General workplan

Based on our multidisciplinary and complementary expertise around NGS, our pioneering work for diagnostic application of NGS (gene panels and exomes) and access to all genetic patient cohorts in a national consortium (including all clinical genetic centres in the Netherlands), we will develop personalized care pathways for rare disease through involvement of all relevant stakeholders. Using a multidimensional model of clinical utility,10 we will provide for the first time evidence on the utility and cost-effectiveness of a (rapid) WGS-first care pathway. Clinical validity of WGS and rapid genetic testing (by WES) has been demonstrated sufficiently2,7,8. For instance, evidence of effectiveness for NGS-based testing has been unarguably been demonstrated by an increase in diagnostic yield for rare Mendelian disorders, ID and other clinical and genetic heterogeneous disorders2,3,5,11-16. Moreover, more accurate therapeutic interventions were offered in 18% who obtained a diagnosis3 and changes in clinical care were reported in 49% of newly diagnosed families.8 It was furthermore noticed that if NGS had been the first tier genetic test –performed at symptom onset– time to diagnosis (TTD) would have been reduced by 77 months.8 It is needless to say that a TTD of >6.5 years is unsatisfactory for NND patients, but unacceptable for critically ill newborns given that patient outcome may depend on treatment options instilled by a genetic diagnosis, subsequently lessening morbidity and mortality.7,17 To assess the clinical utility of a (rapid) WGS-first approach, we propose a prospective parallel study design (PPD) in which patients receive both the standard diagnostic pathway as well as the WGS-first pathway. For NICU patients, the WGS-first will be assessed as instant test. Our PPD allows us to directly compare the outcome measures, including diagnostic yield and costs associated with each pathway, not biased by the clinical heterogeneity of the study cohort itself.
WP list
The project is divided into 5 work packages. In the list below the titles of the work packages and the involvement of the partners in different work packages is summarized. Per work package different tasks and deliverables have been identified. See under “work package description” for more details.
  • WP1 - Clinical utility study and health technology assesment
  • WP2 - Standardized format for WGS anylysis and reporting
  • WP3 - Datasharing
  • WP4 - Counseling support and patient empowerment framework
  • WP5 - Project management

WP description (incl. deliverables) Strategies to reach our main aims include the following work packages and timelines:

Simplified schematic presentation of our parallel study design and overview of the work packages defined to assess the clinical utility of a WGS-first approach for NDD and NICU patient. Recruited patients will undergo both routine diagnostic testing including a vast amount of (genetic) diagnostic test (WP1). In addition, patients will simultaneously start the WGS-first approach. To enable this WGSfirst approach in a uniform way over the participating centres, we will develop standardized formats for reporting (WP2) and data sharing tools facilitating clinical interpretation of genetic variants (WP3). Time-to-diagnose and health care resource use and its effect on quality of life measures will be monitored throughout the course of the project (WP1). Both pathways will subsequently compared and evaluated at various aspects of clinical utility (WP1). Along side, a counseling support and patient empowerment framework will be developed (WP4) which will generate an advisory document on WGS and patient data gouvernance.



In this WP, we will perform the clinical utility study on implementing WGS as first tier diagnostic test. A prospective parallel design will allow to compare the standard diagnostic pathway and the WGS first pathway at various outcome measures, including the diagnostic yield, the impact on medical decision making, cost-to-diagnosis. These outcomes will be subsequently used to perform a budget impact analysis and to model various scenarios to establish the position of WGS as first tier test.


In WP2 we will develop a standardized format for data analysis pipelines at the laboratory level, based on bioinformatics expertise and hardware infrastructures to manage the massive sets of data produced by WGS, in collaboration with WP3 for the development of a data sharing infrastructure at the national level.


Data sharing will be done within the Working group for data sharing of the genetic laboratory society VKGL. This group consists of laboratory specialists and bioinformaticians of each centre. Of note, part of the implementation and deployment of the databases to be used is already financed by BBMRI and the centres themselves.


WP5: Project management

WP5 concerns the overall co-ordination of the project by participant 1, assisted by a project manager. They take care of management of contractual, financial, legal, administrative, scientific issues, project meetings.