In this second part, we use the ENGAGE Consortium as a case study to examine the impact of the challenges of research using previously collected data sets. First, we describe the general characteristics of the studies comprising ENGAGE and the nature of their original consents (A). Next, we analyze the information given to the research participants and how these documents deal with issues identified as potential hurdles for retrospective research (B).
(A) General characteristics: ENGAGE
The 39 ENGAGE cohorts originate from 13 different countries and are part of population-based follow-up studies (19), family studies (7), twin studies, (6) and case–control settings or case-only studies (7).33
The size of the ENGAGE cohorts varies from data sets of <10
000 samples per data set (67% of all cohorts) to data sets of >50
000 samples per data set (6% of all cohorts). Collectively, the data from these 39 cohorts represent human genetics data sets from >600
000 individuals. ENGAGE is a 5-year project that was funded by The European Community's Seventh Framework Programme (FP7/2007–2013) in 2008.
The genetic and phenotypic data made available to ENGAGE were collected at a time when their possible future use in ENGAGE was unknown. Analyses of electronic copies of the information leaflets and informed consent forms (‘Information Documents' or ID) used in the ENGAGE cohort studies identified the main challenges emerging from the use of already collected data for the purpose of retrospective research. In all, 52 studies from the 39 cohorts of ENGAGE were analyzed. This represents 95% of the ENGAGE cohort studies. Although six ENGAGE partners are from Nordic countries, 62% (32) of the cohort studies are from Nordic countries. It should be noted that the results below are based on our analysis of the content of the information documents given to the participants. Neither other consent mechanisms used in different countries nor national legal frameworks were investigated.
About two-thirds of the ENGAGE cohort studies are regionally representative (34), with participants recruited from specific, small, or medium-size towns or regions, usually through the county hospital or the regional biobank. The remaining studies (18) recruited participants countrywide. Furthermore, 88% (46) of the data collected in the 52 cohort studies are <20 years old. Most of the studies are longitudinal designs and were often added onto similar previous studies (eg, KORA, Tromsø, NFBC). The majority recruited only adults; 13% (7) also recruited minors, usually for the purpose of following up mothers and their infants until a certain age.
All studies had local research ethics committee approval, and research participants received an information sheet describing the research and/or an informed consent form at the time of recruitment. Normally, clinical and health information was collected by means of questionnaires and samples (eg, blood sample, urine sample). Some studies included more in-depth medical examinations (eg, ECG).
(B) Mechanisms within ENGAGE
The information documents given to the research participants describe the mechanisms used in retrospective research under the following categories: (i) broad consent; (ii) multilayered consent; (iii) secondary use; (iv) withdrawal; (v) recontact/reconsent; (vi) deceased persons; and (vii) anonymized/coded data. These will be briefly described before analyzing their impact on ENGAGE (viii). shows the frequency at which these various mechanisms were used by ENGAGE cohorts.
Mechanisms used by ENGAGE cohorts. Source: informed consent forms and information leaflets from 52 studies belonging to the 39 ENGAGE cohorts.
(i) Broad consent
Consents can be categorized into two main types. Broad consent is defined as asking the research participants to consent to a wide range of future research,34
whereas specific consent is limited to a specific research. In all, 52% (27) of the studies used broad consent and 48% (25) used specific consent. In 67% (35) of the studies, the information documents specified that the samples taken would be used for DNA extraction or genetic analysis. In the remaining 33% (17), the information provided to participants did not mention genetic research per se
but only biological research (eg, extraction of clinical values such as cholesterol levels).
(ii) Multilayered consent
In all, 12% of studies (6) used a multilayered consent approach. For instance, in some informed consent forms from Norway and Sweden, research participants were given the option to cross out items they did not want to give their consent to (eg, extraction of DNA, recontact for further investigation, merging of results with other registers).
(iii) Secondary use
A total of 63% (33) of the studies mentioned secondary use of collected data. In those 33 studies, seven specified that such research would only be carried out with the approval of a local oversight authority, such as a data inspectorate and/or a research ethics committee. Of the studies, 54% (28) mentioned that the data may be shared with other biobanks or research institutions. In one of three studies (36%), secondary use is not mentioned in the information document. Failure to mention possible secondary use does not necessarily preclude such use, as the national ethical–legal frameworks may not explicitly prohibit it.
In 79% of the studies (41), participants were informed about their right to withdraw from the study. However, the fate of the data and samples on withdrawal is not dealt with uniformly. They can be destroyed, removed, or kept in the biobank. In about one-third of the studies, in which withdrawal is mentioned, the procedure to be followed is not specified.
Of the studies, 36% (19) mention that participants may be recontacted if new research is to be performed or if the data are to be shared with other investigators or biobanks. Four studies mention explicitly that such recontact implies that a new consent will be obtained. In 13% (7) of the studies, mothers and infants were recruited, usually for longitudinal studies with follow-up until a certain age. Among these, two address the issue of informing minors of their participation in the study or obtaining new consent once they have matured or reached legal age. In the first study, researchers would inform the minor of his/her participation at the age of 15 and 18 years. In the second study, researchers inform the minor of data storage and of the possibility of withdrawal.
(vi) Deceased persons
Only 5% (3) of studies explicitly waive consent for the use of data and samples after the death or incapacity of the research participant. In the remaining 49 studies, this issue is not addressed.
(vii) Anonymized/coded data
A total of 92% (48) of the information documents describe respect for confidentiality and the secure use of the health information of participants. In most cases, it is mentioned that the data will be deidentified (eg, coded) or that the participant's identity will not be traceable (anonymized).
(viii) Impact for ENGAGE
In all, 73% of ENGAGE cohort studies use at least one mechanism to facilitate the secondary use of data. Ten studies (19%) use four mechanisms, whereas six use three mechanisms (). Four cohort studies use broad consent in conjunction with another mechanism, either a secondary use statement or a recontact/reconsent mechanism, whereas seven (13%) studies use only a broad consent. Even among the 11 (21%) studies that have a specific consent, 25 cohorts foresee the use of different mechanisms, such as a secondary use statement (7), a recontact/reconsent mechanism (2), a combination of a secondary use statement with a waiver of consent (1), or a recontact/reconsent mechanism with a waiver of consent (1).
Solutions among ENGAGE cohort studies.
Only 14 studies (27%) have no explicit mechanism for the secondary retrospective use of data. Therefore, the data collected by these cohorts cannot be used by ENGAGE partners, unless in accordance with the original consent, or because national legislative and/or ethical frameworks allow such secondary use without the reconsent of the research participant or under an ethics waiver.
It is interesting to note that for the main research areas of ENGAGE (cardiovascular diseases and/or diabetes), 85% (44) of the studies obtained consent to perform such research. This consent corresponds to the overall research objectives of ENGAGE for the majority of research participants of the 52 cohort studies analyzed.
Nevertheless, the practical management of change of status (death, incapacity, reaching legal age, or withdrawal from the study), the secure exchange of data across institutions and borders, and the risk for reidentification represent important challenges for ENGAGE. Because national legislation differs from one country to another, managing data exchange in ENGAGE requires knowledge of existing regulations and a continuous follow-up of international norms. When entering the project, all partners were responsible for ensuring that their data would be used in accordance with the consent given by the research participants. Difficulties may still occur when seeking a renewed consent or approval from a local research ethics committee or data inspectorate. This could lead to expensive and burdensome administrative procedures for the ENGAGE project. These challenges are not addressed in the consent forms. The project, which has already produced a significant number of international scientific publications (the list of ENGAGE publications is available on the ENGAGE public web site www.euengage.org
.), illustrates the need for the evolution of consent, offers a unique opportunity to further work on these issues, and, at the same time, continue to carry out major scientific research.