The ISCA Consortium — Working together to improve the clinical application of microarray testing
The ISCA Education and Ethics Work GroupHanson, K., Ho, D., Mitchell, E., Riggs, E., Savage, M., and Faucett, W.A.
Clinical microarray testing has been recognised as a first-tier diagnostic test for children and adults with developmental delay, intellectual disabilities, autism spectrum disorders and birth defects.1,2 Its use is also expanding into other clinical arenas such as prenatal diagnostics and cancer. Clinical microarray testing is providing both physicians and their patients with better diagnostic and management tools. However, the identification of CNVs of unknown clinical significance, as well as the detection of clinically significant results unrelated to the primary reason for testing, is creating new challenges for both patients and their clinicians.
In response to the growing need to address these challenges, the International Standards for Cytogenomic Arrays (ISCA) Consortium was founded in 2007 by Dr David Ledbetter and Dr Christa Lese-Martin. This group of clinicians, laboratorians, researchers and industry partners is committed to improving the quality of laboratory services and clinical practice as it relates to new molecular cytogenetic technologies. These technologies include array comparative genomic hybridisation and quantitative SNP analysis by microarrays or bead chip technology. The group’s overarching goal is to raise the standard of patient care by improving the quality of cytogenomic microarray testing.
Currently, the ISCA Consortium is focused on the following efforts:
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Establishing recommendations for and developing evidence to support the clinical utility of cytogenomic array testing
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Developing evidence-based standards for cytogenomic array design and for the interpretation of cytogenetic array results
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Building and supporting an open-access public database of genomic array data and associated clinical findings for use by the clinical and research community
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Encouraging laboratory participation
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Educating clinicians on the importance of providing phenotype information with all samples submitted for testing
The database, known as the Clinical CNV Atlas of Human Development, provides a shared venue for the submission of de-identified clinically reported CNVs and corresponding phenotypic data. Genotype and phenotype working groups have developed standards for the submission of genotype and phenotype data (Figure 1), respectively, and are currently developing guidelines to improve the clinical interpretation of microarray results. Another working group consisting of bioinformatics experts oversees data management, curation and ease of use by clinicians and researchers. A separate working group oversees education, engagement and ethics and is responsible for the development of educational materials and an engagement plan to support the project and encourage participation, while including safeguards to insure privacy.
Figure 1: The ISCA Consortium postnatal phenotype form enables standardised submission of genotype and phenotype information.
The ISCA database accepts raw and normalized array data, CNV calls with clinical interpretations, and phenotype information from participating laboratories. The database is hosted at National Center for Biotechnology Information (NCBI) in dbGaP (database of Genotypes and Phenotypes) and dbVar (database of genomic structural Variation). The data is available in two formats:
- CNV calls with their clinical interpretations, which are available to the public in dbVar. In addition, this data will be available through multiple other sources, including the ISCA website, the UCSC Genome Browser, and commercially available array analysis software (e.g. CytoSure Interpret Software).
- Raw and normalised array data; which will be deposited into dbGaP and will require controlled access. Access to data in dbGaP must be approved through the Data Access Committee (DAC) at NIH.
To date, the ISCA consortium consists of 167 laboratories from 30 countries. Several laboratories are already contributing data to the database and this number is growing as each lab works through the submission process. Data has been collected on over 24,000 clinical cases to date. Results are classified as pathogenic, likely pathogenic, uncertain, likely benign, and benign. This classification scheme is based on criteria agreed upon by experts within the ISCA consortium and in conjunction with American College of Medical Genetics guidelines (still currently under review). Membership in the ISCA Consortium is open to all individuals and laboratories involved in cytogenomic array testing who are committed to free data sharing and to participation in a process to develop evidence-based standards and guidelines to improve patient care.
Membership in the ISCA Consortium and database benefits clinicians, researchers and laboratories. The database itself will drive improvement in the quality of clinical practice by allowing for more concise genetic counselling about prognosis, recurrence risks, and information related to ambiguous results. In addition, the consortium shows the value of building strong coalitions between clinicians, families, laboratories, and available support resources. This multi-disciplinary group will create practice guidelines for clinicians and laboratories and help support the integration of new genetic testing technologies into clinical practice.
Laboratories and researchers also benefit. The database provides laboratories with an additional resource for the interpretation and curation of microarray results. Participating laboratories can monitor their own data submissions by comparing them to their data already in the ISCA database. This curation process provides a critical quality assurance check for submitting laboratories. Results with conflicting clinical interpretations can be brought up for review by the ISCA Consortium. ISCA Consortium members also have access to ISCA array design files which are now available through multiple array companies. The current ISCA recommended clinical array is the result of merging designs of existing custom arrays and continues to be improved upon based on recommendations from ISCA Consortium members. Researchers that have been approved for dbGaP access will have a resource for targeted studies on patients with selected CNVs from a standardized central foundation.
To submit data to the ISCA database, laboratories need Institutional Review Board (IRB) approval which can be facilitated through tools found on the ISCA website. The National Institutes of Health (NIH) allows clinical laboratories to submit clinical data to the CNV database using an opt-out mechanism, whereby clinicians and patients are informed of the use of de-identified data and patients are provided a means to withdraw participation. Opt-out notification is based on the following premises:
- Reasonable effort is made to inform the ordering clinicians of the use of de-identified patient data.
- Reasonable effort is made to inform patients of data usage through educational materials.
- Patients must be provided a means to withdraw participation from the database.
Patient confidentiality is protected by removing all patient identifiers such as name, date of birth, and unique laboratory accessioning numbers prior to data submission. Data is submitted using a de-identified case number. The submitting laboratory certifies that appropriate protocols for anonymising data have been followed. The ISCA Consortium has chosen Cartagenia to help facilitate and automate the data submission process.
The ISCA website (Figure 2) provides more information on the Consortium and its members, as well as resources for gaining IRB approval and data submission. Registration is free and members can access the database and it's many tools. For more information on any aspect of the ISCA Consortium and database, contact Erin Riggs at Emory University
Figure 2: The ISCA Consortium website
(www.iscaconsortium.org) provides additional information and resources.
Summary
By joining the ISCA Consortium, clinical laboratories can benefit from enhanced clinical insight brought through the use of standardised, evidence-based microarray designs and subsequent data sharing across the community. This will help drive improvement in the quality of clinical practice and bring significant advancements in patient care.
References
- Miller, D.T., et al. (2010) Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J of Hum Genet. 86, 749–764.
- Manning and Hudgins (2010) Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genetics in Medicine. 12, 742-745
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