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A Reference Meta-model to Understand DNA Variant Interpretation Guidelines

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Conceptual Modeling (ER 2023)

Part of the book series: Lecture Notes in Computer Science ((LNCS,volume 14320))

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Abstract

Determining the role of a DNA variant in patients’ health status – a process known as variant interpretation – is highly critical for precision medicine applications. Variant interpretation involves a complex process where, regrettably, there is still debate on how to combine and weigh diverse available evidence to achieve proper and consistent answers. Indeed, at the time of writing, 22 different variant interpretation guidelines are available to the scientific community, each of them attempting to establish a framework for standardizing the interpretation process. However, these guidelines are qualitative and vague by nature, which hinders their streamlined application and potential automation. Consequently, more precise definitions are needed. Conceptual modeling provides the means to bring clarification within this domain. This paper presents our efforts to define and use a UML meta-model that describes the main concepts involved in the definition of variant interpretation guidelines and the constructs they evaluate. The precise conceptual definition of the guidelines allowed us to identify four common misinterpretation patterns that hamper the correct interpretation process and that can consequently affect classification results. In several proposed examples, the use of the meta-model provides support in identifying the inconsistencies in the observed process; this result paves the way for further proposing reconciliation strategies for the existing guidelines.

M.C. and A.G.S. should be regarded as Joint First Authors.

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Notes

  1. 1.

    https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/variant.

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Acknowledgements

This work was supported by the Valencian Innovation Agency and Innovation through the OGMIOS project (INNEST/2021/57), the Generalitat Valenciana through the CoMoDiD project (CIPROM/2021/023) and ACIF/2021/117, and the Spanish State Research Agency through the DELFOS (PDC2021-121243-I00,MICIN/AEI/10.13039/501 100011033) and SREC (PID 2021-123824OB-I00) projects, and co-financed with ERDF and the European Union Next Generation EU/PRTR.

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Authors and Affiliations

  1. PROS Group, Valencian Research Institute (VRAIN) Universitat Politècnica de València, Valencia, Spain

    Mireia Costa, Alberto García S., Ana Leon & Oscar Pastor

  2. Politecnico di Milano, Milan, Italy

    Anna Bernasconi

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  1. Mireia Costa
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  2. Alberto García S.
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  3. Ana Leon
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  4. Anna Bernasconi
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  5. Oscar Pastor
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Correspondence to Mireia Costa .

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Editors and Affiliations

  1. Federal University of Espírito Santo, Vitória, Brazil

    João Paulo A. Almeida

  2. Universidade de Lisboa, Lisbon, Portugal

    José Borbinha

  3. University of Twente, Enschede, The Netherlands

    Giancarlo Guizzardi

  4. University of Auckland, Auckland, New Zealand

    Sebastian Link

  5. Stockholm University, Kista, Sweden

    Jelena Zdravkovic

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Costa, M., S., A.G., Leon, A., Bernasconi, A., Pastor, O. (2023). A Reference Meta-model to Understand DNA Variant Interpretation Guidelines. In: Almeida, J.P.A., Borbinha, J., Guizzardi, G., Link, S., Zdravkovic, J. (eds) Conceptual Modeling. ER 2023. Lecture Notes in Computer Science, vol 14320. Springer, Cham. https://doi.org/10.1007/978-3-031-47262-6_20

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