ASD children and an animal model of ASD with acquired mitochondrial dysfunction. Future studies need to identify additional parallels between the PPA rodent model of ASD and this subset of ASD individuals with this unique pattern of acyl-carnitine abnormalities. A better understanding of this animal model and subset of children with ASD should lead to better insight in mechanisms behind environmentally induced ASD pathophysiology and should provide guidance for developing preventive and symptomatic treatments.
doi:10.1038/tp.2012.143
PMCID: PMC3566723  PMID: 23340503
acyl-carnitines; autism spectrum disorder; clostridia; microbiome; mitochondrial disease; propionic acid
22.  Comparison of white matter integrity between autism spectrum disorder subjects and typically developing individuals: a meta-analysis of diffusion tensor imaging tractography studies 
Molecular Autism  2013;4:25.
Background
Aberrant brain connectivity, especially with long-distance underconnectivity, has been recognized as a candidate pathophysiology of autism spectrum disorders. However, a number of diffusion tensor imaging studies investigating people with autism spectrum disorders have yielded inconsistent results.
Methods
To test the long-distance underconnectivity hypothesis, we performed a systematic review and meta-analysis of diffusion tensor imaging studies in subjects with autism spectrum disorder. Diffusion tensor imaging studies comparing individuals with autism spectrum disorders with typically developing individuals were searched using MEDLINE, Web of Science and EMBASE from 1980 through 1 August 2012. Standardized mean differences were calculated as an effect size of the tracts.
Results
A comprehensive literature search identified 25 relevant diffusion tensor imaging studies comparing autism spectrum disorders and typical development with regions-of-interest methods. Among these, 14 studies examining regions of interest with suprathreshold sample sizes were included in the meta-analysis. A random-effects model demonstrated significant fractional anisotropy reductions in the corpus callosum (P = 0.023, n = 387 (autism spectrum disorders/typically developing individuals: 208/179)), left uncinate fasciculus (P = 0.011, n = 242 (117/125)), and left superior longitudinal fasciculus (P = 0.016, n = 182 (96/86)), and significant increases of mean diffusivity in the corpus callosum (P = 0.006, n = 254 (129/125)) and superior longitudinal fasciculus bilaterally (P = 0.031 and 0.011, left and right, respectively, n = 109 (51/58)), in subjects with autism spectrum disorders compared with typically developing individuals with no significant publication bias.
Conclusion
The current meta-analysis of diffusion tensor imaging studies in subjects with autism spectrum disorders emphasizes important roles of the superior longitudinal fasciculus, uncinate fasciculus, and corpus callosum in the pathophysiology of autism spectrum disorders and supports the long-distance underconnectivity hypothesis.
doi:10.1186/2040-2392-4-25
PMCID: PMC3726469  PMID: 23876131
Autistic disorder; Asperger; Brain; Human; Imaging; Pervasive developmental disorder
23.  Traumatic Brain Injury Alters Methionine Metabolism: Implications for Pathophysiology 
Methionine is an essential proteinogenic amino acid that is obtained from the diet. In addition to its requirement for protein biosynthesis, methionine is metabolized to generate metabolites that play key roles in a number of cellular functions. Metabolism of methionine via the transmethylation pathway generates S-adenosylmethionine (SAM) that serves as the principal methyl (−CH3) donor for DNA and histone methyltransferases (MTs) to regulate epigenetic changes in gene expression. SAM is also required for methylation of other cellular proteins that serve various functions and phosphatidylcholine synthesis that participate in cellular signaling. Under conditions of oxidative stress, homocysteine (which is derived from SAM) enters the transsulfuration pathway to generate glutathione, an important cytoprotective molecule against oxidative damage. As both experimental and clinical studies have shown that traumatic brain injury (TBI) alters DNA and histone methylation and causes oxidative stress, we examined if TBI alters the plasma levels of methionine and its metabolites in human patients. Blood samples were collected from healthy volunteers (HV; n = 20) and patients with mild TBI (mTBI; GCS > 12; n = 20) or severe TBI (sTBI; GCS < 8; n = 20) within the first 24 h of injury. The levels of methionine and its metabolites in the plasma samples were analyzed by either liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry (LC-MS or GC-MS). sTBI decreased the levels of methionine, SAM, betaine and 2-methylglycine as compared to HV, indicating a decrease in metabolism through the transmethylation cycle. In addition, precursors for the generation of glutathione, cysteine and glycine were also found to be decreased as were intermediate metabolites of the gamma-glutamyl cycle (gamma-glutamyl amino acids and 5-oxoproline). mTBI also decreased the levels of methionine, α-ketobutyrate, 2 hydroxybutyrate and glycine, albeit to lesser degrees than detected in the sTBI group. Taken together, these results suggest that decreased levels of methionine and its metabolic products are likely to alter cellular function in multiple organs at a systems level.
doi:10.3389/fnsys.2016.00036
PMCID: PMC4850826  PMID: 27199685
concussion; epigenetic changes; metabolomics; protein methylation; S-adenosylmethionine; transsulfuration
24.  The evaluation of food allergy on behavior in autistic children 
Background:
Despite many efforts, the etiology of autism remains unknown. Food allergy has been suggested as a pathogenic factor in Autism Spectrum Disorder (ASD). Our aim in this study was to determine whether food allergy could be considered as a risk factor for autistic children.
Methods:
Thirty-nine autistic children were examined by the skin prick test (SPT), and total serum IgE was evaluated by ELISA. SPTs were performed for egg whites, oranges, peanuts, tomatoes, tuna fish, walnuts, aubergines, melons, grapes, and cow milk. Parents and teachers were then asked to exclude these items from the childrens’ diets for six months. After the treatment period, the autistic children who tested positive for food allergies were re-assessed by a standard questionnaire to obtain further information about their medical histories.
Results:
Three of the study’s 39 autistic children (7.7%) tested positive on the SPT. Total serum IgE levels were elevated in 56.4% of the subjects (mean=164±24.5, cut-off >155 IU/ml). The results showed a decreased mean in the childrens’ autistic behaviors on the Children Autism Rating Scale (CARS) after both eight weeks and six months; however, this decrease was not statistically significant.
Conclusion:
Food allergy may play a role in the pathophysiology of autism. We conclude that avoidance of certain foods benefits the behavior of autistic children.
PMCID: PMC4757079  PMID: 26989707
Autism; Food allergy; Skin prick test
25.  A systematic review with meta-analysis of comprehensive interventions for preschool children with autism spectrum disorder (ASD): study protocol 
BMJ Open  2012;2(2):e000679.
Introduction
The aims of this study are to (1) conduct a systematic review of the intervention literature in preschool children with autism spectrum disorder (ASD), including types of interventions that are tested and the classification of outcome measures used and (2) to undertake a meta-analysis of the studies, allowing for the first time the comparison of different approaches to intervention using comparative outcomes. There are a number of alternative modalities of intervention for preschool children with ASD in use with different theoretical background and orientation, each of which tend to use different trial designs and outcome measures. There is at this time an urgent need for comprehensive systematic review and meta-analyses of intervention studies for preschool children with ASD, covering studies of adequate quality across different intervention types and measurement methods, with a view to identifying the best current evidence for preschool interventions in the disorder.
Methods and analysis
The authors will perform a systematic review of randomised controlled trials for preschool children with ASD aged 0–6 years, along with a meta-analysis of qualifying studies across intervention modality. The authors will classify the interventions for preschool children with ASD under three models: behaviour, multimodal developmental and communication focused. First, the authors will perform a systematic review. Then, the authors will conduct a meta-analysis by comparing the three models with various outcomes using an inverse variance method in a random effect model. The authors will synthesise each outcome of the studies for the three models using standardised mean differences.
Dissemination and ethics
This study will identify each intervention's strengths and weaknesses. This study may also suggest what kinds of elements future intervention programmes for children with ASD should have. The authors strongly believe those findings will be able to translated into the clinical practices and patients and their family benefits. Review registration: PROSPERO CRD42011001349.
Article summary
Article focus
This is a protocol of a systematic review and meta-analysis of comprehensive interventions for preschool children with autism spectrum disorder (ASD).
We will conduct a systematic review of the intervention literature in preschool ASD, including type of intervention that is tested and classification of outcome measures used.
We will undertake a meta-analysis of the studies, allowing for the first time the comparison of different approaches to intervention using comparative outcomes.
Key messages
We will classify the interventions for preschool ASD under three models: behaviour, multimodal developmental and communication focused.
We will perform a systematic review and conduct a meta-analysis by comparing the three models with various outcomes.
Strengths and limitations of this study
This study will identify each intervention's strengths and weaknesses.
This study may also suggest what kinds of elements future intervention programmes for children with ASD should have.
The measures used for outcome are varied between studies, and the standardised data will be heterogeneous. We do not assume that each study is estimating exactly the same quantity. However, those heterogeneous data can be synthesised in the analyses using random effects models.
doi:10.1136/bmjopen-2011-000679
PMCID: PMC3298837  PMID: 22396224

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