Implementing genetic tests : infertility and newborn bloodspot screening

M.E. Jansen

Research output: PhD ThesisPhd-Thesis - Research and graduation external


Public Health GenomicsIn recent years disease understanding has expanded through the development of newtechnologies. Chapter 1 describes that one of the major breakthroughs in modern daybiology was the sequencing of the human genome in the Human Genome Project. Genesplay an important role in our bodies’ disease defense mechanisms, but also in ourpredisposition to develop diseases. Information on genotype-phenotype interactioncould inform new diagnostic, treatment, and prevention opportunities. However, beforeimplementation of genetic technologies into health care would get the essential supportfrom stakeholders, several questions will need to be answered. Especially Analyticalvalidity, Clinical validity, Clinical utility, and Ethical, legal, and societal implications arerelevant for the assessment of genetic tests that could be used in specific health caresettings.To integrate genome-based knowledge and technologies into public policy and healthservices Public Health Genomics (PHG) has emerged as a field of expertise. The studiespresented in this thesis fall within this research field. PHG has a broad scope for relevanttechnologies and their responsible implementation into healthcare. In this thesis thefocus will be on two types of genetic screening: in clinical practice and in populationhealth. Chapters 2 - 4 will describe screening to identify women with a high risk of tubalfactor infertility (TFI), and chapters 5 - 7 focus on possible changes in newborn bloodspotscreening (NBS) due to debate driven by innovation in genetic technologies. Both partsdiscuss possibilities for genetic and non-genetic technologies, with emphasis onstakeholder involvement in decisions about implementation.Chlamydia trachomatis associated tubal factor infertilityCurrent standard practice to identify women with a high risk of TFI is an antibodyscreening test for the bacterium Chlamydia trachomatis, because C. trachomatis is themost important cause of female infertility. The sensitivity of the C. trachomatis antibodytest (CAT) to diagnose TFI is estimated to lie between 28 and 62%, which leavesconsiderable room for improvement. Improving the identification of high risk womenaims to prevent unnecessary laparoscopies: the best test available to diagnose TFI, but acostly and invasive procedure.In chapter 2 we investigated whether adding a complementary serological biomarker toCAT could improve screening: a high sensitivity (hs) test for C-reactive protein (CRP). CRPis a biomarker for the level of persistence of an infection, which may indicate a longertime period in which the C. trachomatis bacteria and/or inflammatory response couldhave damaged the fallopian tubes. We replicated an earlier study with promising resultsregarding the addition of CRP as a marker for persistent infection in an independentsample. In our sample of 176 women with fertility complaints, we were not able to confirmthe results from the earlier study, i.e. we did not find a statistically significant associationbetween the combination of CAT and hsCRP in the prediction of TFI. Since C. trachomatis501625-L-sub01-bw-Jansen132is specifically associated with distal adhesions of the fallopian tubes, we also tested inchapter 2 for the association on double sided distal adhesions with each of the testsseparately (solely CAT and solely hsCRP), and with the two tests combined. For thisoutcome we found a statistically significant association between solely the CAT anddouble sided TFI. We did not have enough statistical power to be conclusive on either ofthe analyses, however our study does indicate that the prediction of double sided TFIcould benefit from CAT, but that other grades of TFI might need different biomarkers.One of the potential biomarkers to screen for the course of a C. trachomatis infectioncould be a host genetic test, by analyzing genetic biomarkers relevant for the host’simmune response. Changes in the smallest building block of our DNA - single nucleotidepolymorphisms (SNPs) - can have significant influence on the expression and function ofmolecules in our bodies. Almost 40% of the differences in clinical presentation of C.trachomatis infection are estimated to be explained by genetic variation. SNPs can makean immune response more or less reactive or effective, and influence the course of a C.trachomatis infection. Chapter 3 discusses the value of a SNP-analysis in predicting thedevelopment of TFI after an immune response to C. trachomatis infection. The analyzedSNP located in a gene region coding for the Human Leukocyte Antigen type A (HLA-A).The HLA-A receptor is involved in the recognition of pathogen peptides and initiates animmune response through activating CD8+ T-cells. The study described in chapter 3shows that a SNP (G>A) in the HLA-A gene region has a protective effect on thedevelopment of complications after a C. trachomatis infection. We observed a trend of adecreasing proportion of women carrying this SNP analyzed against an increasing degreeof complications: women with mild symptoms had the largest proportion of G>Avariation,while among the women with double sided tubal pathology none had the G>Avariation.The statistical power was not sufficient to make firm conclusions on the role ofthe SNP, but we hypothesize that carrying the SNP might lead to a weaker affinity of theHLA-A molecule to a C. trachomatis-derived peptide, resulting in a less effective antigenpresentation to CD8+ T cells. Therefore the immune response will be less aggressive,which could lead to less adhesions in the fallopian tubes.Our study in chapter 3 results in a hypothesis for genetic biomarkers to predict theseverity of symptoms after a C. trachomatis infection, and contributes to a considerablebody of evidence for the role of immunogenetics in predicting the course of a C.trachomatis infection. Therefore, chapter 4 focuses on the support amongstgynecologists to use a genetic test in their routine fertility work-up in the future.Ultimately the impact of genetic tests on clinical practice depends on clinicians’ decisionsto order genetic tests, and they play an essential role in interpreting and explaining theresults to their patients. To study the attitude of clinicians towards genetic tests, we useda questionnaire based on interviews with experienced gynecologists in the Netherlandsto explore the barriers and facilitators in a sample from 75% of the Dutch AcademicHospitals. In the questionnaire conducted in chapter 4 clinicians were asked to score a 501625-L-sub01-bw-Jansen133range of statements on barriers and facilitators. 61.7% of respondents stated that theaddition of a genetic test to CAT would increase the screening accuracy for TFI. Theyregarded clinical utility as the most import indicator of the quality of a genetic test.Furthermore, almost 95% of the clinicians scored cost-effectiveness as an importantfactor to gain their support, therefore comprehensive research about the potentialeconomic implications of the introduction of genetic tests should be the next importantstep in the implementation strategy.The changing landscape in newborn bloodspot screeningThe perspectives and support of stakeholders is not only essential in clinical practice, butalso in health policy making. Genetic tests offer a range of possibilities for populationscreening programs, and are specifically debated in NBS. Implementing genetic tests ina publicly funded program, while there is not always consensus on the benefits aimedfor, can be controversial and calls for careful consideration of the implications on thewhole system of NBS. It is especially relevant to take a closer look at the policy processesand decision making in NBS, since most countries use the Wilson and Jungner screeningprinciples as a starting point to shape their NBS program, but currently the resultantprograms are highly different.Chapter 5 focusses on factors that influence decision making in NBS. This chapter aimsto understand what factors influence NBS criteria and how conditions are assessedagainst them. Through a systematic review of scientific literature, combined with astructured analysis of policy documents it offers unique insights into the internationallandscape of NBS. We found five key topics that are discussed in scientific literature, andhave different approaches amongst programs: the beneficiary of NBS, definition ofcriteria, the way conditions are assessed, level of evidence required, andrecommendations after assessment. In the considerations of these topics in chapter 5, itwas found that also in NBS policy government policy lags behind the scientific debate.However, the purpose of NBS is under discussion in both mediums, and evidence-basedand transparent decision making is needed to shape programs in the future. Differencesin the five key topics have the potential to result in increased disparity across NBSinternationally. The criteria and their use in the assessment of conditions are responsiblefor shaping the programs; therefore understanding how they are used in different waysinternationally provides an insight into what NBS might hold in the future. Ultimately,governments need to decide on the role they see for NBS, and agree on an approach todecision making in line with this role.Evidence-based and transparent decision making is also the focus in chapter 6, howeverthe structure of such a process is also discussed. Historically, expansion of NBS programsoften followed an ad hoc consideration of conditions, instead of a structured, transparent,and evidence-based approach. With the expectation of further expansion of NBSprograms with the advent of more genetic technologies, it is important to have robust 501625-L-sub01-bw-Jansen134policy making practices in place, to safeguard the programs. In chapter 6 the elementsto approach policy making are structured based on the steps in the policy cycle: a)agenda setting, b) policy advice, c) policy decision, d) implementation, and e) evaluation.In the literature search conducted, the relevant content for each policy step highlighteda framework for future decisions within the changing international landscape of NBS.Policy making in NBS could benefit from moving towards a process that has its origin inhealth technology assessment (HTA), such as following a process of horizon scanning forevidence based nominations of relevant conditions for NBS. Furthermore, HTAframeworks focus on structurally engaging stakeholders in policy making, such asgovernment, health care professionals, and the public, which is fundamental to modernhealthcare. Support for implementation can only be created by balancing competinginfluences and demands from different perspectives. Ultimately, enhancing internationaltransparency, learning experiences, and harmonization is needed for equity in access toearly care for relevant conditions for infants in all countries.As discussed in chapters 5 and 6, introducing new genetic technologies in NBS couldhave great implications on the programs worldwide. In current NBS policy processes,different stakeholders are involved. Chapter 7 focusses on involvement of the public inNBS policy making; the goals of public involvement, on what levels it can prove to bevaluable, how to define ‘public’, which mechanisms exist to facilitate public involvement,and relevant indicators to evaluate the value of public involvement. From the reviewedliterature it was clear that the public is not always structurally involved in policy making.Since government policies have the potential to impact people’s life, accountabilitytowards to public is important to guarantee support. Moreover, when policy is formedthrough a process with more stakeholder participation it can be found to be morefeasible. The results in chapter 7 describe that public involvement is often ad hoc. Publicinvolvement in NBS centers around patient advocacy, and usually only includes providinginformation. Only involving patient advocates in the discussion on NBS can have strongimplications for the views included, and puts emphasis on conditions that may seemhighly relevant for a small group of the population. Chapter 7 concludes that deliberatingwith the public is essential, but that the framework to do so needs to be clear on thegoals, level, definition, mechanisms, and evaluation. Furthermore, whether NBS is theappropriate program to include all diseases that patient advocates bring to the table,remains to be discussed. Since preconception carrier screening and prenatal screeningcan be considered to have similar paradigms to NBS, developing a public involvementapproach to suit all three programs could prove valuable in ensuring improved healthoutcomes for the population.Improving health outcomes through responsible translationBoth clinical and population health care services are expected to incorporate moregenetic information in the future. Chapter 8 summarizes the main findings of this thesis 501625-L-sub01-bw-Jansen135and the implications for practice. The studies in this thesis contribute to the evidence andexpectations of the added value of genetic information. Key topics are highlighted thatneed to be addressed to facilitate structured consideration and translation of geneticknowledge. In either clinical or population health care services deliberation with relevantstakeholders is of utmost importance to ensure swift implementation of relevant geneticinformation. Only through transparent development and decision making essentialinformation can be gathered on all aspects of a test that could be used in a specificsetting, including the infrastructure and stakeholders involved, to ultimately ensureimproved health outcomes for the target population.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Maastricht University
  • Morre, SA, Supervisor
  • Cornel, Martina, Supervisor
  • Ouburg, S, Co-supervisor
  • van Kranen, Henk J., Co-supervisor, External person
Award date27 Jan 2016
Place of PublicationMaastricht
Print ISBNs9789402800241
Publication statusPublished - 27 Jan 2016

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