Content Analysis of Informed Consent for Whole Genome Sequencing Offered by Direct-to-Consumer Genetic Testing Companies

Whole Exome and Genome Sequencing Applications

The relatively recent development of next-generation sequencing (NGS) technologies has led to a significant decrease in the cost and time required to perform whole genome sequencing (WGS) and whole exome sequencing (WES) (i.e., the sequencing of only protein coding parts of the genome; for the purpose of this article, in which the high-through-put nature of NGS is most salient, both whole genome and whole exome sequencing may be denoted by “WGS” or ”whole genome sequencing”). These technologies are more powerful and potentially cost-effective than previous sequencing technologies and have brought a shift in testing approach from the traditional way of testing only one or a few specific genes to obtaining the sequencing information from hundreds or even all the genetic variants in a genome [Wright et al., 2011].

To date, the use of genomic sequencing approaches has proved to be useful in both the research context and clinical context; for instance, in providing molecular diagnoses for Mendelian disorders [Yang et al., 2013], for disorders with complex phenotypic presentations such as intellectual disabilities, or neurological diseases [de Ligt et al., 2012; Martin et al., 2014], potentially enabling targeted therapeutic strategies in some cases [Salleh et al., 2013]. WGS can also be used for disease risk predictions [Heo et al., 2013], preconceptional carrier testing [Chrystoja and Diamandis, 2014], and prenatal testing [Carss et al., 2014]. In the short to medium-term future, other applications of WGS in healthcare may materialize, including for newborn screening [Solomon et al., 2012], tissue matching [Wright et al., 2011], or screening of embryos [Harper et al., 2013]. Despite these technical possibilities, it is important to note that there are still concerns regarding the accuracy, interpretation of results, cost-effectiveness, as well as ethical issues [Dewey et al., 2014].

Given the relative novelty of NGS in the clinic and the resulting uncertainty related to implementation, the ethical concerns are numerous, and include, but are not limited to, issues related to the informed consent (IC) process, unsolicited findings management, opportunistic screening, secondary use of data, data management and storage, privacy and confidentiality, duty to re-contact patients (once new information arises), responsibility toward and communication with family members. All these outstanding issues currently challenge the effective and responsible implementation of genome-based approaches in health management [Pinxten and Howard, 2014] and need to be addressed. Herein, we focus on the ethical issues of the IC process in the more specific commercial context of direct-to-consumer (DTC) high-throughput sequencing, which overlap with many of the concerns related to the clinical context.

DTC Genetic Testing Companies

Relatively recently, WGS services have also been advertised and offered directly to consumers by some companies. These private, for-profit companies operate outside of the conventional public healthcare system and advertise genetic tests directly to consumers predominantly via the Internet. However, companies are increasingly requiring consumers to contact a healthcare professional (HCP) in order to obtain a test and/or the test results [Howard and Borry, 2012]. Such genetic tests which “are commissioned by the consumer but where a medical practitioner or health professional is involved in the provision of the service” also fall in the scope of DTC genetic tests according to “A Common Framework of Principles” on DTC genetic testing (GT) issued by the Human Genetics Commission (UK) [Human Genetics Commission, 2010].

The phenomenon of DTC GT, even before WGS was being offered in this context, has received a lot of attention regarding ethical issues, such as the questionable scientific validity and utility of the tests on offer [McGuire and Burke, 2011], the adequacy of information provision and the IC procedure [Howard et al., 2010], the potential need for medical oversight and genetic counseling [Hogarth et al., 2008], the testing of children [Borry et al., 2009], the research activities conducted by DTC GT companies [Howard et al., 2010], and the potential burden on the healthcare system [McGuire and Burke, 2011]. The adequacy of legislations concerning the activities of DTC GT companies has also been discussed [Kalokairinou et al., 2014]. Considering the vast amount of genomic data obtained in WGS as well as difficulties in being able to properly assess or interpret each variant, one could consider that many, if not all, of the ethical, legal, and social implications previously addressed at the DTC GT field are amplified in the context of companies offering WGS directly to consumers. As such, this particular type of DTC GT deserves further attention and study.

IC for WGS

In the context of WGS, appropriate provision of information about the testing seems to be a particular challenge considering the complexity of the technology used, the volume of information generated, and the wide-ranging nature of findings. The entire sequence of the genome may provide an unprecedented amount of information of various clinical significance and predictive value, which may change with time [Wright et al., 2011]. Furthermore, these results may have profound implications for the (psychological) health (care) and reproductive choices of a patient as well as his or her relatives.

Given these challenges, various authors have proposed models for IC and attempted to determine the necessary elements of an adequate IC process for WGS [ACMG Board of Directors, 2013; Ayuso et al., 2013; Bunnik et al., 2013, 2014; Jamal et al., 2013; Henderson et al., 2014]. Ayuso et al. 2013 specifically analyzed articles from the academic literature and guidelines from “societies” concerning IC for genetic studies and WGS. The authors found a high level of consistency among the documents reviewed and proposed a minimum list of information that should be addressed in IC for WGS: the scope of the test, a description of the test process, the possible benefits and risks, the availability of alternative tests, the voluntary nature of the test, the possibility of refusal, the future use of the samples and the data, the confidentiality of the outcomes, and management of incidental findings (IFs), pre-test counseling [Ayuso et al., 2013]. Moreover, the authors found that the majority of the documents they studied suggest that IC for WGS should be given explicitly [Ayuso et al., 2013] (this is understood as being relevant in a context where WGS is only one of the tests being used for diagnosing a disorder, and so an explicit consent should be obtained specifically for the WGS).

Jamal et al. 2013 also developed “core elements” of content and procedures for IC, data sharing, and results management for WES; even though conducted in a research context, the former overlap with core elements of IC identified by Ayuso et al. (2013) for the clinical context [Jamal et al., 2013]. Furthermore, Jamal et al. (2013) used the core elements to evaluate the practices and policies of 6 U.S. CLIA- certified labs offering clinical exome sequencing, including the presence of the suggested elements in IC forms and their readability. The analysis revealed that laboratory policies vary widely, indicating that developing standards for best practices among exome sequencing providers may be beneficial.

Similarly, Henderson et al. 2014 have analyzed IC forms used in nine NIH-funded studies aiming to develop best practices for clinical applications of WGS. On the basis of the analysis, the authors have proposed recommendations, which “can serve as a checklist to help identify gaps and resolve ambiguities in consent forms for sequencing,” and which are related to the issues outlined by Ayuso et al. 2013. For example, Henderson et al. (2014) suggest describing the meaning of positive, negative, and uncertain results, outlining the role of CLIA (Clinical Laboratory Improvement Amendments) certification, and stating the likelihood of obtaining IFs. Furthermore, IC forms for WGS have also been analyzed in the context of cancer studies. The examination of these IC forms has revealed the tendency for using samples in other, unspecified types of studies and sharing data with other researchers [Allen and Foulkes, 2011].

Furthermore, IC and the provision of information on company Websites have been investigated in the context of DTC GT companies revealing the inadequacies of these practices [Howard et al., 2010; Lachance et al., 2010; Singleton et al., 2012]. None of the studies, however, specifically addressed IC for WGS in the context of companies advertising or selling WGS directly to consumers. Therefore, herein we present an exploratory qualitative study of the information salient to the IC process, which is provided on Websites of companies offering WGS in the commercial DTC context. In particular, we present information regarding the following elements salient to IC: (1) pre-test counseling, (2) expected benefits and possible risks, and (3) management of IFs. The information from company Websites is then further contextualized and discussed against the backdrop of guidelines such as those from the Presidential Commission for the Study of Bioethical Issues (PCSBI) [Presidential Commission for the Study of Bioethical Issues, 2013], recommendations for IC for WGS by Ayuso et al. 2013, and the American College of Medical Genetics (ACMG) recommendations for the reporting of secondary findings [Green et al., 2013].

The DTC WGS Companies Identified and the Studied Website Documents

Four companies, Illumina, Gentle, Gene By Gene, and Inneova, were identified for this study. At the time of this analysis they offer WES and/or WGS as well as provide different types/scope of data/results and analysis (e.g., carrier status, pharmacogenomics). The basic description and information regarding these four companies are outlined in Table 1.

All the studied companies advertise their services directly to consumers on the Internet. However, some Websites also contain sections dedicated to physicians, who are required to order the test, except for the company Gene By Gene's offer of research and consumer testing, for which the company does not require a HCP.

All the analyzed Websites of the companies provide at least one document and/or a section on the Web page that needs to be agreed to or signed in order to undertake the test (Table 1). Three companies have documents on their Website with “consent” in the title; meanwhile, Gene By Gene only has a “Terms and Conditions” section of the Website and specifies that in case of “Clinical Genetic Testing,” the physician has to obtain IC from the consumer; however, it does not state whether this includes a physical document that must be signed by the consumer: “Prior to placing an order, the ordering physician or genetic counselor is responsible for obtaining the informed consent from the patient whose sample is being sent for testing (…)” (https://www.genebygene.com/pages/terms). Such a statement is not included in the section for “Research and Consumer testing” in “Terms and Conditions” of Gene By Gene (https://www.genebygene.com/pages/terms).

The results of the content analysis regarding the following elements of IC: pre-test counseling, benefits and risks, as well as IFs are presented below and shown in Tables 2-4.

Pre-Test Counseling

Another company Gentle, vaguely suggests some form of pre-test counseling to consumers in its IC section of the Web page: “If you still have unanswered questions, be sure to ask us or your physician before you agree to take the DNA test being offered by us.” (https://www.gentlelabs.com/consent?content_only = true). No information about pre-test counseling was found on the studied Websites’ sections of Gene By Gene and Inneova.

Benefits and Risks

In the studied sections of the Websites, all the companies provide general information about benefits and risks; however, specific sections labeled “Benefits” and “Risks” are explicitly distinguished only in the IC documents of Illumina and Gentle. More specific subthemes were identified within the subjects Benefits and Risks (Table 3, in bold in columns 2 and 3); these were used to classify the benefits and risks information, and were derived and modified from the classification outlined by Ayuso et al. 2013.

Three companies outline that the results may indicate disease risks and predispositions (Table 3). Moreover, Illumina and Gentle state that test results may help to make more informed healthcare choices; Gentle adds that the knowledge from the testing may empower persons to make “important life planning decisions.” Furthermore, Gentle outlines as a benefit, gaining knowledge about one's carrier status, the possibility of adjusting drug therapy based on the genetic results, and gaining insight into one's ancestry. This company also mentions as a benefit the possibility of participating in research studies conducted by the company.

All the companies provide, at least, a general and/or short description of risks related to undertaking WGS (Table 3). The types of risks and concerns mentioned include the following: medical and physical risks, psychological risks, discrimination risks, and implications for family members. Implications for reproductive choices are mentioned only by one company, Inneova: “I realize the possible far-reaching implications of the information obtained through predictive genetics testing in affecting my life choices as well as those of my relatives, children, and unborn children” (http://www.inneova.com/contenu.php?page = terms.php).

IFs and Categorization of Genetic Information

Only one of the analyzed companies, Illumina, directly addresses the issue of IFs in its IC form (Table 4). The company refers to the first version of the ACMG‘s recommendations for reporting of IFs (2013) [Green et al., 2013] and together with the results of Undiagnosed Disease Test provides an IFs report that may contain information on some of 57 variants unrelated to the indication for testing. Meanwhile, in the consent form for Illumina's Predisposition Screen test, the possible findings are categorized (into: childhood onset and adult onset; subcategories: medically actionable, not medically actionable, cancer, neurologic conditions) and the consumer has the possibility to opt out of some of them. Although Gentle does not mention IFs, the company does emphasize that customers can choose to exclude any condition from the analysis: “It is important to mention that you can choose to exclude any of the tests from the results before submitting your sample.” (https://www.gentlelabs.com/consent?content_only=true).

IC in the Context of DTC WGS Companies

The content analysis of DTC companies described herein has been conducted using some of the elements of IC for WGS in the clinical setting recommended by Ayuso et al. 2013. It should be noted that there are significant differences between the offers of WGS in a “traditional” clinical genetics context versus the commercial DTC setting, even if the latter involves a HCP. As explained in the recent guideline issued by the PCSBI: “Clinicians owe stringent fiduciary duties to patients, which entail an obligation to act in furtherance of the patient's best interests. Non-clinician DTC providers have less stringent duties, including duties that might be limited or circumscribed by contract. Consumers should be made aware of these distinctions prior to consenting to undergo DTC testing.” (p. 103–104) [Presidential Commission for the Study of Bioethical Issues, 2013]. Indeed, in the context of DTC companies, the contract describing the conditions of the service is usually stated in terms of service, to which a consumer has to agree prior to buying the test. However, if the purpose of the test is health-related, signing a contract cannot fully replace the function of IC, which aims, among others, to provide understandable and balanced information about the test [Bunnik et al., 2014]. The tests included in this study are advertised as having (to some extent) a health-related purpose or as clinical tests, therefore, the presence of adequate IC in the studied DTC companies appears to be advisable.

Explicit IC and Pre-Test Counseling

Explicit IC, which is recommended by Ayuso et al. 2013 for clinical WGS, may be defined as one for which “Those who request consent must provide an explicit statement of the nature and purposes of a proposed course of action, its effects, risks and other features, to those whose consent is sought. Those who are asked to consent must show explicitly that they understand this information and agree to the proposal” [Manson and O'Neill, 2007]. The process of explicit IC typically involves documents, signatures, and formal statements [Manson and O'Neill, 2007]. Therefore, in this study, we have focused on the documents or the sections of the Websites to which the consumers have to agree in order to be tested. However, in order to be genuine, IC should not be reduced to signing a document but it should be a process involving dialogue with a qualified HCP to ensure that the patient truly understands the information provided and is competent to make a choice [European Society of Human Genetics, 2010].

Although all four companies provide some form of document addressing consent, only Illumina requires pre-test counseling understood as face-to-face consultation with a physician. In the other studied companies, most of the tests have to be ordered by the physician, meaning that the consumer has to contact one in order to be tested. This, however, does not guarantee that adequate counseling takes place, given the concerns about the expertise in genetics and impartiality of the HCPs [Howard and Borry, 2012]. Indeed, including a third party HCP in the process raises the question of who bears the (fundamental) ethical and legal responsibility for taking adequate consent? Of course, the HCP must adhere to the general medical code of conduct, but depending on her/his specialty, is (s)he aware of the specific guidelines for GT?

Another important result that brings attention to the involvement of HCPs in testing is a lack of involvement of a physician in undertaking the consumer test in Gene By Gene company. Although “Terms and Conditions” state that the services listed in the “Research and Consumer Testing” section “are not to be used to diagnose, prevent, or treat any condition or disease or to ascertain the state of health for any individual” (https://www.genebygene.com/pages/terms), the description of the test suggests that it may provide health-related information: “Sequencing of the exome can help identify variants that may be the genetic cause of a wide range of traits and conditions.” (https://www.genebygene.com/pages/research#). Therefore, the involvement of a genetics professional seems to be advisable also in the case of “Research and Consumer Testing” of Gene By Gene, which could prevent misinterpretation of the results or unnecessary follow-up care.

In addition, although the non-clinician DTC provider may have less stringent duties as stated by the PCSBI [Presidential Commission for the Study of Bioethical Issues, 2013], the full role of a clinician in the DTC context still remains blurry. It is unknown to what extent physicians in the DTC context follow the same protocol as geneticist follow in the traditional healthcare system.

Another aspect related to IC is the potentially low readership of the consent documents analyzed herein. It has already been shown that most of the consumers read very little of the terms of service agreements (e.g., when purchasing software [Maronick, 2014] or accessing Wi-Fi). This may suggest that although the documents have the word “consent” in the title and/or are aimed to be read and agreed to, the consumers are not acquainted with their content. This issue requires further analysis to assess the accessibility and readability of such documents.

Information about Benefits and Risks

This may be misleading as consumers may not read the sections “Terms of Service” or “Terms and Conditions” [Howard et al., 2010], but rather take the decisions based on the information available on the main Web pages. Finally, information about the potential risks in the documents of Inneova and Gene By Gene may make an impression that it was designed or written more in a way to protect the company from any liability rather than to explain and inform about potential disadvantages, for example, “I agree that ICL (…) assumes no liability for any stress, strain, hardship, adverse medical condition, financial loss, or other circumstances that I may suffer as a result of the receipt or reference to any predictive genetics test results and/or interpretations thereof supplied to me by ICL” (http://www.inneova.com/contenu.php?page=terms.php).

Some of the findings presented herein are in line with the results of the study of Singleton et al. 2012 on informed choice in DTC GT companies, which focuses on the Websites of the DTC GT companies containing consumer-focused content excluding terms and conditions and privacy statements, therefore being to some extent complementary to this study. Singleton et al. (2012) found that the amount of information describing benefits outweighed risks statements and that the Websites presented conflicting information stating that the tests can help to prevent diseases, simultaneously giving information that the test cannot be used for diagnosis or treatment. Similarly, Skirton et al. (2015) found that misleading, conflicting or incomplete information was present on the Websites of DTC companies offering non-invasive prenatal testing.

Incidental/Secondary Findings

The last but not the least element of IC analyzed in this study is the management of IFs. The term “incidental findings” refers to “results that are outside the original purpose for which a test or procedure was conducted” [Presidential Commission for the Study of Bioethical Issues, 2013], whereas secondary findings are results being sought deliberately because of the recommendations of an expert body as it has been defined by the PCSBI in the report on incidental and secondary findings [Presidential Commission for the Study of Bioethical Issues, 2013]. The issue of incidental and secondary findings appears particularly relevant in the context of WGS generating vast amount of data for analysis [Burke et al., 2013]. Therefore, this topic has been discussed at great length and various expert societies have addressed it in recommendations. The PCSBI emphasizes the role of IC, and for the particular context of DTC companies suggests that the providers should develop adequate procedures to manage IFs and provide consumers with understandable materials explaining these procedures [Presidential Commission for Study of Bioethical Issues, 2014]. The ACMG also has issued recommendations for the reporting of secondary findings, obtained in WGS (although they use the term IFs, this is misleading since what they describe is opportunistic screening and not the strictly “unsolicited” findings) [Green et al., 2013]. This policy statement of the ACMG suggests that secondary findings concerning 24 indicated conditions (related to 56 gene variants affecting function) should be sought and reported, however the patient may refuse the analysis of some of these genes if they are unrelated to the indication for testing, which should be done during the process of IC [Green et al., 2013; ACMG Board of Directors, 2014]. In contrast, the recommendations of the European Society of Human Genetics which address IFs do not provide a specific list of reportable conditions but rather suggest narrowing the scope of the sequence analysis and developing guidelines and protocols [van El et al., 2013] in order to reduce the chances of encountering IFs all together. Finally, some authors propose models of stratification of information derived from WGS, including incidental/secondary findings, which will help the discussion with, and the decision-making by the patient [Berg et al., 2011; Ayuso et al., 2013].

Only one company out of the four studied addresses the issue of incidental/secondary findings and provides a report on IFs complying with the recommendations of ACMG [Green et al., 2013] (hence conducting opportunistic screening). However, the company does not indicate in the IC form for True Genome Undiagnosed Disease Test whether the consumer has an opportunity to opt out of the analysis of some of the genes listed by the ACMG. Furthermore, according to the report on IFs issued by the PCSBI [Presidential Commission for the Study of Bioethical Issues, 2013] as well as the recent update of the recommendations for reporting secondary findings in genome-scale sequencing [ACMG Board of Directors, 2014] the term “incidental findings” used by Illumina is not adequate and in order to comply with the guidlines mentioned it should be replaced by the term “secondary findings”. Nevertheless, in the IC for Undiagnosed Disease Test Illumina seems to implement the recommendation included in the primer on IFs for DTC providers [Presidential Commission for the Study of Bioethical Issues, 2014], which advise to prepare a plan for the management of incidental and secondary findings and to provide easily accessible information for consumers about this procedure.

The IC form for Illumina's Predisposition Screen test introduces categories of genetic information which consumer may choose not to receive exercising his/her “right not to know” some of the medical information. The categories of genetic information introduced by Illumina are to some extent in line with those suggested by Ayuso et al. 2013 as they arrange the conditions according to the time of onset and medical actionability facilitating the choice of consumers [Ayuso et al., 2013].