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DEBATE Open Access Ethical issues in human genomics research in developing countries Jantina de Vries 1,2* , Susan J Bull 1,2 , Ogobara Doumbo 3 , Muntaser Ibrahim 4 , Odile Mercereau-Puijalon 5 , Dominic Kwiatkowski 2,6 and Michael Parker 1 Abstract Background: Genome-wide association studies (GWAS) provide a powerful means of identifying genetic variants that play a role in common diseases. Such studies present important ethical challenges. An increasing number of GWAS is taking place in lower income countries and there is a pressing need to identify the particular ethical challenges arising in such contexts. In this paper, we draw upon the experiences of the MalariaGEN Consortium to identify specific ethical issues raised by such research in Africa, Asia and Oceania. Discussion: We explore ethical issues in three key areas: protecting the interests of research participants, regulation of international collaborative genomics research and protecting the interests of scientists in low income countries. With regard to participants, important challenges are raised about community consultation and consent. Genomics research raises ethical and governance issues about sample export and ownership, about the use of archived samples and about the complexity of reviewing such large international projects. In the context of protecting the interests of researchers in low income countries, we discuss aspects of data sharing and capacity building that need to be considered for sustainable and mutually beneficial collaborations. Summary: Many ethical issues are raised when genomics research is conducted on populations that are characterised by lower average income and literacy levels, such as the populations included in MalariaGEN. It is important that such issues are appropriately addressed in such research. Our experience suggests that the ethical issues in genomics research can best be identified, analysed and addressed where ethics is embedded in the design and implementation of such research projects. Background Recent years have seen an explosion of scientific interest in the use of human genomic variation to study com- mon complex diseases. The hypothesis is that human genetic diversity can be used as a tool to study the cau- sal mechanisms of disease. Examples include Genome- Wide Association studies (GWAS) and, more recently, projects that make use of next-generation sequencing. Over the past 5 years, GWAS have proven very valuable in identifying regions of the genome that affect resis- tance or susceptibility to a wide range of common dis- eases, although the method provides simply a starting point, and a range of other approaches will be required in future to fully characterise and understand the complex genetic determinants of human health and dis- ease. To date, whilst many such studies have taken place focussing on a wide range of conditions, hardly any of these have been applied to diseases that primarily affect people in lower income countries [1,2]. There are good ethical reasons for encouraging medi- cal research on diseases affecting populations with lower average income and literacy levels. Substantial global inequalities exist in health measures such as mortality, quality of life and disease incidence. These persist despite increasing levels of overall wealth [3,4]. Even today, only a small proportion of medical research focuses on the problems primarily affecting the worlds poorest people [5]. Applying the methods of genomics research to these diseases is one way to address this imbalance. Genomics research raises a number of ethical chal- lenges wherever it is carried out [6,7]. Some of the * Correspondence: [email protected] 1 The Ethox Centre, Department of Public Health and Primary Care, University of Oxford, Old Road Campus, Headington, Oxford, OX3 7LF, UK Full list of author information is available at the end of the article de Vries et al. BMC Medical Ethics 2011, 12:5 http://www.biomedcentral.com/1472-6939/12/5 © 2011 de Vries et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Ethical issues in human genomics research in developing countries

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DEBATE Open Access

Ethical issues in human genomics research indeveloping countriesJantina de Vries1,2*, Susan J Bull1,2, Ogobara Doumbo3, Muntaser Ibrahim4, Odile Mercereau-Puijalon5,Dominic Kwiatkowski2,6 and Michael Parker1

Abstract

Background: Genome-wide association studies (GWAS) provide a powerful means of identifying genetic variantsthat play a role in common diseases. Such studies present important ethical challenges. An increasing number ofGWAS is taking place in lower income countries and there is a pressing need to identify the particular ethicalchallenges arising in such contexts. In this paper, we draw upon the experiences of the MalariaGEN Consortium toidentify specific ethical issues raised by such research in Africa, Asia and Oceania.

Discussion: We explore ethical issues in three key areas: protecting the interests of research participants, regulationof international collaborative genomics research and protecting the interests of scientists in low income countries.With regard to participants, important challenges are raised about community consultation and consent. Genomicsresearch raises ethical and governance issues about sample export and ownership, about the use of archivedsamples and about the complexity of reviewing such large international projects. In the context of protecting theinterests of researchers in low income countries, we discuss aspects of data sharing and capacity building thatneed to be considered for sustainable and mutually beneficial collaborations.

Summary: Many ethical issues are raised when genomics research is conducted on populations that arecharacterised by lower average income and literacy levels, such as the populations included in MalariaGEN. It isimportant that such issues are appropriately addressed in such research. Our experience suggests that the ethicalissues in genomics research can best be identified, analysed and addressed where ethics is embedded in thedesign and implementation of such research projects.

BackgroundRecent years have seen an explosion of scientific interestin the use of human genomic variation to study com-mon complex diseases. The hypothesis is that humangenetic diversity can be used as a tool to study the cau-sal mechanisms of disease. Examples include Genome-Wide Association studies (GWAS) and, more recently,projects that make use of next-generation sequencing.Over the past 5 years, GWAS have proven very valuablein identifying regions of the genome that affect resis-tance or susceptibility to a wide range of common dis-eases, although the method provides simply a startingpoint, and a range of other approaches will be requiredin future to fully characterise and understand the

complex genetic determinants of human health and dis-ease. To date, whilst many such studies have taken placefocussing on a wide range of conditions, hardly any ofthese have been applied to diseases that primarily affectpeople in lower income countries [1,2].There are good ethical reasons for encouraging medi-

cal research on diseases affecting populations with loweraverage income and literacy levels. Substantial globalinequalities exist in health measures such as mortality,quality of life and disease incidence. These persistdespite increasing levels of overall wealth [3,4]. Eventoday, only a small proportion of medical researchfocuses on the problems primarily affecting the world’spoorest people [5]. Applying the methods of genomicsresearch to these diseases is one way to address thisimbalance.Genomics research raises a number of ethical chal-

lenges wherever it is carried out [6,7]. Some of the

* Correspondence: [email protected] Ethox Centre, Department of Public Health and Primary Care, Universityof Oxford, Old Road Campus, Headington, Oxford, OX3 7LF, UKFull list of author information is available at the end of the article

de Vries et al. BMC Medical Ethics 2011, 12:5http://www.biomedcentral.com/1472-6939/12/5

© 2011 de Vries et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.

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issues identified in the literature to date include consent[8,9], privacy [10-12] and the collection, storage andrelease of genomic data [13,14]. Despite the existence ofa substantial and developing literature on the ethicalissues arising in genomic studies, this literature has asyet not adequately addressed the specific ethical chal-lenges presented by genomics research which takesplace in the context of collaborative global health part-nerships between high and low income countries. Thispaper aims to begin to address this gap by reporting onthe ethical challenges that have been identified in thedevelopment of the Malaria Genomic Epidemiology Net-work (MalariaGEN), a partnership of malaria researchersin over 20 countries supported by the Grand Challengesin Global Health Initiative [15].Malaria is a so-called complex disease, involving an

intricate immunological pathway and dynamic relation-ships between the human, the mosquito and the malariaparasite [16-18]. Malaria is one of the leading causes ofinfant mortality in tropical countries, causing the deathsof nearly 1 million children under five in 2006 [19], aswell as debilitating illness in a quarter of a billion peopleworldwide [19,20]. By combining large-scale epidemiolo-gical studies with state-of-the-art genomic technology,GWA studies hope to use human genetic diversity as atool to study the causal mechanisms of disease [17].MalariaGEN research is conducted in several countriesin Africa, Asia and Oceania. An overview of study sitescan be found on the project website, http://www.malariagen.net. Whereas our experience is relevant topopulations in these countries, we believe that whatessentially distinguishes the MalariaGEN research fromother genomic research conducted in wealthier partsof the world, is lower average income and literacylevels. Our findings may therefore be equally relevantto genomic research conducted on poorer populationsin other parts of the world.

Discussion: Ethical Issues in Human GenomicsResearch in Lower Income Countriesi. Protecting the interests of research participantsWhilst genomics research presents important ethicalchallenges in the recruitment of participants regardlessof where it is conducted, prospective participants inlower income countries are more likely to be poor andto have limited access to healthcare, education andother resources. This means that the carrying out ofresearch in these setting invariably presents challengesof a different order to those in higher income countries.In this section, we explore the particular challenges pre-sented by genomic research for community participationand the obtaining of valid consent.

Community engagementDriven both by recognition of the need for locally rele-vant health research in lower income countries, and byawareness of the potential for exploitation in contexts ofvulnerability and inequality [21], collaborative partner-ship and social value have been proposed as benchmarksagainst which the ethics of research in lower incomecountries should be measured [22,23]. The empirical lit-erature that exists on community partnership tends toshow that the achievement of these benchmarks mayonly really be possible in the context of effective andsustained community engagement and accountability[24-26]. Community engagement strategies therefore areincreasingly seen as a key element of ethical best prac-tice in research. Despite this growing emphasis on theimportance of community engagement however, there isstill relatively little published experience or evaluation ofengagement in practice. There is certainly a need formore research in this area, and for the sharing of mod-els of good practice.Notwithstanding its importance, the actual achieve-

ment of successful and appropriate community engage-ment presents a number of practical and ethicalchallenges. Some of these relate to the question of howthe relevant community is to be identified and repre-sented [24,27]. Others concern the identification andestablishment of procedures, principles and mechanismsof engagement that are fair, inclusive, accountable andappropriate to the research setting [28,29].In the course of its development, a number of issues

specific to international collaborations were identified bythe MalariaGEN Network. One of these concerned therelationship between the need to establish shared goodcommunity engagement practices across the network onthe one hand, and the need for sensitivity to local varia-tion on the other. MalariaGEN studies were conductedacross a wide range of settings, spanning from referralhospitals in urban areas to traditional rural villages.Each of these settings involved very different kinds of‘communities’, all with their own decision-makingstrategies.In the context of such diversity, identifying common

ground where researchers can share experiences andinsights is inevitably challenging. The extent to which‘best practice’ can be shared and translated across suchcontexts will depend on a wide range of factors particu-lar to the nature of the research and its location(s). Inpractice, MalariaGEN researchers across the networkengaged in some form of community engagement, butthe majority of such initiatives were developed ad hocby researchers in the absence of agreed-upon guidelinesfor best practice or even a toolkit for community

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engagement. The limited guidance currently availablepresents important challenges for researchers in mean-ingfully engaging with research communities.Another practical challenge in the context of commu-

nity participation in genomics research concerns how toexplain to communities what the study involves in waysthat are accessible and make understanding and engage-ment possible. Some suggestions have been made abouthow to explain key terms of genomic studies [30], butthe extent to which such abstractions effectively explainthe risks and benefits involved remains yet to be seen.Particularly challenging is the fact that many of thepotential harms and benefits of genomics research relateto populations rather than to individuals [31]. Whetherthis is an important feature of genomic studies for com-munities and participants, and how it could best beexplained and discussed, requires further investigation.Within the context of MalariaGEN, we did not resolve

ways of addressing these challenges. The complexity ofcommunity engagement exercises is widely acknowl-edged [24,27,32], and there may not be a one-size-fits-all solution. But in our experience, these are importantchallenges in the context of international collaborativegenomics research, and are going to require carefulattention in the establishment and maintenance of suc-cessful research networks. Scientific researchers cannotbe expected to face these challenges alone, and con-structive collaboration is needed with others knowledge-able in local community structures and processes andethics, preferably as an integral part of the researchprocess.Valid consentValid consent for research participation must be ade-quately informed and understood, voluntary, and givenby someone who is competent to do so [33]. It alsorequires the processes through which consent isobtained to be locally appropriate [34]. Designing andimplementing consent processes in the context of colla-borative genomics research on populations characterisedby lower average income and literacy levels presentsmany challenges. Some of the difficulties relating to thedevelopment and implementation of consent processesin lower income countries have been discussed in theliterature [35-38]. However, little of this addresses theparticular issues presented by the novel field of geno-mics research.A critical challenge to achieving valid consent in lower

income countries arises in relation to providing appro-priate information to participants in a comprehensiblemanner [39]. In genomics, challenges are presented bythe need to explain concepts such as ‘genetics’, ‘geno-mics’, ‘data release’, and the reasons underlying the needto collect large numbers of healthy population controls[28]. It may be possible to link these concepts to local

knowledge of genetics, for instance that particular facialtraits are often inherited within families [40]. Butalthough it may be possible to explain some aspects ofgenomics research in ways that are not entirely alien toresearch participants, ensuring that participants givevalid consent for genomic studies remains a significantchallenge.There are other challenges to obtaining valid consent

for genomics research. Information produced by geno-mic research has, for example, the potential to be infor-mative about people other than the research participant.There has been much discussion about the importanceof privacy protection for individual research participantsin genomic studies [41-43]. Where personal identifiersare removed from genomic datasets there may arguablybe limited risk of participant identification. Yet evenwhere this is the case, there remains a possibility thatunwanted information about populations, communitiesor families will be revealed. At the population level,GWA studies have for example the potential to revealthat a stigmatising condition is more likely to occur inone population than another [8]. In that sense, it raisesthe possibility that genomic data could be used in waysthat would have adverse effects for the populationsinvolved, possibly through generating research resultsthat could be used to stigmatise groups based on theirgenetic make-up [44,45]. There may be a need to takethis kind of issue seriously when designing consent pro-cesses for genomics.The MalariaGEN Network has sought to address some

of these challenges through the collaborative develop-ment of an informed consent template and guidelinesfor informed consent http://www.malariagen.net/home/ethics/consentpolicies.php. These were developed byand for MalariaGEN researchers and in consultationwith some ethics committee members. In addition, theMalariaGEN ethics team (JdV, SB and MP) discussedthe consent procedures, challenges and best practicewith researchers and fieldworkers at several researchsites. Particular challenges with regard to consent werehow to collect consent in emergency situations, andhow to explain the rationale for collecting samples fromhealthy children. A key strategy of genomic studies, likethe MalariaGEN study, is comparing genomic databetween children that are ill with malaria (the cases)and healthy children (the controls). The collection ofboth types of samples raised issues with regard to con-sent. Namely, children presenting at the hospital wereoften severely ill and required immediate medical assis-tance. Timing of consent in this emergency setting pre-sented a real challenge in these cases. On the otherhand, the genomic study requires the collection of bloodsamples from healthy children as well. Explaining thereason for collecting blood samples from healthy

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children also constituted important challenges for theMalariaGEN study. The complexities of resolving theseissues were such that further empirical research wasconducted at two MalariaGEN research sites, with theaim of investigating how best to obtain consent forgenomic studies in low income countries. Papers report-ing on the results of these studies are forthcoming.

ii. Regulating human genomics researchWhere genomics research focuses on diseases affectingpopulations with lower average income and literacylevels, it tends to take place in collaborations betweenresearchers from higher and lower income countries.For example, whereas the infrastructure for genotypingand whole genome analysis is usually based in higherincome countries, the patients affected by the diseasesare based in lower income countries. This distributionof research resources raises important issues about theuse of archived samples, sample ownership and ethicsreview by multiple committees.Sample export and ownershipBecause GWA studies require access to sophisticatedlaboratories and large-scale genotyping facilities withattendant statistical expertise, most of which are cur-rently only available in a few countries in the world,samples collected for GWA studies are often exportedfor processing, quality control and genotyping. Theexport of samples from lower income countries isincreasingly seen to present important ethical issuesboth by researchers and by research ethics committees[46]. Many of these arise from concerns from research-ers and ethics committees in the samples’ country oforigin that once samples have been exported, their con-trol over subsequent use will be limited [47,48]. At leastpart of the concern is that whilst samples were oftencollected for a particular purpose on the basis of a rela-tionship of trust between researcher and research parti-cipant, this relationship of trust may become dilutedwhen samples from different studies are used inresearch abroad by scientists who have never met theparticipants nor are familiar with the samples’ countryof origin. Upshur and colleagues argue that importantcontextual understandings such as the cultural value oftissues and samples may get lost if researchers who haveno knowledge of the culture prevalent in the place inwhich samples were collected, perform the majority ofwork and analysis on the samples [47]. The absence ofagreed-upon policies for export, sample handling anddestruction [48,49], as well as the fear that samples maytake on monetary value in international research [50],can aggravate such concerns.A key challenge for genomics research conducted on

populations with lower average income and literacylevels is how conditions can be created under which it

is possible for researchers and research ethics commit-tees to feel confident that samples and data will be usedappropriately, and that the decision-making process fortheir use is sufficiently transparent. In MalariaGEN, theexport of samples was found to be a particular stum-bling block for ethics committees. The committeesrequired detailed information on the need to exportsamples, as well as descriptions of the exact samplehandling. Specific Material Transfer Agreements(MTAs, Case 1) describing in detail the nature of thework to be carried out in foreign laboratories, as well asprocedures for sample return or destruction at the endof the project, were instrumental in addressing some ofthese concerns. In some instances, submission of signedMTAs was a requirement for ethics approval.

| Case 1 | Material Transfer AgreementsA Material Transfer Agreement is a contract betweentwo parties involved in a research project that specifiesexactly the nature of work that is to be done on mate-rials given by the one party to the other. It typicallyconsists of specifications of the following elements:• the materials to be transferred;• the exact work to be done on the materials;• the conditions of storage of the materials, includingfor instance details on building access and security;• the people that are to work with the samples, typi-cally the heads of research groups and all the mem-bers of their group;• the duration of the collaboration;• an agreement about data sharing and collaborationin analysis;• procedures for agreeing on any other work that isnot covered in the current MTA.MTAs are an important means of protecting theinterests of the researchers collecting and supplyingsamples. In MalariaGEN, they were instrumental inaddressing the concerns of ethics committees regard-ing ownership, long-term storage and sample re-use.

It is important to remember, however, that whereasMTAs can play a significant role in organising the legalresponsibilities in the research process, they cannotaccommodate all the above challenges. In particular,issues of perceived symbolic (non-legal) ownership overDNA, and concerns about whether a populations’genetic material relates to its identity, have long playedan important role in genetic and genomics research[51-53]. In addition, where genomics research takesplace in the context of resource inequalities betweenresearch partners, the concentration of samples andresources in particular partner sites raises questionsabout fairness, ethical oversight, benefit sharing, andlong-term development of capacity at all research sites.

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In MalariaGEN, a number of attempts have beenmade to address these more exacting challenges, inaddition to MTAs and research contracts. First, the net-work developed a capacity building scheme in whichyoung researchers from all partner sites were trained inthe analysis of genomic data (see section Capacity Build-ing). Second, the network recognised the need to enableall contributing researchers to analyse their own databefore it was made publicly available and incorporatedthis into the MalariaGEN Data Release Policy http://www.malariagen.net/home/downloads/16.pdf. Third, thenetwork sought to develop software that allows theremote analysis of genomic data - meaning that Malaria-GEN researchers anywhere in the world could analysedata without the need to invest in expensive in-houseinfrastructure for data analysis and storage. Funding hasalso been obtained to fund a PhD studentship to explorethe issues relating to the collection, storage and exportof biological samples and to work towards the develop-ment of recommendations on good practice.

Archived samplesSuccessful GWA studies require the collection of verylarge numbers of samples and well-characterised pheno-types. This is labour-intensive and time consuming,even in well-resourced health systems. Moreover, theconditions and lack of infrastructure for treatment andresearch in lower income countries are often not condu-cive to the rapid collection of the very large numbers ofsamples required for genomic studies. Significantimprovements in malaria treatment and prevention[54,55] also mean that fewer samples are available forresearch on that disease. Taken together, these factorsmean that GWA studies such as MalariaGEN need torely heavily on the use of archived samples.The use of archived samples raises a number of

important ethical challenges. The relatively recent devel-opment of genomics means that it is unlikely that con-sent to studies conducted a few years earlier would haveincluded it. Questions therefore arise about how deci-sions about the re-use of such samples should be madeand who should be making them. One issue concernsthe legitimacy of ethics committees to represent theviews of research participants and to decide on re-useon their behalf [48,49,56]. Further issues arise aboutwhether there are cases in which re-consent should berequired or whether there are forms of researchfor which new samples should be collected altogether.A balance may need to be struck between the ethicalimplications of collecting many thousands of new sam-ples against the ethics of using archived samples withless than ideal consent.For MalariaGEN, almost all contributed samples were

originally collected for research on malaria, but only a

subset was collected with consent for genomic orgenetic studies. All ethics committees reviewing theMalariaGEN studies approved the inclusion of archivedsamples in the prospective genomic study. Only in onesite did researchers decide to re-consent participantswhose samples were collected many years ago, but thiswas mainly because the research design of the particularsub-study required taking additional samples.

Ethics reviewInternational collaborative research projects need toobtain ethics approval from a multitude of committeesfrom around the world. This can be a daunting task,especially where committees express different or con-flicting points of view or place additional requirementson researchers [57], such as changes to a consent formthat has already been approved by another ethicscommittee.The review of genomic studies is challenging: the

science is difficult to comprehend [58], the studies arehypothesis-generating rather than hypothesis-testing, usevery large sample numbers [59,60], and generate verylarge amounts of data that can be analysed many timesfor different purposes. In addition, genomic studies takeplace in a context where data sharing is the norm [61].This raises ethical challenges that may not be familiar tomembers of ethics committees. Ethics committeesreviewing research in this area may not have had thetraining or experience to enable them to identify andanalyse the key ethical issues - a well-recognised pro-blem also in other research fields [62-64]. In addition,many of the key ethical challenges of GWA studies haveonly been identified fairly recently. Pertinent issues likeconsent and privacy remain the topic of debate [43],and consensus about the best approach to accommodatethese challenges in research has not been reached.It is therefore hardly surprising that obtaining ethics

approval for the various MalariaGEN studies was a sig-nificant challenge. Over twenty ethics committees insixteen countries reviewed and approved the study, withreview taking up to a year to complete at some partnersites (see Case 2). For many of these committees, theMalariaGEN study was one of the first genomic studiesto be reviewed.The MalariaGEN study was approved by all ethics

committees, although in some cases the approval pro-cess consisted of multiple rounds of correspondence toclarify study design and rationale. Overall, there wasconsiderable homogeneity in the concerns raised bycommittees in various countries. The main points raisedconcerned: how to ensure that participants give valid(informed) consent; justifications for the export of sam-ples and specification of the procedures for samplereturn or destruction at the end of the project; ensuring

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the appropriate recognition of local investigators’ contri-butions and capacity development; ensuring that geno-mic data will not be used to harm populations orcountries; and ways of assigning benefits to the countryor community that donated the samples.A particular challenge relates to fast increases in the

number of genetic variants that can be reasonably geno-typed for a project like MalariaGEN. Genomics is a fast-moving field and new technological opportunities aredeveloped monthly. These ought to be exploited tomaximise the power of genomic studies; yet they maymean that the ethics approval is outdated.MalariaGEN adopted two ways of approaching the

challenge of obtaining ethics review. First, it held anumber of ethics workshops to which members of someof the ethics committees were also invited. In this way,MalariaGEN received some very important feedbackabout what were perceived to be the key ethical chal-lenges by ethics committee members, which could inturn be integrated into project policies and proposals.Second, when the Network was seeking to address parti-cular issues, such as data sharing, it sought to establishworking relationships with ethics committees to receivefeedback on proposed policies. This enriched the Net-work’s thinking about particular ethical challenges relat-ing to the MalariaGEN studies.

| Case 2 | Ethics Review and theMalariagen Ethics Team

The MalariaGEN Network has adopted an integra-tive approach to ethics, with a team of ethicists work-ing alongside researchers to identify and addressethical challenges relevant to the scientific project.One way in which this approach has benefitted theNetwork is in providing assistance during ethicsreview. In consultation with project members, theMalariaGEN ethics team developed template infor-mation about the project, including informationabout the methodology, preliminary data sharingprinciples and ethical issues. This information wassubsequently used by many local researchers in theirMalariaGEN ethics application.The MalariaGEN ethics team also provided assis-tance in interpreting and answering any queries thatethics committees raised in the review process, or inliaising between project management and ethics com-mittees in addressing local concerns. Lastly, the ethicsteam provided a bridge between ethics committeesand researchers in addressing pertinent ethical chal-lenges at later stages in the project. Most impor-tantly, it facilitated a discussion of ethicalconsiderations important in the context of datasharing.

iii. Protecting the interests of scientistsin the developing worldA fundamental principle underlying many genomicsresearch projects is that data should be shared withthird party researchers for secondary analysis. Whereasthis principle may be ethically laudable in promotingthe utility of data, it is also based on an assumption thatall researchers have equal access to the data, and com-parable facilities and abilities to analyse it. This assump-tion does not hold for all researchers, and especially notfor those based in low-income countries. A specificfocus on equality and fairness may be necessary to pro-tect the interests of those researchers.Data sharing and data releaseThere are strong scientific and ethical arguments forsharing genomic data as the full scientific value of aGWA study may not be realised unless it is analysed bydifferent methods and combined with other datasets.Despite the ethical importance of promoting the avail-ability of genomic data to the scientific community [65],moves towards open access have also generated a signif-icant literature concerning the compatibility of openaccess with important ethical principles and values [61].The range of ethical issues identified is extensive. Itincludes concerns about: privacy and whether anonymitycan be guaranteed [10]; data security [11]; the implica-tions of collecting and storing vast amounts of data andits uncertain future use; the implications of data releasefor populations and for family members of participants[7]; the need to strike a proper balance betweenresearch and protection [65]; the development of appro-priate governance mechanisms [31]; the implications fortrust, consent and autonomy [45,66]; commercialisation;and the ethical importance of the sustainability ofdatabases.While MalariaGEN was founded with open access in

mind [13] it was clear that the development of an effec-tive, appropriate approach to GWA data releaserequired widespread consultation across the networkand with external stakeholders. After extensive discus-sion within the Network, and consultation with partiesoutside it, it was concluded that it would be inappropri-ate to provide unrestricted public access to GWA dataon individuals accompanied by specific phenotypic data.Following consultation, it was agreed that access toMalariaGEN datasets would be mediated via an inde-pendent data-access committee and that researcherswould be granted access to genotyping data and to alimited amount of clinical and demographic data onlyafter signing a legally-binding data-access agreementwhich placed restrictions on the acceptable usesto which MalariaGEN data can be put [14]. The princi-ples set out in the MalariaGEN Data Access Policy

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incorporate key ethical principles that MalariaGENresearchers agreed should be respected by any thirdparty using the genomic data. Particularly important fac-tors in deciding to regulate data access were the poten-tial for genomic data associated with ethnicity to lead toethnic stigmatisation and the importance of ensuringthat future data uses are compliant with the purposesfor which the samples were collected.Another key reason for adopting a managed approach

to data release was the view that an ethical data releasepolicy must also be combined with adequate protectionsfor researchers in lower income countries. Where datais open access, training and capacity building activitiesare necessary to ensure that researchers in the lowerincome countries have a fair chance to publish theiranalyses of the study [14].Capacity buildingA significant challenge for sustainable GWA studies inlower income countries concerns the development ofresearch capacity across participating research sites.Where researchers are engaged in the collection of largenumbers of samples, it is vital that they are also in aposition to analyse research results, and to use theircontribution for career development. Capacity buildingwould also allow scientists to enlarge their analyses toadditional, locally-held phenotypes or to build on keygenomic findings to develop further research projects.Such projects could aim at understanding the biologicalmechanisms relating to the genetic effect, or undertak-ing additional genetic studies. For GWA studies, capa-city building is also imperative as benefit sharing as themain outcomes of the research are likely to be expertiseand knowledge, rather than treatments.After genotyping or sequencing is completed, GWA

studies are strongly reliant on bioinformatics and com-putational technology and infrastructure, but not allthese need to be present at the site where analysis isconducted. Especially when data is accessed from a dis-tance, genomic analysis is relatively affordable. Thus,genomic methodology may offer excellent opportunitiesfor real and sustainable involvement from researchers inlower income countries (See Case 3). A key bottleneck,however, is the ability to work with genomic data.

| Case 3 | Capacity Building in Genomics inDeveloping Countries

The relative affordability of genomic analyses, oncedata has been generated, may mean that thisresearch methodology lends itself well for successfulcapacity building. A key aim of sustainable GWASought to be that all researchers are able to analyseand publish analyses of their data. However, in orderto ensure that all research sites are capable of

conducting site-specific analyses, the following needto be considered:Central Data Repository: Genomic data files arelarge and require very significant computationalresources for confidential storage. For successful localanalyses, it may not be necessary to store the data atall research sites; rather, a central data repositorymay be a solution. A prerequisite, however, is thatsuch a repository can easily and securely be accessedat a distance, and that tools exist that allow for rele-vant data to be extracted and/or analysed whennecessary. It also requires a trusted body to maintainand share the data.Local Infrastructure: Ideally, investigators aroundthe world should be in a position to analyse genomicdata, and combine it where appropriate with clinicaldata held locally. This would maximise the utility ofgenomic data, provide career incentives, and possiblygenerate new research findings that are specific forthe populations that donated samples. But such ana-lyses will only take place if sufficient resources areavailable locally to support them. Necessary for localanalyses are• effective high-speed connectivity to the Internet;• high speed computers;• human resources including well-trained IT staffand bioinformatics scientists;• a supportive institutional environment that allowsstaff to acquire the necessary skills, and that providescareer opportunities.Network Infrastructure: Where research takes placein international collaboration, then the networkshould identify strengths and weaknesses for all part-ner sites, and be committed to sharing these withothers. In particular, the network should seek to sup-port local analyses, for instance by making a dataanalyst available to all sites. Also, regular meetingopportunities to discuss particular challenges, as wellas a mentoring scheme to support junior researchersmay be considered.

In the context of MalariaGEN, this challenge wasaddressed in a training programme in which juniorresearchers from the participating research centresreceived intensive training in the analysis of genomicdata [15]. They participated in several data analysisworkshops and were also invited to the annual Malaria-GEN meetings where they presented site-specific ana-lyses. In addition, they received support to develop andsubmit conference abstracts, and a sub-group alsoreceived support to apply for PhD fellowships.While this capacity building programme was success-

ful in engaging young local researchers in genomic

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studies, this is also a vast and difficult area that requireslong-term investment and commitment from all partiesin research. On the contrary, research projects oftenhave to rely on short-term research funding and havemilestones that need to be met. Also, it can only beexpected to be successful if linked into a supportive andstable institutional environment. To train a group ofenthusiastic and young people in the scope of a fewyears to a standard where they can successfully analysegenomic data is then a significant challenge.Second, although software can be developed which

allows researchers to conduct analyses at a distance, itinevitably requires stable Internet connections. Althoughthe majority of research centres around the world nowhave fairly stable access to the Internet, some centresremain unconnected. In the context of an internationalcollaborative research project it is unfeasible to developcomputational and networking capacity at all theresearch sites, which means that some sites may remainat a disadvantage in terms of data utilization and analy-sis. Site visits and local exchange of facilities may be asolution to this problem.

SummaryThe application of GWA methodology to poverty-related diseases presents a wide range of ethical chal-lenges. As our experiences with MalariaGEN haveshown, the three key challenges highlighted in the litera-ture to date - namely consent, privacy and data release -are by no means an exhaustive list. The ethical issuesrelevant to GWA studies conducted on populations withlower average income and literacy levels also includeissues around the inclusion and reuse of archived sam-ples, export of samples, ethical review and capacitybuilding. We believe that identifying and addressingethical considerations should be integral to the develop-ment of responsible whole-genome studies in recogni-tion of the need to develop appropriate responses toissues that are relevant to populations in low-incomecountries.The fact that collaborative genomics research in lower

income countries involves the establishment of largeand diverse scientific networks bringing together diverseand interdependent forms of expertise and institutionsin higher and lower income countries, means thatresponsibility for the ethical dimensions of such researchis inevitably shared. Important issues such as ownershipof samples and data and capacity to analyse genomicdata need to be addressed for such studies to be suc-cessful. In addition to establishing means of developingconsensus about ethical issues to be addressed in theirresearch, networks need to determine how best to tailorthe implementation of ethical principles to individualresearch sites.

In this paper, we have described the experiences ofexploring and addressing the ethical issues that emergedin the context of the research of the MalariaGEN Net-work. But one size does not fit all and the developmentof appropriate responses to these ethical issues will needto be conducted on a case by case basis. What will linkinternational genomics research projects, though, arethe more general principles of justice, ownership andthe fair distribution of resources. Given the urgent needto alleviate the disease burden for people living in lowerincome countries, and the tremendous opportunity toredress wider issues of global injustice and inequality,the need to tackle and resolve the ethical challenges sur-rounding GWA studies is as important as it is acute.

Abbreviations UsedGWA: Genome Wide Association; MalariaGEN: Malaria Genomic EpidemiologyNetwork; MTA: Material Transfer Agreement

Acknowledgements and FundingWe thank our many colleagues who helped to us to identify and addressthe ethical issues in the MalariaGEN Consortium. They include theMalariaGEN Lead Investigators and Project Management Committee, theethical review bodies at MalariaGEN partner institutions in malaria-endemiccountries and many of our colleagues in the field of bioethics.MalariaGEN’s primary funding is from the Wellcome Trust (077383/Z/05/Z)and the Bill & Melinda Gates Foundation via the Foundation for the USNational Institutes of Health (566) as part of the Grand Challenges in GlobalHealth initiative. Additional support is provided by Wellcome Trust SangerInstitute core funding and the Medical Research Council (G0600230). JdVreceives funding from a Wellcome Trust Biomedical Ethics Studentship (WT083326/Z/07/Z). MP and SB receive funding from a Wellcome TrustEnhancement Award in Biomedical Ethics (087285/Z/08/Z).The funders had no role in the decision to submit the article or in itspreparation.

Author details1The Ethox Centre, Department of Public Health and Primary Care, Universityof Oxford, Old Road Campus, Headington, Oxford, OX3 7LF, UK. 2TheWellcome Trust Centre for Human Genetics, University of Oxford, RooseveltDrive, Oxford, OX3 7BN, UK. 3Malaria Research and Training Centre, Facultyof Medicine, Pharmacy and Odonto-Stomatology, University of Bamako, POBox: 1805 Point G, Bamako, Mali. 4Institute for Endemic Diseases, Universityof Khartoum, Medical Campus, Qasser Street, PO Box 102 Sudan. 5InstitutPasteur, Unité d’Immunologie Moléculaire des Parasites, 28 Rue du Dr Roux,75724 Paris, Cedex 15, France. 6Wellcome Trust Sanger Institute, Hinxton,Cambridge, CB10 1SA, UK.

Authors’ contributionsJdV, SJB and MP prepared the manuscript. OD, MI, OMP and DK commentedon all versions and made substantial contributions to the final draft of thepaper. All authors read and approved the manuscript before submission.

Competing interestsThe authors declare that they have no competing interests.

Received: 4 October 2010 Accepted: 18 March 2011Published: 18 March 2011

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