The VALIDATE handbook

Front matter

VALIDATE handbook

Wija Oortwijn Laura Sampietro-Colom (eds.)

VALI DATE Values in doing assessments of healthcare technologies

Table of Contents

Foreword Part1 Introduction

1 First things first EU Erasmus+ project VALIDATE Scope of this handbook A task for HTA?

Elements of the VALIDATE approach and preview of this handbook Case study: Non-Invasive Prenatal Testing References

Foreword

We are delighted to present the first handbook addressing how to integrate empirical research (facts) and normative inquiry (values) when assessing health technologies (HTA). This handbook is one of the products of the “VALues In Doing Assessments of healthcare TEchnologies” (VALIDATE) project. The VALIDATE project was initiated to complement how HTA is currently conducted. In current approaches to HTA, evidence is often considered value free (neutral), independent from the perspective of stakeholders. With the VALIDATE approach we show that facts and values are intertwined. This means that HTA should be considered as a type of policy analysis, wherein the assessment of safety, clinical and cost-effectiveness of health technologies, as well as their wider ethical, legal, and social implications is conducted from the view that these aspects are closely interrelated, and wherein stakeholders are involved in a more productive way throughout the process of HTA (i.e., an integrative HTA approach). To reach this objective, an e-learning course has been developed, which will help students to deepen their understanding of the policy and societal context of HTA, the role of stakeholders in HTA, and the interplay between facts and values in identifying the relevant questions and evidence to be addressed in an assessment of health technologies (https://validatehta.eu/e-learning-course/). This handbook is a supporting tool for the e-course since it reflects its theoretical basis as well as presents pragmatic applications through case-studies. Nevertheless, this handbook provides the necessary information and knowledge to guide those who want to embark on an integrative HTA approach, therefore it can be also used as Standalone tool.

This handbook is directed to anyone who wants to understand, initiate, or broaden and deepen their knowledge and skills of HTA. Therefore, the targeted audience is broad, including Master/PhD students in HTA, health policy and management, health sciences and biomedical sciences, national/regional/academic HTA scientists, public health professionals, industry, health services researchers and policy makers.

We very much hope that this handbook will serve as a ready-reference among

TA doers and users, contributing to improved evidence-informed deliberative decision-making. Engaging stakeholders actively in deliberations throughout the

TA process enables exchange of views on argumentation and evidence. This will create an opportunity for more cohesive and inclusive societies.

The VALIDATE Consortium

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CHAPTER 1 First things first

This first chapter of the handbook introduces you to the background and aims of the VALIDATE project and its approach to Health Technology Assessment (HTA). After discussing the general challenges related to the implementation and use of health technology, and the role of HTA in addressing these challenges, the ideas that guide the VALIDATE approach to HTA are introduced. An overview of the handbook is provided, in which these ideas are further developed. This chapter ends with introducing the central case study (Non-Invasive Prenatal Testing) that is revisited in every chapter to help the reader better comprehend and relate on how the VALI-

DATE approach is implemented in practice.

ey messages of this chapter: the VALIDATE approach states that values and normative analysis are an integral part of HTA and offers an approach for taking this into account.

After reading this chapter, you will be able to understand the central elements of the VALIDATE approach and know in which chapters of this handbook you can find elaborations of these elements.

EU Erasmus+ project VALIDATE

In the EU Erasmus+ strategic partnerships project “VALues In Doing Assessments of healthcare TEchnologies” (VALIDATE), Health Technology Assessment (HTA) agencies and academic institutes are collaborating to introduce and train the next generation of HTA experts to a novel, integrative approach to HTA. The objective of

1 For more information about EU Erasmus+ projects: https://ec.europa.eu/programmes/erasmus-plus/ opportunities/strategicpartnerships-field-education-training-and-youth_en; more information on the VALIDATE project can be found on: https://www.validatehta.eu.

Chapter 1 | First things first 15 the VALIDATE project is to develop an approach to HTA that allows for the integration of empirical analysis and normative inquiry, associated teaching materials and opportunities for internships for HTA students. To achieve this goal, a consortium of seven academic and HTA organizations (Radboudumc, Universita Cattolica del Sacro Cuore, Linkóping Universitet, Departamento de Salud, University of Amsterdam, Norwegian University of Science and Technology, Hospital Clínic de Barcelona) has developed a consensus statement on what knowledge and skills are required to conduct this novel type of integrative HTA. Based on the consensus statement, an e-learning course and this handbook were developed to educate the next generation of HTA experts in conducting integrative HTA. The handbook can be seen both as an alternative and a supplement to the e-learning course.

This handbook will introduce you to the HTA approach developed in the VALIDATE project; we explain, and discuss all the elements of the approach, and provide examples of how the approach could be used. This first chapter will provide an overview of the VALIDATE approach, the contents of the handbook, and the rationale behind VALIDATE. A more in-depth discussion of the philosophy of VALIDATE, that is inspired by pragmatism, can be found in Chapter 7 of this handbook.

Scope of this handbook

Because the VALIDATE approach is primarily aimed at providing a methodology for identifying and addressing normative decisions and issues related to the practice of HTA, with a focus on moral and societal values, the discussion of legal aspects and frameworks is beyond the scope of this handbook. Although legal frameworks set boundaries for the practice of HTA, and it is highly relevant to be aware of them, an HTA practitioner still needs skills to address normative questions (because they are not always answered or are even raised by legal frameworks) and to identify different interpretations of the values that may have been the original impetus for a legal framework.

A task for HTA?

We are living at a time in which our lives are increasingly technological lives. What we do, how we communicate, the way in which we experience and interact with the world, is more and more determined by technology. Also, in the domain of health, technology is shaping our way of doing things.? We make use of, among others, drugs, devices, vaccines, different ways of organizing healthcare systems, to prevent, diagnose or treat medical conditions and promote health. Although these technologies enable us to improve our health, they also give rise to complex questions concerning the nature of human life, the sustainability and equity of healthcare systems, and their potential impact on our society.

Given these extensive uses of health technology, healthcare systems continuously need to adapt to the challenges that are associated with it. This implies many decisions that need to be made, and to introduce more rationality into decision- and policy-making the area of HTA emerged as an important scientific response to such policy-related endeavours. HTA is a “multidisciplinary process that uses explicit methods to determine the value of a health technology at different points in its lifecycle. The purpose is to inform decision-making in order to promote an equitable, efficient, and high-quality health system” (O'Rourke et al, 2020).

From its very inception, practitioners of HTA? have been committed to the comprehensive study of the consequences associated with the use of health technologies (i.e., the study of a broad spectrum of consequences, ranging from clinical to economic and social aspects). This grew out ofan awareness that health technology can have profound, unintended, and unforeseen consequences, that need to be taken into account when making decisions about the use of such technologies. t was recognized that there are different types of impact that need to be addressed in HTA: safety, clinical effectiveness, cost-effectiveness, and the ethical, legal, and social implications (also known as ELSI) of health technology. Despite this original impetus for HTA to perform this comprehensive study of implications of health technology, its focus has been often narrowed to issues of affordability (Daniels et al, 2016; Lehoux, 2006; ten Have, 2004). Assuming that the budget for healthcare is limited, and that technology is the main cost-driver in healthcare, HTA is

N

Although a general definition of ‘technology’ is hard to give, and there are many discussions on this concept and its nature, we will use the term to refer to “The application of scientific or other organized knowledge - relating to tools, techniques, products, processes, methods, modes of organisation, or systems - to practical tasks”. And a health technology is: “Any intervention developed to prevent, diagnose or treat medical conditions; promote health; provide rehabilitation; or organize healthcare delivery.” In healthcare, technology encompasses: drugs, diagnostic tests, devices, equipment and supplies, medical and surgical procedures, support systems, and organizational and managerial systems (source: www.htaglossary.net).

With ‘HTA practitioner’ we refer to anyone who may be involved in conducting assessments of health technology. Given the multidisciplinary nature of this exercise, this may involve people from diverse disciplines, ranging from ethics to social sciences to biomedical sciences.

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Chapter 1 | First things first 17 often reduced to answering questions like /s this technology effective? Is it safe? Does it provide ‘value for money’? Although answering these questions may be necessary, it may not cover the broad range of issues and concerns that are raised by health technologies and that need to be addressed by decision-makers. What is the value of specific innovations? What impact do they have on clinical practice, population health, and social development? The importance of these questions is recognized, but in the current practice of HTA these questions are often neglected or addressed separately as ethical, legal, and social issues (Bellemare et al, 2018; Lehoux et al, 2007).

Although there can be many practical and methodological reasons for this current situation of separate analyses in HTA, one fundamental problem is that the analysis of these different types of impact (e.g., safety, clinical effectiveness, cost-effectiveness, ELSI) are seen as completely different in their epistemic nature (i.e. ‘epistemology’ is the study of the nature, origin, and scope of knowledge; Refolo, Sacchini, 2016). This distinction between different types of analysis suggests that there are different ways of studying a health technology: 1. Through empirical research (e.g., studying safety, clinical and cost-effectiveness) 2.

Through normative inquiry (e.g., studying ethical, legal, and social implications)

Consequently, an assessment of aspects such as safety and cost-effectiveness is seen as objective and consisting of the collection of empirically testable facts, whereas studies of the wider implications (Ethical, legal and social issues) are seen as subjec tive and solely involving value judgments (Legault, Suzanne, 2018, Refolo, Sacchini, 2016). This view makes it very hard to see how HTA could legitimately integrate these ‘different’ types of inquiry, especially when value judgments may be seen as a threat to the legitimacy of HTA itself (Ducey et al, 2017). This also leaves decision-makers uncertain as to how, if at all, to take into account ethical issues.

As a result, health technologies and the practices that are created by them seem to be completely distinct from moral values. It is as if they occur in completely separate, mutually inaccessible, domains, being divided between a ‘neutral’ domain (e.g., facts about consequences of health technology) and a ‘value-laden’ domain (e.g., ideas about the (un)desirability of health technology). Consequently, it becomes very difficult to answer questions on the desirability of (a particular) using health technology that move beyond presuming that this is captured by assessing their effectiveness and cost-effectiveness. To be able to answer these broader questions on the value of health technology an integrative approach is needed wherein the study of safety, clinical and cost-effectiveness of new healthcare technologies and their wider ethical, legal and social implications are closely integrated. Therefore, a critical analysis of a strict fact/value distinction in HTA is needed to foster an integrative approach to HTA.

Going back to basics

Instead of assuming a strict dichotomy between empirical and normative aspects of health technology, we propose an approach towards HTA that aims to complement the current practice of HTA and allows it to assess health technologies in a more inclusive fashion (including different consequences and properties of health technology, as well as different stakeholder perspectives). Our goal isto present a framework that supports a more integrative approach to HTA, wherein the study of safety, clinical and cost-effectiveness of new health technologies and their wider ethical, legal, and social implications are closely integrated, and stakeholders are involved in a more productive way throughout the process of HTA. This could help HTA in addressing the type of policy questions that were actually the original impetus for developing (health) technology assessment (Lehoux et al, 2007; Lucivero, 2016; Torgersen, 2019). This means going back to the roots of HTA, defined as a form of policy research (Banta et al, 1993). It should also help HTA to address the needs of a population and developments in the organization of healthcare systems related to including the patients and citizens perspective in decision-making (Abrishami et al, 2017).

Elements of the VALIDATE approach and preview of this handbook

Overview of this handbook The goal of this handbook is to deepen your understanding of the different elements of the VALIDATE approach. The structure of this handbook is as follows:

Part 1: Introduction = Chapter 1: First things first (Bart Bloemen & Gert Jan van der Wilt) = Chapter 2: The fact/value dichotomy (Pietro Refolo & Dario Sacchini)

Part 2: Making it work

= Chapter 3: The method of reconstructing interpretive frames (John Grin) = Chapter 4: Scoping (Wija Oortwijn)

Chapter 1 | First things first 19

= Chapter 5: Approaches in ethics with a touch of meta ethics (Bjørn Hofmann & Lars Sandman) = Chapter 6: Context matters (Iñaki Gutiérrez-lbarluzea & Laura Sampietro-Colom)

Part 3: The philosophy of VALIDATE = Chapter 7: A philosophical summary of the VALIDATE approach (Bart Bloemen & Gert Jan van der Wilt)

Part 4: Conclusion = Chapter 8: Summing up VALIDATE (Wija Oortwijn & Gert Jan van der Wilt)

In the following, an overview of the elements of the VALIDATE approach is provided together with a preview of the different chapters in this handbook. This will help you with getting an idea about what you will learn by reading these chapters.

The VALIDATE approach

The VALIDATE approach starts with revisiting the fact/value dichotomy in HTA.

In contrast to the dominant interpretation described above, our starting point is

that each type of impact of a health technology have both an empirical and a norma-

tive (or value) dimension:

=" Safety: refers to the sort of outcomes that we wish to avoid because of our commitment to avoiding harm (the principle of ‘non-maleficence’).

= Clinical effectiveness: refers to benefits obtained in clinical practice and are the sort of outcomes that we wish to achieve because of our commitment to doing good (the principle of 'beneficence”), e.g., prolong life, alleviate suffering, restore functioning, etc.

= Cost-effectiveness: refers to the sort of outcomes that we wish to achieve because of our commitment to distributive justice/fairness (e.g., proportionality between resource commitment and reduction in burden of illness; to ensure equitable access to healthcare).

So, ethical questions concerning the desirability of a health technology are guiding the assessment of the impact of a health technology as depicted in Figure 1.

SAFETY

CLINICAL EFFECTIVENESS

COST-EFFECTIVENESS

ETHICS

Figure 1 Normativity of assess

SAFETY

> CLINICAL EFFECTIVENESS

COST-EFFECTIVENESS ment aspects

Therefore, ELSI questions concerning health technology are not in a separate category with respect to the nature of their analysis, and the role of value judgments. And in every empirical inquiry, the following questions need to be addressed: (i) What sort of things matter to us, and for what reason? (ii) What sort of things may happen when we would start using this we obtain reliable knowledge? In technology? (iii) And, about what sort of things can other words, HTA is not a matter of collecting THE facts, but a matter of collecting facts that are considered to be:

= Relevant: which consequences are desirable or to be avoided in view of values to which we are committed;

background theory and/or evi specific context?

Amenable to scientific inqui

Plausible: which consequences can be plausibly associated (on the basis of dence) with the use of a health technology in a ry: which consequences can be studied by methods of inquiry that are held to produce reliable knowledge and understanding?

Chapter 2 will provide more information about the history of the fact/value dichotomy, the criticism it received, its role in HTA, and our reconceptualization of the relation between facts and values in HTA.

HTA as a form of policy research

Another important element of the VALIDATE approach is that we view HTA as a form of policy research. Given that HTA aims to provide decision-makers with information on policy alternatives, it should actually be able to address policy-related questions that are raised by health technology. As already discussed, these questions move beyond the affordability of health technologies and demands an integration of empirical and normative ana needs of a population and decisi efficient, and high-quality health ysis. This requires that HTA takes into account the on-makers, to be able to contribute to an equitable, care system (Abrishami et al, 2017).

Chapter 1 | First things first 21

To take this policy context into account, HTA should make use of insights from policy sciences. Starting with the realization that there may be different views in society and cultures wh en it comes to what is regarded as relevant and plausible policy options with respect to the use of health technology, we should learn how to explore and address thi s pluralism. Understanding these different views is essential when determining which types of information should be produced in an HTA.

To explore and understand these views, we propose to make use of the method of reconstructing interpretive frames. This method aims to, by involving and interviewing stakeholders, reconstruct the conceptual schemes that stakeholders use (often implicitly) to make sense of concrete situations and guide their actions. These interpretive frames consist of t he following elements:

= Judgment of solutions: What is likely to work? Which measures could be helpful in addressing this hea helpful, and why not?

feasible in this context

= Problem definitions:

th problem? Which measures would probably not be s this health technology likely to be effective, appropriate,

“Y

What are the key problems of the current situation? Which problems are encountered by patients, their families, healthcare providers or healthcare managers = Background theory:

in the care of...?

What are the main causes and mechanisms responsible for the current situation? = Normative preferences: What is desirable? What is it that we would like to achieve and what is it that we would like to avoid?

These interpretive frames can be considered a type of tacit knowledge: they remain mostly implicit, but can be made explicit. The method for this is called reconstructing interpretive frames. Th underlying judgments o a critical, constructive s e purpose of making factual and normative assumptions n health interventions and technologies explicit is to enable crutiny of those assumptions and to foster learning among stakeholders. Moreover, the output of this reconstruction can be used to understand the type of policy problem you are dealing with and to make decisions on which type of information should be produced or collected in an assessment.

Chapter 3 will provide more information about the method of reconstructing interpretive frames and insights from policy sciences that are relevant to the practice of HTA.

HTA and the importance of scoping

When the type of policy problem you are dealing with is clear, you have to translate this into research questions. This process of translating policy problems into research questions is called scoping. To avoid answering the wrong questions, neglecting the concerns and values of decision-makers and stakeholders, it is important that the HTA community addresses more clearly what matters to the relevant healthcare system, as well as the relevant stakeholders, and the reasons why.

This should be done before the start of an actual assessment, and based on this the relevant research questions to be addressed should be identified. This could ensure the relevance of the information collected during an assessment, and help policy-makers in explaining their decisions to the populations they serve.

Chapter 4 will provide more information about how to define the objectives and research questions of an HTA by a systematic exploration of relevant aspects of a policy problem and the involvement of stakeholders. It integrates the lessons of Chapters 2 and 3: because the relevance of facts depends on the adopted perspective, and there are different perspectives in society with respect to the desirability of health technology, the objectives of an HTA should be defined by taking into account these perspectives.

HTA and the importance of normative analysis

An important element in defining the objectives and research questions of an HTA is the explication and clarification of what makes a health technology desirable. This helps in identifying relevant outcome measures. For example, the use of cost-effectiveness analysis should be supported by ethical arguments that explain why maximizing efficiency is a relevant goal to be realized by the use of a health technology. The relation between maximizing efficiency and realizing an equitable, efficient, and high-quality healthcare system should be made clear. Such a normative analysis not only helps in improving the consistency between decisions that are informed by HTA, it also prevents that HTA focuses upon aspects that are not considered relevant by decision-makers and the population.

Acknowledging a central role for normative analysis in HTA evokes several questions: How can ethical questions be addressed in HTA? Is there more to ethics than just opinions? Which methods can be used?

Chapter 1 | First things first 23

Chapter 5 will discuss the possibility of moral knowledge, different approaches to normative analysis, and introduces an overview of methods for conducting normative analysis in the context of HTA.

HTA and the importance of context

When conducting an HTA, you should also be aware that HTA is context-dependent. Whether the outcomes of an assessment should inform decisions at the national level, regional level, or at the level of a hospital, makes a difference when it comes to its objectives and research questions. In addition, the consequences of health technology are context-sensitive. The effects of health technology are influenced by the needs and demographics of a population, characteristics of a healthcare system, characteristics of the technology itself, the legal framework that guides its implementation, and cultural and social features of the situation in which it is used. These contextual factors all influence the conditions of use of health technology, and should be taken into account to increase validity ofthe outcomes of an assessment.

Chapter 6 introduces you to several aspects of the context of HTA and shows the importance of context during the assessment process, and discusses the particular perspective of hospital-based HTA.

The philosophy of VALIDATE

To conclude, a central tenet of the VALIDATE approach is that HTA is a practice in which facts and values meet. To be able to address policy-related questions, HTA should not only provide information on the plausibility of claims on potential consequences of health technology, it should also assess the desirability of these consequences. This requires both an understanding of the technology and its (potential) impact, as well as being able to think about this impact in light of a set of norms and values. As stated before, this means that normative analysis is an intrinsic part of HTA.

To propose such a central role for normative analysis in HTA may evoke a critical response. A widely held view - also within the context of HTA - is that there are no ways of rationally resolving disagreements on normative issues. This position is called moral scepticism, which refers to a diverse collection of views that deny or raise doubts about various roles of reason in morality. If we are not able to offer a response to this position, the consideration of ethical issues in HTA is seriously hampered. Therefore, we need to rethink our position towards the nature of ethical issues in HTA.

Chapter 7 will elaborate our view on the nature of ethical issues in HTA, presenting a response to moral scepticism. This response is based on the philosophical tradition of pragmatism. After reading Chapter 7, you will understand the relation between pragmatism and the VALIDATE approach.

The handbook will end with a summarizing chapter, and a glossary of specific terms used. For those of you not very familiar with the topics discussed in this handbook itis highly recommended to have a look at the glossary.

Case study: Non-Invasive Prenatal Testing

To help you understand the VALIDATE approach, and relate the different elements to a real-world example, every chapter will return to the case study of Non-Invasive Prenatal Testing (NIPT). Itis an example of a health technology that may be used in many different ways and, therefore, raises different ideas about its desirable use. In the following sections, we will shortly introduce this case study by providing background information and highlighting important issues related to assessing NIPT.

Prenatal screening

In many countries, pregnant women are offered different screening tests during pregnancy to identify any complications, diseases, or disorders at an early stage. The primary purpose of screening is to detect early disease or risk factors for disease in large numbers of apparently healthy individuals. Therefore, a major difference with diagnostic tests is that screening tests can be offered to individual who have no symptoms or any or any prior reasons for suspecting a higher chance at disease. In the case of prenatal screening tests, this means that they can be offered to any pregnant women irrespective of any prior knowledge on an increased risk of their unborn child having any medical conditions (e.g., based on age or genetic conditions in the family). This differs with available diagnostic tests that only offered based on a certain form of suspicion that the unborn child will have a specific medical condition.

Besides blood tests that screen for infectious diseases and provide information on blood group, and a structural ultrasound scan that tests for anatomical anomalies, an important category of prenatal screening tests is those that aim to detect foetal chromosomal abnormalities. These tests identify genetic conditions of the unborn child, often focusing upon trisomy 13 (Patau syndrome), 18 (Edwards syndrome),

Chapter 1 | First things first 25 and 21 (Down syndrome). Until recently, the screening strategy for these conditions consisted of offering combined first-trimester screening (CFTS) which entails an ultrasound examination and testing blood serum markers that collectively estimates the risk of a trisomy. After a positive test result (increased risk of trisomy), prospective parents where offered the choice to take an invasive prenatal test (e.g., amniocentesis, chorionic villus sampling) to confirm diagnosis or refrain from further testing (Hui et al, 2017).

Non-Invasive Prenatal Testing (NIPT)

In recent years, Non-Invasive Prenatal Testing (NIPT) has rapidly transformed the prenatal screening landscape. Following the discovery of cell-free foetal DNA, NIPT was introduced in clinical practice in 2011 and became increasingly available to pregnant women worldwide (Gadsboll et al, 2020, Hui et al, 2017, Van der Meij et al, 2019). NIPT is a prenatal screening procedure that analyses cell-free foetal DNA, which circulates in the mother's blood during pregnancy, in order to obtain information about the foetal genotype. Because only a blood sample of the mother is needed, the procedure does not pose any additional risks of a miscarriage that are associated with the available invasive tests (amniocentesis, chorionic villus sampling). Besides this reduction in risk of procedure-related miscarriage it has other potential advantages. It can be performed relatively early during pregnancy (around the 10" week of pregnancy), it could have a higher reliability than existing tests, and could potentially be used to analyse the entire foetal genome which provides the option of detecting conditions for which no other screening protocol exists.

The integration of NIPT in clinical practice is often being performed in a stepwise manner. For example, in the Netherlands the Dutch NIPT consortium (a multidisciplinary collaborative partnership among different stakeholders involved in public prenatal care) was granted a governmental license to introduce NIPT in the context of an implementation study trial (Trial by Dutch Laboratories for Evaluation of Non-

Invasive Prenatal Testing, TRIDENT). In TRIDENT-1, starting in 2014, women with a positive combined test result could choose between NIPT or invasive diagnostic testing. In April 2017, a follow-up study started (TRIDENT-2), in which al/ pregnant women are offered the choice between a combined test or NIPT (Van der Mejj et al, 2019), see also Figure 2. A unique feature of TRIDENT-2 is that women who elect NIPT can choose a report on chromosomes 21, 18 and 13 either with or without information on the other autosomal chromosomes (i.e., excluding sex chromosomes).

Positive

Combined test test result

(blood test, ultrasound scan, age, duration of pregnancy) Positive

Positive test result test result

TRIDENT-1 study

Combined test (blood test,

Positive test result ultrasound scan, OR age, duration of pregnancy) TRIDENT-2 study

Figure 2 Changing prenatal screening practice in The Netherlands

Potential uses of NIPT

In implementing NIPT, countries make many different decisions with respect to whether it is offered commercially or as part of a national screening program, whether it is offered to all pregnant women or only for women with a particular risk, different ways of reimbursement, and which genetic conditions to screen for (Gadsboll et al, 2020). Especially the aspect of the scope of NIPT (i.e., which genetic conditions are screened) leads to many decisions and debate. Because NIPT could potentially offer genome-wide information, there are many potential models of offering NIPT ranging from screening on specific genetic conditions to proving whole-genome coverage. This stirs debate on whether information on risk factors for late-onset disease, abnormalities related to a mild phenotype, gender, or genetic information on non-clinical conditions should be provided.

Chapter 1 | First things first 2y