The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12614000773639
Ethics application status
Approved
Date submitted
12/07/2014
Date registered
21/07/2014
Date last updated
24/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Clinical Validation Study to Determine Whether Whole Genome Sequencing (WGS) can Assist with Autopsy Findings for Families who have Experienced a Perinatal Death Without any Definitive Cause
Scientific title
Trio Analysis using Whole Genome Sequencing to Assist Interpretation of Autopsy Findings for Families who have Experienced a Perinatal Death Without any Definitive Cause
Secondary ID [1] 284973 0
None
Universal Trial Number (UTN)
U1111-1159-2295
Trial acronym
WGS Clinical Validation Study to Assist with Perinatal Autopsy
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Genetic Causes of Perinatal Death 292476 0
Condition category
Condition code
Human Genetics and Inherited Disorders 292786 292786 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
It is planned to perform Whole Genome Sequence (WGS) testing on the DNA samples of approximately 100 infants where autopsy findings where indeterminate, as well as their parents (a ‘trio analysis’) to further elucidate the cause of death. In its raw form, the WGS data output will provide information on all 6 billion nucleotides from both nuclear and mitochrondrial DNA. This data will then to be interrogated using a validated bioinformatics approach to determine the relevance of such information to firstly known causes of perinatal death and later, to causes that have not been directly linked with perinatal death
Intervention code [1] 289802 0
Diagnosis / Prognosis
Comparator / control treatment
The Wellderly database will be accessed to provide comparator/control genetic information to compare with the study cohort. This is a private database located within the Scripps Insitute and includes full genomic information on approximately 1000 healthy individuals over the age of 80. The project began in 2008 with the aim of recruiting 2000 healthy individuals that are over 80 years of age.
Control group
Historical

Outcomes
Primary outcome [1] 292637 0
To perform a complete genomic sequence on up to 100 perinatal cases which have previously undergone a comprehensive autopsy, as well as their parents (‘trio analysis’). Following bioinformatics interrogation of the trio data, comparison with a wide range of databases and correlation with the autopsy findings, significant test results (of gene variants) will be validated using standard clinical diagnostic procedures such as the Sanger sequencing technique.
Timepoint [1] 292637 0
3 months following recruitment
Primary outcome [2] 292672 0
Computation genomce analysis (Cga) tools will be used to identify variants of interest that will be filtered by attributes pertaining to inheritance, coding DNA sequence, donor, acceptor and impact to investigate variants observed in parents and their offspring. Comparisons will then be made against the Wellderly database to ascertain the level of clinical significance to assign to any unusual genetic characteristics.
Timepoint [2] 292672 0
3 months following recruitment
Secondary outcome [1] 309394 0
To assess the effect of the Whole Genome Sequencing (WGS) results on the original perinatal autopsy findings and whether this result contributes towards our understanding of the cause of death, and thus impacts on the management of future pregnancies.
Timepoint [1] 309394 0
3 months following recruitment

Eligibility
Key inclusion criteria
Criteria for Inclusion – Perinatal Cases:
1. Perinatal death occurring at Mater Mother’s Hospital between 2010 and 2014;
2. After attempting to contact both parents, minimally one parent has been contacted after 3 attempts and is willing to participant in this clinical trial

Criteria for Inclusion – Biological Parent Participants:
1. A baby (from 20 weeks gestation to 28 days postpartum) who passed away at Mater Mother’s Hospital between 2010 to 2014
2. Able to attend at least the initial study visit for informed consent and blood collection
3. Important medical information pertaining to the deceased infant is part of the mother’s medical notes
Minimum age
0 Hours
Maximum age
28 Days
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Criteria for Exclusion – Perinatal Cases:
1. Coronial Case
2. Insufficient or inadequate DNA sample
3. Only the father is contactable and critical medical information about the deceased infant resides in the mother’s medical notes.
4. One parent refuses permission for their child’s DNA to be used for the study.

Criteria for Exclusion – Biological Parent Participants:
1. A baby (from 20 weeks gestation to 28 days postpartum) who passed away at Mother Mother’s Hospital between 2010 and 2014 that was/is the subject of a coronial investigation
2. A concurrent condition that may limit the decision-making capabilities of the participant during the informed consent process
3. Blood Donation of >450ml within 30 days of the initial study visit

Study design
Purpose
Screening
Duration
Cross-sectional
Selection
Defined population
Timing
Both
Statistical methods / analysis
This project application describes an extension of the genetic component of the routine perinatal autopsy and thus the deleterious (disease-associated) genetic variants in each individual child will be assessed in accordance with their personal autopsy findings and clinical status. The project does not address a ‘disease population’ vs. a ‘normal population’ in the conventional research design sense. Therefore we will not be using conventional statistical approaches (i.e. disease population vs. normals) to evaluate the data.

Thus, the usual arguments about a minimal sample size do not apply to this study. However, based on industry standards for early phase proof of concept (POC) IVD clinical trials, a study population of 100 (pertaining to the primary outcome variable) is considered to be sufficient to detect any clinically significant linkages in both lethal and non-lethal variants and documented pathophysiology.

The Intent-to-Treat (Diagnose) Population will include all WGS test results irrespective of whether the trio datasets are complete. The Intent-to-Diagnose population will be used for analysis of the primary efficacy endpoint.

The Per-Protocol Population comprises complete trio datasets where there is WGS test results for the deceased infant or infants as well as both parents as well as all relevant clinical information. The Per-Protocol population will be used for analysis of the secondary efficacy endpoint.

The bioinformatics plan has been structured to assess the functional impact and clinical relevance of all SNP variants. From this analysis, major functional variants can be identified and their relationship to clinical pathology and radiology results will then be assessed. Furthermore, linkage analysis will be performed within the trio datasets to determine whether the mutations are spontaneous or whether they have been inherited from a parent or parents.

In brief, Computation genome analysis (Cga) tools will be used to identify variants of interest that will then be filtered on the following attributes ‘inheritance’, ‘coding DNA sequence’ (CDA), ‘donor’, ‘acceptor’ and ‘impact’, to investigate variants observed in parents and their offspring.

It is planned to access the Wellderly database at Compete Genomics, a genomic database with full genomic data on 1000 people who have lived long and healthy lives. Comparisons will be made with a “normal” population to ascertain the level of clinical significance to assign to any unusual genetic characteristics. Furthermore, Ingenuity software will be applied to prioritize variants of autosomal dominant inheritance.

Other data mining software used to interrogate complex system biology datasets such as Integrative Genomics Viewer (IGV) and OmniViz will be used to visualize information and determine the significance of variants that are not as well described.

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 2715 0
Mater Mother's Hospital - South Brisbane
Recruitment postcode(s) [1] 8442 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 289593 0
Hospital
Name [1] 289593 0
Mater Health Services
Address [1] 289593 0
Raymond Tce
South Brisbane QLD 4101
Country [1] 289593 0
Australia
Primary sponsor type
Hospital
Name
Mater Health Services
Address
Raymond Tce
South Brisbane QLD 4101
Country
Australia
Secondary sponsor category [1] 288277 0
None
Name [1] 288277 0
Address [1] 288277 0
Country [1] 288277 0
Other collaborator category [1] 278054 0
Commercial sector/Industry
Name [1] 278054 0
Complete Genonmics
Address [1] 278054 0
2071 Stierlin Court
Mountain View
California 94043
Country [1] 278054 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291328 0
Mater Health Services Human Research Ethics Committee (EC00332)
Ethics committee address [1] 291328 0
Raymond Tce
South Brisbane QLD 4010
Ethics committee country [1] 291328 0
Australia
Date submitted for ethics approval [1] 291328 0
Approval date [1] 291328 0
03/06/2014
Ethics approval number [1] 291328 0
HREC/14/MHS/74

Summary
Brief summary
Approximately one percent of pregnancies result in a death during the perinatal period, which extends from 20 completed weeks of gestation until 28 days after birth. The causes of unexpected death during this period range from obvious gross structural abnormalities, placental dysfunction and transplacentally-acquired infections, to cases where there is no apparent reason for the early demise of the fetus or neonate.
A percentage of these perinatal deaths that have no detectable gross structural abnormalities may, for example, occur due to underlying cardiac channelopathies, cardiomyopathies and potentially, some forms of epilepsy. Such conditions at a development stage may not leave any clinically significant characteristics at autopsy such as histological abnormalities detectable with light microscopy or anatomical changes normally observed with MRI.
In essence, this study is an extension to the usual genetic analysis component of our perinatal autopsy protocol, enabled by a new technology that is currently maturing. Thus, the rationale of this trial is to provide more information on the cause of perinatal death and improve the clinical management of families whose babies have died during the perinatal period.
Trial website
None
Trial related presentations / publications
None
Public notes

Contacts
Principal investigator
Name 49910 0
Prof Deon Venter
Address 49910 0
Mater Pathology
Level 7
Corporate Services Bldg
Raymond Tce
South Brisbane QLD 4101
Country 49910 0
Australia
Phone 49910 0
+617 3163 2073
Fax 49910 0
Email 49910 0
Deon.Venter@mater.org.au
Contact person for public queries
Name 49911 0
Prof Deon Venter
Address 49911 0
Mater Pathology
Level 7
Corporate Services Bldg
Raymond Tce
South Brisbane QLD 4101
Country 49911 0
Australia
Phone 49911 0
+617 3163 2073
Fax 49911 0
Email 49911 0
Deon.Venter@mater.org.au
Contact person for scientific queries
Name 49912 0
Prof Deon Venter
Address 49912 0
Mater Pathology
Level 7
Corporate Services Bldg
Raymond Tce
South Brisbane QLD 4101
Country 49912 0
Australia
Phone 49912 0
+617 3163 2073
Fax 49912 0
Email 49912 0
Deon.Venter@mater.org.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary