Human Genetic Testing in Austria: An Overview of Reviews of Massive Parallel Sequencing (MPS) - Application Areas, Clinical Evidence, and Implications for Healthcare

Duration: April 2025 – November 2025 (7 PM)
Language: English (with German summary)

Background:
Human genetic testing encompasses various methods for analysing human genetic material. Massive parallel sequencing (MPS) – including Next Generation Sequencing (NGS/Short-Read) and Third Generation Sequencing (TGS/Long-Read) – has emerged as a key technology. These methods enable simultaneous analysis of numerous DNA fragments, making genetic diagnostics faster while significantly expanding applications in medical care. This development creates new possibilities in diagnostics and therapy planning but also raises complex questions regarding evidence assessment, integration into standard care, and ethical implications. The increasing availability of these technologies requires evidence-based decision-making foundations for healthcare systems [1].

The benefit assessment of human genetic testing is complex. On one hand, primary studies and systematic reviews on genomic data showed methodological weaknesses and limited evidence regarding patient-relevant endpoints [2, 3]. On the other hand, genomic medicine offers potential for more meaningful study designs through targeted patient selection strategies and validated surrogate markers for more efficient and adaptive study designs [4].

A recent, unpublished review by GÖG (Gesundheit Österreich GmbH) analysed human genetic services, including organisational aspects, in selected countries (Belgium, Netherlands, Germany) [5]. The analysis focused on service catalogues, reimbursement systems, and access pathways to genetic diagnostics, identifying significant differences between countries regarding structure, level of detail, and scope of genetic service catalogues. Additionally, a recent AIHTA Rapid Review provided an overview of sequencing technologies already in use and under development, as well as their application fields [6].

Both the GÖG report [5] and the AIHTA Rapid Review [6] identified a broad spectrum of application fields for human genetic testing, primarily aiming at personalised medicine through genetic diagnosis of rare diseases and metabolic disorders, molecular pathology testing in oncology (tumor profiling, liquid biopsy), or pharmacogenetics. Both reports particularly emphasised requirements for genetic counseling, quality assurance systems, and cross-national cooperation models for rare genetic diseases. The challenges in implementing MPS technologies were also addressed: large data volumes, high costs, complex result interpretation, and ethical questions regarding incidental findings.

Building on this preliminary work, the present project aims to systematically map clinical indications categorised by application fields, evaluate the clinical evidence of selected MPS technologies, particularly as Austrian social insurance providers (SV) are planning a benefit catalogue for human genetic testing.

Project Objectives:
This project aims to systematically review evidence from systematic reviews on human genetic testing with a focus on MPS technologies for decision-makers in the Austrian healthcare system. Specifically:

1. Identification of clinical indications structured by application fields of human genetic testing from systematic reviews/HTA reports.
2. Assessment of evidence on the benefits of selected MPS-tests, considering diagnostic accuracy as "linked evidence" as well as reported clinical consequences and patient-relevant endpoints.
3. Structured presentation of organisational, economic, and ethical implications of selected MPS tests.
4. Provision of a basis for prioritising human genetic services with a focus on MPS for possible inclusion in the benefit catalogue.

Non-Objectives:
The following aspects will not be addressed in the project:

• Complete de novo assessment of all available human genetic tests
• Detailed cost analyses or budget impact analyses of individual tests
• Legal assessment of data protection and liability issues
• Systematic evaluation of primary studies on individual genetic tests

Research Questions:
RQ1: Which clinical indications structured by application fields for human genetic testing are evaluated in systematic reviews and HTA reports?

RQ2: What evidence exists on the benefits of prioritised human genetic testing regarding:

• diagnostic accuracy as "linked evidence"
• clinical consequences and patient-relevant endpoints (e.g., therapy changes, morbidity, mortality, quality of life)

RQ3: What organisational, economic, and ethical implications are reported in the literature in connection with the prioritised human genetic tests?

Methods:
Study Design
Overview of Reviews with multi-stage approach:

1. Initial scoping: Comparison of an SV list of human genetic services with international literature
2. Short-list: Prioritisation of 3-5 tests/indications in coordination with the umbrella organisation of Austrian Social Insurance Providers (DVSV). Economic implications (e.g., estimated quantities, costs) will be assessed together with the Social Insurance providers to create the short-list.
3. Evidence analysis: Systematic synthesis for prioritised MPS/indications

PICO: Literature inclusion criteria:

Abbreviations: HTA...Health Technology Assessment; NGS...Next Generation Sequencing; TGS...Third Generation Sequencing

Information Sources & Search Strategy
Systematic database search:

• PubMed/MEDLINE
• Embase
• Cochrane Library
• International HTA Database
• PROSPERO (for ongoing reviews)

Hand search:

• Reference lists of identified reviews
• Websites of relevant HTA agencies (e.g., NICE, IQWiG, CADTH)
• Websites of relevant professional societies

Search strategies will be carried out using keywords and validated filters for systematic reviews.

Literature Selection and Data Extraction:

Screening: Two independent authors will screen titles/abstracts and full texts according to pre-defined criteria. The selection process will be presented in a PRISMA flow diagram.

Data extraction: Relevant information on study characteristics, methods, and main results (PICO) will be extracted using piloted data extraction tables. Extraction will be performed by one author with verification by a second person.

Quality Assessment:
The quality of included systematic reviews will be assessed using ROBIS [7] by two independent authors. The results will be considered in the data synthesis.

Data Synthesis:
RQ1: Narrative description of identified clinical indications structured by application fields with tabular overview.

RQ2: Narrative synthesis of evidence on diagnostic accuracy and clinical consequences according to the EUnetHTA Core Model for diagnostic tests [8].

RQ3: Structured summary of reported organisational, economic, and ethical implications.

All work steps will be conducted using the four-eyes principle and quality-assured through internal and external review.

Timeline:

References:

1. Williams GA, Liede S, Fahy N, Aittomaki K, Perola M, Helander T, et al. Regulating the unknown: A guide to regulating genomics for health policy-makers. Policy Brief 38. Brussels: European Observatory on Health Systems and Policies; 2020.
2. Ioannidis JPA, Khoury MJ. Evidence-based medicine and big genomic data. Hum Mol Genet. 2018;27(R1).
3. Phillips KA, Deverka PA, Sox HC, Khoury MJ, Sandy LG, Ginsburg GS, et al. Making genomic medicine evidence-based and patient-centered: a structured review and landscape analysis of comparative effectiveness research. Genet Med. 2017;19(10):1081-91.
4. Ioannidis JPA, Khoury MJ. Are randomized trials obsolete or more important than ever in the genomic era? Genome Med. 2013;5(4):32.
5. Gesundheit Österreich GmbH (GÖG). Human genetic services in the standard care of selected countries. Unpublished report. Vienna: GÖG; 2024.
6. Jeindl R, Mayer-Ferbas J. Massive parallel sequencing – technologies for high-throughput analysis of genetic-genomic data sets. Rapid Review Nr. 015. Vienna: HTA Austria – Austrian Institute for Health Technology Assessment GmbH; 2024.
7. Whiting P, Savovi? J, Higgins JP, Caldwell DM, Reeves BC, Shea B, et al. ROBIS: A new tool to assess risk of bias in systematic reviews was developed. J Clin Epidemiol. 2016;69:225-34.
8. EUnetHTA [Internet]. [cited on 10.03.2025]. Available from: https://web.archive.org/web/20230201055231/https:/www.eunethta.eu/about-eunethta/