Inclusion of dosimetric data as covariates in toxicity-related radiogenomic studies

A systematic review
  • Noorazrul Yahya
  • Xin-Jane Chua
  • Hanani A. Manan
  • Fuad Ismail
Original Article



This systematic review evaluates the completeness of dosimetric features and their inclusion as covariates in genetic-toxicity association studies.

Materials and methods

Original research studies associating genetic features and normal tissue complications following radiotherapy were identified from PubMed. The use of dosimetric data was determined by mining the statement of prescription dose, dose fractionation, target volume selection or arrangement and dose distribution. The consideration of the dosimetric data as covariates was based on the statement mentioned in the statistical analysis section. The significance of these covariates was extracted from the results section. Descriptive analyses were performed to determine their completeness and inclusion as covariates.


A total of 174 studies were found to satisfy the inclusion criteria. Studies published ≥2010 showed increased use of dose distribution information (p = 0.07). 33% of studies did not include any dose features in the analysis of gene-toxicity associations. Only 29% included dose distribution features as covariates and reported the results. 59% of studies which included dose distribution features found significant associations to toxicity.


A large proportion of studies on the correlation of genetic markers with radiotherapy-related side effects considered no dosimetric parameters. Significance of dose distribution features was found in more than half of the studies including these features, emphasizing their importance. Completeness of radiation-specific clinical data may have increased in recent years which may improve gene-toxicity association studies.


Radiotherapy Genetic association studies Dose-response relationship, radiation Radiation effects Genetic testing 

Verwendung von dosimetrischen Daten als Kovariaten in Studien zur Korrelation von genetischen Parametern mit Nebenwirkungen der Strahlentherapie

Ein systematischer Review



Dieser systematische Review untersucht die Verwendung und den Nutzen dosimetrischer Parameter als Kovariaten in Studien, die genetische Informationen mit dem Auftreten von Nebenwirkungen der Strahlentherapie assoziieren.

Material und Methoden

Originalarbeiten, die genetische Parameter mit Normalgewebekomplikationen nach Strahlentherapie verknüpfen, wurden unter Verwendung von PubMed identifiziert. Die Verwendung von dosimetrischen Daten wurde anhand von Angaben zur verschriebenen Dosis, der Fraktionierung, der Zielvolumenauswahl oder der Dosisverteilung geprüft. Ob diese Daten als Kovariaten in der Modellierung zur Anwendung kamen, wurde im Statistikteil der jeweiligen Arbeit geprüft. Die Korrelation mit der betrachteten Nebenwirkung wurde dem Ergebnissteil entnommen. Mittels deskriptiver Statistik wurden die Verwendung von dosimetrischen Parametern und deren prognostischer Wert zusammengefasst.


Insgesamt 174 Studien erfüllten die Einschlusskriterien. Studien, die ab 2010 veröffentlicht wurden, schlossen häufiger Informationen zur Dosisverteilung ein (p = 0,07). Von den Studien zur Vorhersage von Nebenwirkungen anhand von genetischen Daten berücksichtigten 33 % keine Dosisparameter. Nur 29 % schlossen dosimetrische Parameter ein und zeigten deren Ergebnisse. In 59 % dieser Studien waren die dosimetrischen Parameter signifikant mit der betrachteten Nebenwirkung korreliert.


Ein großer Anteil an Studien zur Korrelation von genetischen Markern mit strahlentherapiebedingten Nebenwirkungen berücksichtigte keine dosimetrischen Parameter. Ein signifikanter Einfluss dieser Parameter wurde jedoch in über 50 % aller Studien gefunden, die diese eingeschlossen hatten, was deren Relevanz unterstreicht. Die Nutzung dosimetrischer Parameter hat sich in den letzten Jahren erhöht, was zur Verbesserung entsprechender Studien geführt haben könnte.


Strahlentherapie Genetische Assoziationsstudien Dosis-Wirkungs-Beziehung, Bestrahlung Bestrahlungseffekte Gentest 



We acknowledge funding from the National University of Malaysia (GGPM-2017-095). We thank Steffen Lock and Muaz Azhari for the German translations.

Compliance with ethical guidelines

Conflict of interest

N. Yahya, X.J. Chua, H.A. Manan and F. Ismail declare that they have no competing interests.

Ethical standards

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

66_2018_1303_MOESM1_ESM.xlsx (38 kb)
Supplementary Material A: Final studies included in the analyses


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Faculty of Health SciencesThe National University of MalaysiaKuala LumpurMalaysia
  2. 2.Radiology DepartmentThe National University of MalaysiaKuala LumpurMalaysia
  3. 3.Radiotherapy & Oncology DepartmentThe National University of MalaysiaKuala LumpurMalaysia

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