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SynapDx Autism Gene Expression Analysis Study (STORY) (STORY)

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ClinicalTrials.gov Identifier: NCT01810341
Recruitment Status : Completed
First Posted : March 13, 2013
Last Update Posted : December 17, 2014
Information provided by (Responsible Party):

Study Description
Brief Summary:

This study will prospectively enroll approximately 880 children, at least 18 months and less than 60 months of age, who have been referred to a pediatric developmental evaluation center. Enrolled children will have blood drawn for RNA gene expression analysis and optionally for metabolite, lipid and DNA analysis and undergo a clinical evaluation to determine the presence or absence of a diagnosis of ASD.

The primary objective of this study is:

- To develop an algorithm to classify blood RNA gene expression patterns to maximize agreement between the classification and a clinical assessment of presence or absence of Autism Spectrum Disorders (ASD).

The secondary objectives of this study are:

  • To develop an algorithm to classify plasma metabolite and/or lipid profiles in such a way as to maximize agreement between the classification and a clinical assessment of presence or absence of ASD.
  • To prospectively assess the clinical sensitivity and specificity of the plasma metabolite and/or lipid profile classification algorithm in a separate population consisting of children referred to a developmental evaluation clinic for a possible developmental disorder (DD).
  • To evaluate clinical sensitivity and specificity of various combinations of gene expression signature, metabolite and/or lipid signatures, and presence of ASD-associated genetic variation detected by chromosomal microarray analysis (CMA) or sequencing protein-coding regions of the genome.

Condition or disease

Detailed Description:

The primary aim of this study is to define a gene expression signature indicative of ASD and to establish its clinical sensitivity and specificity. Clinician diagnosis of ASD will be made using DSM-5 as the reference standard instrument. The widely used diagnostic instrument Autism Diagnostic Observation Schedule (ADOS-2) is a typical component of the clinical assessment for a child diagnosed with ASD and this evaluation will be performed on all study participants. Secondary aims of this study are (1) to define metabolite and lipid signatures indicative of ASD and establish their clinical sensitivity and specificity and (2) to determine clinical sensitivity and specificity of various combinations of gene expression signature, metabolite and/or lipid signatures, and presence of ASD-associated genetic variation detected by CMA and sequencing protein-coding regions of the genome

Analyses: Details of the analysis will be specified in a Statistical Analysis Plan (SAP), which will include procedures for handling outliers, missing data, and differences across sites. The SAP will be reviewed and approved by a committee of Principal Investigators (PIs) before unblinding of the validation set.

Primary analyses: The primary outcomes of the study will be the estimates of the clinical sensitivity and specificity of the SDX-002 test to classify subjects according to DSM-5 ASD diagnosis, with associated 95% confidence intervals. Sensitivity and specificity will be assessed on the Validation Phase population based on agreement with the clinical diagnosis of presence or absence of Autism Spectrum Disorder by DSM-5 (published May 2013).

The gene expression signature will be trained on the 500 subject Development Phase set, using 5-fold cross validation over the results of several machine learning algorithms, including partial least squares, support vector machines, and boosted decision trees. The training procedure will generate estimated ROC curves for each method, as well as confidence intervals for the area under the curve (AUC). The final choice of a machine-learning algorithm will be based on AUC, as well as on the estimated performance at the chosen operating point on the ROC curve. The operating point will be chosen to provide high sensitivity at an acceptable specificity.

Secondary analyses: In the majority of patients enrolled to date, consent was obtained for collection of an optional bio-repository sample. The intended analysis of the bio-repository samples has now been established (see also, secondary objectives listed above). The metabolomic and lipomic signatures will be similarly assessed on the subset of the 500 subjects in the Development Phase set who consent to a bio-repository sample. In addition to the gene expression signature, metabolite and/or lipid signatures and DNA analysis will be combined with the gene expression signature in various configurations and the impact of these additional measures on clinical sensitivity and specificity will be evaluated. If these additional metabolomic/lipomic signatures and/or DNA analyses improve test performance, these elements may be included in the SDX-002 assay.

Sensitivity and specificity the final SDX-002 assay will also be assessed among subpopulations using demographic information and the results of developmental testing. There are likely to be few subjects in many of these subpopulations and caution will be used in interpreting the results. Planned subpopulation analyses include gender, age, ethnicity, ASD DSM-IV-TR diagnostic subcategory, DSM-5 ASD severity level (social communication and restricted interests/repetitive behaviors) and ADOS-2 scores.

Study Design

Study Type : Observational
Estimated Enrollment : 880 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: SynapDx Autism Spectrum Disorder Gene Expression Analysis Study
Study Start Date : March 2013
Primary Completion Date : July 2014
Study Completion Date : December 2014

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Groups and Cohorts

Development Group
In the Development Phase, analyses will be performed until the classification algorithm is finalized.
Validation Group
The Validation Phase will assess the performance of the finalized classification algorithm in 300 subjects.

Outcome Measures

Primary Outcome Measures :
  1. RNA gene expression in peripheral blood [ Time Frame: Within 30 days of collection ]

Secondary Outcome Measures :
  1. Metabolites, lipids and DNA variation in peripheral blood [ Time Frame: Within 30 days of collection ]

Biospecimen Retention:   Samples With DNA
Peripheral blood

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Months to 60 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Children 18 months to less than 60 months referred to a developmental evaluation center for evaluation of a possible developmental disorder.

Inclusion Criteria:

  • Referred to a developmental evaluation center for evaluation of a possible developmental disorder, other than isolated motor problems.
  • At least 18 months and less than 60 months.
  • Parent/legal guardian has been informed about the study and has signed an informed consent form.

Exclusion Criteria:

  • Prior reliable diagnosis of Autism Spectrum Disorder (i.e. prior evaluation by a multi-disciplinary team has already reliably established Autism Spectrum Disorder diagnosis).
  • Unable or unwilling to complete study procedures.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01810341

  Hide Study Locations
United States, Arizona
Melmed Center
Scottsdale, Arizona, United States, 85254
United States, California
Miller Children's Hospital
Long Beach, California, United States, 90806
UC Davis MIND Institute
Sacramento, California, United States, 95817
United States, Georgia
Emory University
Decatur, Georgia, United States, 30033
United States, Illinois
Rush Medical Center
Chicago, Illinois, United States, 60612
United States, Indiana
Riley Hospital for Children
Indianapolis, Indiana, United States, 46202
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
Lurie Center Massachusetts General Hospital
Lexington, Massachusetts, United States, 02421
United States, New York
Mount Sinai School of Medicine/Seaver Center
New York, New York, United States, 10029
Institute for Behavioral Research on Staten Island
Staten Island, New York, United States, 10314
United States, North Carolina
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27517
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37212
United States, Texas
Baylor College of Medicine/Texas Children's Hospital
Houston, Texas, United States, 77054
United States, Washington
Seattle Children's
Seattle, Washington, United States, 98121
Canada, Alberta
Glenrose Rehabilitation Hospital
Edmonton, Alberta, Canada, T5G 0B7
Canada, Ontario
Holland Bloorview Kids Rehabilitation Hospital
Toronto, Ontario, Canada, M4G 1R8
Sponsors and Collaborators
Study Director: Barbara Rathmell, MD SynapDx Corp
More Information

Responsible Party: SynapDx
ClinicalTrials.gov Identifier: NCT01810341     History of Changes
Other Study ID Numbers: 12002
First Posted: March 13, 2013    Key Record Dates
Last Update Posted: December 17, 2014
Last Verified: December 2014

Keywords provided by SynapDx:
Autism Spectrum Disorders
Gene expression
Developmental Delay

Additional relevant MeSH terms:
Autistic Disorder
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurodevelopmental Disorders
Mental Disorders