Ethca concerns for whoe genome

and whoe exome sequencng

studes
Informed consent
Genomc studes nvovng human research sub|ects typcay requre
ethca cearance from reevant nsttutona revew boards (IRBs) or
research ethcs commttees (RECs) before commencng. Ths process
nvoves members of the IRBs/RECs determnng whether the research
protoco w gather suffcent nformed consent from study partcpants
to ensure that these ndvduas are abe to make nformed decsons
regardng potenta rsks and benefts of vountary partcpaton
|9|. The consent procedure shoud be an on-gong process, whch
nvoves more than ony an nta nformed consent document:
researchers shoud engage prospectve study partcpants n frequent
dscussons about ther research, as we as gve them adequate tme
to decde whether they wsh to partcpate n the proposed research,
ensurng that partcpants rease that partcpaton s vountary. In
certan settngs, consutatons wth the communty may aso be
approprate (see the secton, Chaenges and opportuntes n the
Afrcan context, beow).
NIH-funded research nvovng human sub|ects s guded by the US
Department of Heath and Human Servces Pocy for the Protecton of
Human Research Sub|ects Code of Federa Reguatons, 45 CFR Part 46
|10|. Of reevance to research n Afrca s the fact that the nformed
consent process of pro|ects funded by the H3Afrca Intatve w be
requred to compy wth the so-caed Common Rue (.e. subpart A of
45 CFR Part 46) |11|. Pubshed n 1991, a arge part of these
reguatons were derved from concepts from the Bemont Report
|12,13|, a report that paces emphass on: () respect for persons, ()
benefcence and () |ustce. The Common Rue s the basc pocy for
the protecton of human research sub|ects for federay funded
research n the USA. The pocy covers aspects such as genera
requrements for nformed consent and crtera for IRB membershp
and oversght.
The nformed consent document shoud contan a varety of dfferent
eements presented n a concse manner to ensure that partcpants
can easy comprehend the text. Eements normay ncuded are a
bref descrpton of the pro|ect, the goas of the research, the potenta
rsks and benefts of partcpaton, return of resuts, optons for
wthdrawa from research and data sharng pans. It s mperatve for
the nformed document to be wrtten n accessbe anguage to
promote research partcpant autonomy and awareness of potenta
benefts or harms of partcpaton.
Data sharing
One of the key aspects of genomc research, whch s frequenty
adopted by these studes (ncudng those studes nvovng WGES), s
the concept of data sharng through databases to aow for the
secondary use of data. Such data sharng has been empoyed n the
fed of human genomcs snce the advent of genome wde assocaton
studes (GWAS) |14|. Increasng data access has aowed genomc
datasets to be thoroughy anaysed, and has afforded research groups
wthout data-generatng capacty the opportunty to nterrogate
genomc data.
The reated benefts to socety of these data sharng practces have ed
certan pubc fundng agences as we as |ournas to requre
researchers to depost genomc data and correated dedentfed
phenotypc nformaton nto pubc databases. For exampe, the
federay-funded NIH expects research resources generated by NIH
pro|ects to be shared wth the scentfc communty uness there are
adequate reasons that woud |ustfy that exempton (e.g. data sharng
not covered n the orgna consent documents, nsttutona poces,
etc.) |15|. Exampes of such databases ncude the Database of
Genotypes and Phenotypes (dbGaP) and the European Genome-
phenome Archve (EGA). These databases were orgnay operated
under open access modes; ths practce, however, s no onger
endorsed by the NIH and Wecome Trust snce a study by Homer et a.
|16| dspayed that certan genotypc nformaton makes t s possbe
to determne whether a partcuar ndvdua partcpated n a GWAS
|17|.Currenty, these databases are typcay operated under
restrcted/controed access and data access commttees oversee the
dssemnaton of such data.
As ustrated by Homer et a. |16|, despte the practca obscurty of
genomc data, prvacy and ssues pertanng to dentfabty are
nherent concerns when genomc data sharng s
practced. Addtonay, prvacy rsks are not excusve to the genomc
research partcpants themseves, but extend to ther fames
too. Athough persona dentfers are removed from genotype-
phenotype data n pubc databases, the rsk of the nference of
ndvduas by data ntruders st exsts due to rchness of such data
and ncreasng numbers of dfferent types of pubc databases |17-
21|. Therefore dbGaP and EGA requre users requestng to gan access
to ndvdua genotype-phenotype nformaton to sgn agreements that
state that data w not be used to attempt to dentfy partcpants and
that data confdentaty w be mantaned. These are data use
certfcaton |22| and data access agreements |23|, respectvey. It s,
however, mpossbe to guarantee absoute confdentaty to research
partcpants n genomc studes, and t s mportant that such a caveat
s ncuded n the nformed consent document. Fnay, once the data
have been deposted n these databases, wthdrawa from research -
an opton frequenty found n nformed consent documents - becomes
chaengng |2|.
For these reasons, the senstve nature of genomc data wth regards to
dentfabty and prvacy, as we as stgmatsaton and dscrmnaton
that coud resut from data breaches, are ma|or concerns n these
studes, whe the physca harms of partcpatng n such research are
usuay mnma (e.g. the pan experenced due to bood draw): unke
tradtona cnca research, the ma|or harms of genomc research are
not physca, but psychosoca n nature |9|. These rsks of data sharng
need to be carefuy measured aganst the potenta oss of medca
advancement to socety through wthhodng the data.
Participant identifiability
The deuge of data that are generated n WGES studes dffer
dramatcay from DNA mcroarray-based GWAS snce, theoretcay, a
the genetc varants that change proten sequences n an ndvdua are
cataogued, heghtenng the ethca and ega concerns encountered n
tradtona genetc studes. The extensve nature of these WGES data,
as we as nks to correspondng phenotypc and fama data,
ncreases the kehood of dentfabty of research partcpants and
compcates the nformed consent process |24,25|.These concerns
provde chaenges for IRBs/RECs as we as nvestgators wantng to
conduct WGES studes, snce due to the emergng nature of WGES
technooges, emprca evdence and poces regardng these concepts
are ackng.
Due to these concerns, the contents of the nformed consent document
come under ncreased scrutny n WGES studes. Ths s of partcuar
reevance to sampes that were coected before NGS era of medca
genomc research, and IRBs/RECs coud concude that partcpants
need to re-consent to the WGES part of the study. Athough the goas
of tradtona genetc and genomc studes do not dffer greaty from
WGES studes, there s st some debate whether research partcpants
need to be specfcay nformed about the use of WGES n a study, and
f so, how extensve and n what anguage the descrpton of the WGES
approach shoud be n the consent document |4,26|. Practcng
genomc data sharng s aso another potenta ssue here f the
ndvduas were not advsed about ths concept n the orgna
nformed consent documents |27|.Further, WGES approaches are far
more prone to uncover secondary or ncdenta research fndngs (.e.
those not reated to the prmary research ams/scope of the study) and
f there s to be an opton for such resuts to be returned to research
partcpants, ths shoud be carfed n the nformed consent document
|28|. Ths ast concept w be dscussed n more deta ater.
The use of broad consent has been suggested as a possbe souton to
aow for genomc data to be shared as we as permttng the ncuson
of DNA sampes n borepostores |14,29|. Ths w come under
heghtened nspecton wth the advent of WGES studes, snce the use
of broad consent modes opens concerns about decreased research
partcpant autonomy and may mpar ther abty to make nformed
decsons |14,25|. The feasbty of usng narrow consent modes for
borepostores s questonabe; snce ths woud hamper research
outputs from these resources and coud necesstate excessve re-
contact of research partcpants. Research nvovng potenta
borepostory partcpants n the US ndcates that prvacy s a notabe
concern for these ndvduas and shoud be addressed n future
nformed consent documents |30|.
The prvacy rsks assocated wth WGES data sharng are ncreased due
to the scope of these data, whch ncude nformaton on rare aees as
we as varants of cnca utty that w ad n re-dentfcaton of
sampes. Research has shown that t may be possbe to use DNA chp
data from the HapMap Pro|ect |31| to predct the potenta surnames of
partcpants from ths ntatve |20| and t has recenty been dspayed
that smar strateges, usng free, pubcay avaabe resources, can
be empoyed wth persona genome datasets to dentfy f anaysed n
con|uncton wth other avaabe data (e.g. age and pace of brth) |21|.
Further, as the toos to anayse WGES data mprove, profng of
dentfabe phenotypc trats w become more straghtforward |19,32|
and Mendean dseases, whch are frequenty ncuded n WGES
studes, are aso easer to re-dentfy due to ther rarty and unque
pedgrees that are often ncuded n pubcatons.
Return of research results and secondary/incidental
findings
Due to the fact that WGES technooges effcenty anayse the entre
genome and exome respectvey; secondary, ncdenta or unreated
fndngs that were not part of the orgna research hypothess may be
encountered, whch paces emphass on the researchers duty to
nform partcpants of such resuts. The demma faced by
genetc/genomc researchers n handng such fndngs s not new, yet
the scope of the resuts generated by WGES exponentay ampfes
the probabty of encounterng these fndngs exponentay |33|. It has
been suggested that ethca obgatons and ega dutes for returnng
research resuts may exst |28,34-38|. For exampe, Wof et a. |34|
hghght the reevant ethca concepts of recprocty between
researchers and ther partcpants and the wefare and autonomy of
the research partcpants; and ega obgatons such as the
deveopment of management pans for secondary/ncdenta resuts, as
we as the mpementaton of these when requred. The mora duty to
warn research partcpants of secondary/ncdenta varants of nterest,
however, needs to baanced aganst opposng dutes such as the mts
of benefcence, excessve burdens on researchers, and the fact that
returnng resuts may be harmfu (e.g. cause anxety) |39|.
If an opton to return secondary/ncdenta fndngs to research
partcpants w be gven n a study, t s mportant to determne what
resuts can |ustfaby be returned to these ndvduas n order to
mnmse rsks and ncrease benefts of such a practce. Snce t s not
feasbe to return a WGES data that have been assocated wth cnca
phenotypes to partcpants, researchers must determne whch type of
genetc varants shoud be returned to research partcpants.Current
thnkng suggests that these varants shoud have cnca reevance,
have mpcatons for heath and are medcay actonabe
|26,33,40|.Categorca approaches such as the bnnng of genomc
varants accordng to cnca reevance durng nterpretaton may ad n
reducng such data nto manageabe portons |41|. Expert, confdenta
consutaton sometmes may be requred to predct the reevance of
partcuar fndngs |42| and shoud be ncorporated nto the desgn of
the nformed consent process |34|. Durng the nformed consent
process, t s aso mportant to expan to the partcpants the
mpcatons of returnng secondary/ncdenta fndngs and then to
subsequenty determne whether the research partcpants woud opt
to receve these resuts, and what ther expectatons are n ths
regard. Further, ensurng anaytca vadty through addtona
verfcaton steps and ncorporaton of genetc counseng are
mportant steps to ncude n dscosure pans |28|.
Despte these recommendatons, debate exsts wth regards to the
practce of returnng secondary/ncdenta fndngs from WGES
research and other genomc studes. Some have suggested that the
return of research resuts may dstort the ne between research and
cnca practce |9,37| and that burdensome ega abtes for
researchers may be created |43|. Another compcaton arses when
attemptng to determne what resuts are consdered cncay reevant
and how substanta the reated rsks need to be n order to be
consdered meet the crtera for such return |36,42,44|. Ths s
partcuary chaengng wth nove varants, whch s hghy reevant for
WGES research |4|. In ths regard, t s mportant to draw a dstncton
between GWAS and WGES studes. GWAS-assocated oc for most
dseases are often assocated wth sma-to-moderate rsk (Odds Ratos
of 1.3-1.6) and have ow predctve vaue for an ndvdua. Therefore,
ther cnca reevance and potenta for beng actonabe are qute
mted. WGES studes on the other hand often fnd codng mutatons
wth arge effect szes, some of whch are aready annotated as
dsease-causng (for exampe n the Human Gene Mutaton
Database). For nstance, t s estmated that heathy ndvduas carry,
on average, approxmatey >2 robust dsease-causng mutatons n
ther genomes |45|. Ths makes the ssue of secondary/ncdenta
fndngs far more compex n WGES studes.
The aspects dscussed above need to be consdered when desgnng
quafed resuts dscosure programs |39| and shoud be ncorporated
nto future research studes attemptng to generate emprca evdence
on return of secondary/ncdenta fndngs. Intatves such as My46
|46|, whch ams to gather partcpants opnons and preferences for
the return of WGES research resuts, shoud ad n better
understandng the ntrcaces of ths concept better.Sets of gudenes
and pocy statements produced by workgroups from organsatons
such as the Amercan Coege of Medca Genetcs and Genomcs |47|
wth regards to the appcaton of NGS technooges n cnca settngs
(ncudng secondary/ncdenta fndngs) coud aso provde usefu
nformaton for research envronments. Addtonay, a premnary
study of specasts opnons for the management of WGES
secondary/ncdenta fndngs - ordered for cnca purposes - cted 64
genetc condtons or genes that have strong evdence for return to
patents |48|. As such sts emerge, they coud hep gude research
studes. In the nterm, t s mportant for researchers to work
ntmatey wth ther respectve IRBs/RECs durng processes such as
the revew of WGES research protocos.
Chaenges and opportuntes n the Afrcan context
Cultural and genetic diversity in Africa
It s essenta to perform WGES studes n Afrca to ensure that the
benefts of genomc medcne are aso eventuay reased n these
popuatons. Conductng research n the cuturay as we as
genetcay dverse popuatons of Afrca, however, requres unque
consderatons to ensure that ths research s performed n a manner
that s respectfu to cutura dfferences; and communty engagement
can be hepfu n certan stuatons. Prevous arge-scae genomcs
pro|ects nvovng ndgenous Afrcan popuatons, such as the HapMap
Pro|ect |31|, amed to document unforeseen ssues and ensure that
cuturay senstve research was acheved through consutaton wth
communty advsory groups |49,50|. For exampe, certan tssues and
materas may have unque cutura sgnfcance n specfc Afrcan
popuatons and researchers need to be aware of such facts when
coectng sampes for genomc research |51,52|.
It s mportant for advsory groups to be representatve of the soco-
economc makeup of the actua communtes |53|, yet gudenes for
conductng communty engagement are notaby ackng |54|. The
seecton of the approprate members for such advsory groups s
therefore a ma|or concern |53-55|, and can ead to what has referred
to as pseudo-communty engagement |53|. Despte the fact that
approprate communty engagement can be a compex, tme-
consumng process, t ads n estabshng strong coaboratons
between researchers and research partcpants |56|. Ths s n contrast
to so-caed parachute research |57|, whch does not promote
sustanabe research condtons and creates feengs of dstrust of
research amongst the respectve communtes. If performed correcty,
communty engagement heps address group concerns, ncreases the
communtys understandng of the respectve research, ads n
preventng expotaton, enhance recrutment of research partcpants
and heps mantan openness and transparency between researchers
and potenta study partcpants. Such processes can aso be used to
determne how the respectve popuatons woud ke to be named and
descrbed n subsequent research.
Studes are requred wth regards to opnons of rsks assocated wth
dentfabty caused by genomc research n the Afrcan context. The
rsks assocated wth dentfabty assocated wth partcpatng n
genomc research w be of ncreased concern when dseases/dsorders
that have stgma assocated wth them n Afrca are studed
(e.g. menta heath |58| and HIV/Ads |59|). Addtonay, n Afrca
ndvduas frequenty defne themseves wth regards to a communty,
rather than as a one ndvdua |60|. Therefore, these dfferences to
Western thought need to acknowedged and the potenta for group
harm resutng from ncuson of certan ethnc groups needs to
consdered.
As mentoned above, the resuts of genetc/genomc research,
ncudng WGES studes, may resut n concerns about dscrmnaton
and stgmatsaton due to research fndngs |61,62|. In the US,
Godenberg et a. |63| found that the potenta for genetc research to
cause group stgmatsaton coud nfuence whether ndvduas decde
to partcpate n the study, a concern especay apparent amongst
Afrcan-Amercan respondents. De Vres et a. |64| noted that ths
genomcs-reated concern coud be reevant for ethnc groups n Afrca
for whch stgmatsaton and dscrmnaton s aready present. The
unfortunatey ong st of past and on-gong ethnc confct and voence
n many Afrcan countres suggests that ths s a rea concern. In other
words, genomcs fndngs coud be used as one more pece n
hghghtng perceved dfferences between ethnc groups that are used
to promote such confcts. On the other hand, t shoud be noted that
other dstngushng characterstcs (e.g. n skn coour, heght, or
festye) are aready beng so msused. Therefore, t s uncertan f
genomcs fndngs woud exacerbate such ssues than what currenty
exsts or f, n fact, the genomc smartes between ethnc groups w
ead to a greater apprecaton of the shared humanty of a peopes,
rrespectve of ther ethncty or outward appearance. An addtona
concern s that when the fndngs of popuaton genomc studes do not
correspond wth cutura beefs/soca narratves, ths may aso cause
group harm and/or create mstrust n the utty of genomcs n such
socetes. The fng of patents and the potenta commercasaton of
research fndngs s an addtona ssue for genomc research n
deveopng countres |53|, and rases the concepts of beneft sharng
and genomc soveregnty |65|. Researchers need to be prepared for
ths possbty when conceptuasng ther research.
Availability of resources in Africa
Conductng genomc research n resource-mted settngs, such as
those n Afrca, offers a unque set of chaenges. Comprehenson
barrers to the nformed consent process may be present due to the
mted ncome and teracy eves of partcpants as we as anguage
dfferences that may be encountered |54|. For exampe, ths s
ustrated by the fact that 30.5% of the words vng anguages have
an Afrcan orgn, yet these dverse anguages are spoken by ony
12.2% of goba popuaton |66|. These concerns are further ampfed
n WGES studes due to the compex nature of such technooges
empoyed |4|, and the requred roe of IRBs/RECs: unfortunatey, many
board members may not be adequatey traned to hande genomcs-
reated research |36,37|. Wth ncreasng WGES n Afrca over the next
fve years, the aready mted number of oca IRBs/RECs w be paced
under an ncreased burden, wth mted tranng and fundng for these
commttees on the contnent |67-69|. Due to the coaboratve nature
of WGES, ethca cearance w frequenty be requred from mutpe
IRBs/RECs, further compcatng matters.
IRBs/RECs aso need to determne protocos for WGES-reated
secondary/ncdenta fndngs n the Afrcan context. Loca
crcumstances need to be consdered, such as the feasbty of re-
contactng partcpants (for return of resuts or re-consent) n certan
studes as we as n resource-mted settngs. Even f t may not be
fnancay vabe to undertake a tme-consumng search for
secondary/ncdenta varants |42|, researchers may have an ethca
obgaton to return such varants f encountered durng the prmary
research process |34|. Ths stuaton, however, s aso set to change as
the process of genome anayss to dentfy reevant varants becomes
ncreasngy refned and automated. Another aspect that needs to be
consdered s that we do not currenty know the penetrance range of
dfferent varants that are cassfed as dsease-causng, whch s
especay reevant for Afrcan stuatons where understuded and
unque genetc and envronmenta backgrounds are present |45|.
Equay mportant s the verfcaton step that s requred before the
dscosure of secondary/ncdenta fndngs to research
partcpants. Current recommendatons n the US requre verfcaton
through aboratores conformng to the Federa Governments Cnca
Laboratory Improvement Amendments (CLIA); and researchers workng
n Afrca w have to determne whether oca recommendatons can
ensure accurate vadaton of fndngs. For exampe, n South Afrca,
the South Afrcan Natona Accredtaton System |70| s responsbe for
Internatona Organzaton for Standardzaton (ISO) accredtaton of
cnca aboratores n the country (e.g. ISO 15189 and ISO 17025).
Where resources are mted, t may prove necessary to perform
vadaton n foregn aboratores that compy wth CLIA or equvaent
protocos.
Once the reevant varants have been confrmed va verfcaton,
quafed genetc counseors shoud return these resuts at an
approprate eve for fu partcpant understandng. The mted
numbers of genetc counseors n Afrca may hamper ths process. A
recent revew noted that ony 26 genetc counseors were sted on the
reevant mang st for the Southern Afrcan Socety for Human
Genetcs |71,72|, and even n deveoped countres the number of
genetc counseors s mted (e.g. n the US there s approxmatey one
counseor to 135 000 ndvduas) |44|.
In the context of resource poor countres (ke many n sub-Saharan
Afrca), the ssue of what s actonabe becomes much more compex
than n Western natons. Assumng avaabty of WGES fndngs, there
s mted capacty to provde genetc counseng, trace and contact
famy members, nsttute preventve measures (when appcabe) and
foow up patents and ther fames. Therefore, the ack of resources
and the generay poor heath care systems may mt (and thereby
defne) what s actonabe n WGES fndngs.Autonomy may aso be
hampered n such stuatons, where t woud be dffcut to convey
compex concepts, such as actonabe fndngs, to research sub|ects
when genomc teracy s mted. There s a ack of emprca evdence
on the atttudes towards the return of secondary/ncdenta n
ndgenous Afrcan popuatons, whch shoud be addressed n future
studes. Emergng evdence from studes of Afrcan Amercan atttudes
towards WGES suggest that these ndvduas are ess key to want to
receve genetc resuts |73|.
Lmtatons to addressng such ethca consderatons for WGES n
Afrca thus ncude poor teracy and communcaton resources for the
nformed consent process; poor fnanca resources for secondary
anayss, mted resources for approprate vadaton and return of
secondary data to partcpants, and mted capacty for heath
nterventons based on secondary fndngs. Investng n Afrca by
provdng fundng for ethcs processes wthn WGES research, however,
w ad n capacty budng on the contnent and address some of
these mtatons.
Implications for informed consent and data sharing
processes in Africa
Dverse popuatons, such as those found n Afrca, requre unque
consderatons for the nformed consent process to acqure vad
consent |50|.We wshed to understand how nformed consent wth
Afrcan partcpants was undertaken for prevousy pubshed Afrcan
genome studes, and requested access to tempates of nformed
consent documentaton from a number of dfferent genomc studes
nvovng ndgenous Afrcan popuatons, n order to anayse key
concepts that were covered n these documents. In genera, the
nformed consent form tempates used for the genomc studes n
Afrca are not avaabe to externa researchers, except for those used
by arge-scae pro|ects of human genetc varaton (.e. the HapMap
Pro|ect |31| and the 1000 Genomes Pro|ect |74|) as we as the Maara
Genomc Epdemoogy Network (MaaraGEN) |75|. Attempts at
accessng nformed consent documentaton from the correspondng
authors of studes where these tempates were not pubcay avaabe
proved generay unsuccessfu. Ths may have been due to nsttutona
poces (e.g. tempate consent form documentaton coud perhaps be
consdered propretary nformaton).
Informed consent processes for genomc research n Afrcan
popuatons have prevousy been brought under scrutny |76|,
hghghtng the need to carefuy consder these processes and ensure
that the forms cover the requred concepts and are wrtten n an
accessbe anguage. Furthermore, the processes and documentaton
for nformed consent shoud be avaabe to a nterested partes, n
the nterests of transparency. The potenta ngustc barrers n Afrca
were mentoned prevousy |77|, but these may be more easy
overcome f scentfc |argon s avoded whe usng anguage famar to
the partcpants |53|. Loca vernacuar terms that have potenta
derogatory connotatons to partcpants shoud be avoded, dstnctons
between cnca care and research shoud be artcuated and t shoud
be emphassed that research partcpaton s vountary |78|. Where
possbe, oca fed workers shoud understand the study adequatey n
order to perform recrutment and shoud engage n feedback to other
members of the research team |79|.
Effcent methods to convey compcated concepts durng the nformed
process are requred to mnmze nconvenence for research
partcpants. Persons entrusted to gather nformed consent shoud
verbay go through the documentaton n the home anguage of the
research partcpants, who shoud aso be gven suffcent tme to
consder whether they wsh to partcpate n the study. Audo- or vdeo-
recorded verba consent coud be used n certan stuatons where
research partcpants are terate |80|.
Wth regards to data sharng, poces that were estabshed for the
MaaraGEN, whch conducted genomc research n numerous sub-
Saharan Afrcan countres, may serve as a prmer for future WGES
studes n Afrca, especay those nvovng arge consorta
|81|. Acceptabe uses of data and data sharng for dfferent parts of
MaarGEN are determned by an ndependent data access commttee,
n consutaton wth oca IRBs/RECs, whe consderng the respectve
consent that was obtaned |82|. Fnay, the network has adopted a
noteworthy approach to nteectua property ssues, where potenta
royates w go to partcpatng communtes and not the nvestgators
where possbe |75|. A ethcs documentaton, ncudng the nformed
consent tempates, are avaabe to the pubc.
In the subsequent secton reevant South Afrcan egsaton for WGES
studes w be dscussed n reaton to UK and US aws, usng ths case
study to gan a better understandng of potenta ega ssues n Afrcan
countres. South Afrca has been chosen not ony for ts reatve
convenence (beng known by the authors), but aso due to the fact
that t often serves as a egsatve bueprnt for other (especay
Angophone) Afrcan countres, and s therefore a pertnent pont of
departure for further research and comparatve anayss wthn the
greater Afrcan contnent.
Lega ssues around prvacy, nformed consent and
data sharng
From a ega pont of vew, the two most mportant sub|ect rghts wth
regard to medca research are the rght to body ntegrty and the
rght to prvacy. The former rght pertans to the methods used n
acqurng sampes for research, and egsaton such as the Natona
Heath Act 61 of 2003 of the Repubc of South Afrca reguates the
poston. In ths regard, wrtten nformed consent s requred for the
remova of boogca matera for use n genetc research. The atter
rght reates to how any data derved from such research shoud be
deat wth, whch s the focus of ths paper.
The rght to prvacy has been most famousy descrbed as the rght to
be eft aone |83|, and ncudes the rght to contro the dssemnaton of
nformaton about ones prvate fe. In the modern context, the rght to
prvacy s guaranteed ether expressy, n the Consttuton of the
Repubc of South Afrca, 1996, or the UKs Human Rghts Act, 1998, for
exampe, or mpcty - as s the case n the USA, where the Supreme
Court stated n Grswod v Connectcut 381 U.S. 479 (1965) that the
rght s nferred. In addton, the rght to prvacy can aso be protected
through prvate cv acton, ether by means of dect/tort, a breach of
confdence, or contractua remedes (see Natona Meda v |ooste 1996
(3) SA 262 (A); R v Department of Heath |2001| O.B. 424; Restatement
(Second) of Torts, Amercan Law Insttute, 1977).
To gve effect to prvacy rghts, many countres have adopted
egsaton not ony to provde a genera framework, but aso
specfcay to dea wth the nstances reatng to medca
research. Accordngy, we sha dscuss and evauate these egsatve
measures, ookng at South Afrca, the UK (as both a soveregn state as
we as a member of the EU), and the USA. Ths s done n order to
ascertan to what extent South Afrca adheres to nternatona
standards, and to dentfy what steps, f any, can be taken n order to
brng t n ne wth them.
Wth regard to specfc egsaton deang wth medca ethca
concerns, the South Afrcan poston s reguated by the Natona
Heath Act 61 of 2003, whch prmary concerns tsef wth aspects
reatng to the rght to body ntegrty. Furthermore, Reguaton 13 of
the Reguatons reatng to the use of Human Boogca Matera (2012)
provdes some gudng prncpes n reaton to the storage and fow of
genetc nformaton. In ths regard, nsttutons that keep or dscose
genetc matera records and other ndvduay dentfabe or reated
heath nformaton must ensure, among other thngs, that the
nformaton s treated confdentay and anonymousy f used for
research purposes, and that wrtten nformed consent s obtaned
before a persons specfc nformaton s reeased to any reevant
person. In the USA, the Heath Insurance Portabty and Accountabty
Act (HIPAA) of 1996 provdes reguatons reatng to prvacy and
securty of patent-cent records, but does not cover de-dentfed
nformaton. Addtonay, the Patent Safety and Ouaty Improvement
Act of 2005 contans more strngent reguatons regardng patent
nformaton to ncrease patent safety. It woud seem, therefore, that
equvaent protecton s granted n the USA, athough seemngy ony
nsofar as t reates to the doctor-patent reatonshp, rather than the
poston of genetc research partcpants, and, whe possbe, t s
unsure f the egsaton woud be nterpreted extensvey enough to
ncude them as we. Some of these concerns were aso recenty rased
n a US report on prvacy and progress n whoe genome sequencng
|84|. In the UK, no addtona specfc egsaton apparenty exsts
regardng prvacy n genetc research, athough case aw on ths ssue
ndcates that the prmary concern of the aw s to protect the
confder/patents persona prvacy, whch can be safeguarded through
anonymsaton (see R v Department of Heath |2001| O.B. 424;
Common Servces Agency v Scottsh Informaton Commssoner |2008|
UKHL 47). It woud seem, therefore, that, n genera, f anonymty can
be guaranteed, the use and transfer of databases contanng WGES
research shoud not be overy probematc. However, n nstances
where ndvdua dentfcaton (or rather, re-dentfcaton) s possbe,
addtona measures woud have to be mpemented.
Over and above the prvacy concern, an addtona rsk that can
potentay manfest woud be that the nformaton obtaned coud be
used to dscrmnate aganst a research partcpant. In ths regard,
specfc protecton s drecty guaranteed n the USA through the
Genetc Informaton Nondscrmnaton Act (GINA) of 2008, and
ndrecty n South Afrca through the Empoyment Equty Act 55 of
1998 and the Promoton of Equaty and Preventon of Unfar
Dscrmnaton Act 4 of 2000. The UK does not, however, provde ega
protecton n ths regard, and, therefore, confdentaty and the
protecton of persona nformaton become crtca ssues
|85|. Accordngy, the genera egsatve framework surroundng ths
aspect w be evauated.
It s submtted that the UKs ack of drecty pertnent egsaton (as
shown above) shoud not be a concern, due to the broad protecton
granted through the Data Protecton Act, 1998 (whch s the ocased
mpementaton of EC Drectve 95/46, the so-caed Data Protecton
Drectve). The Act seeks to protect the prvacy of any nformaton
reatng to a vng ndvdua who can be dentfed from the data tsef
or from the data and other nformaton, whch s n the possesson of
the controer of such data. In terms of Schedue 1 to the Act, certan
data protecton prncpes (whch are unversay appcabe n the EU)
must be adhered to, ncudng that data must be processed fary and
awfuy. Accordngy, data shoud be processed sub|ect to the
purposes for and the condtons under whch t was acqured, whe
adherng to a reevant ega prncpes (be they found n egsaton,
conventons, or otherwse), and aso bearng n mnd the nature of the
data tsef. Wth regard to the atter aspect, a dstncton s drawn
between merey persona data and senstve data. Senstve data, n
terms of Schedue 3, ncudes nformaton reatng to the race or ethnc
orgn of a person, or ther physca or menta heath. In terms of the
Act, far and awfu processng of such data entas that the data
sub|ect gve expct consent uness, among other thngs, the
nformaton s necessary to protect the vta nterests of data sub|ect or
another person, deberatey made pubc by the data sub|ect, or s
used by a heath professona and s necessary for medca purposes. In
ths regard, t s submtted that WGES research coud be seen to be
senstve data that woud requre expct consent. Ths
notwthstandng, t must be noted (as shown above) that UK courts are
of the opnon that suffcenty anonymsed data woud not be
probematc.
In genera, data protecton n South Afrca s currenty reguated by
Chapter VIII of the Eectronc Communcatons and Transactons Act 25
of 2002, whch ony deas wth nformaton obtaned through eectronc
transactons, and whch, therefore, woud n a kehood not appy to
most nstances of WGES research.Addtonay, the specfc provsons
of the Act have ected other crtcsm |see Van Der Merwe et a. |86||
due to the fact that the data protecton prncpes do not adhere to
acceptabe nternatona standards (for nstance, no speca treatment
s afforded for senstve data) and are vountary n nature. To address
these shortcomngs, new egsaton has been proposed n the form of
the Protecton of Persona Informaton B (B9-2009), whch provdes
for greater securty, openness and accountabty, and aso creates a
dstncton between standard and speca persona nformaton whch
woud ncude nformaton reatng to WGES research, and woud
requre expct consent for purposes of processng. Accordngy, the
B, f enacted, w brng South Afrcan data protecton aws n ne wth
EU standards, and aso serve to strengthen the current framework for
prvacy n WGES research n South Afrca.
In contrast to the strngent reguaton found n the European Unon,
and the subsequent South Afrcan attempts to keep n step wth these
requrements, the USA has no specfc protecton regardng data
prvacy of ndvduas over and above what has aready been stated,
except for ncdenta reguaton |87|. The fact that there s no
nternatona harmony n ths regard s probematc, as both the UK
Data Protecton Act and the EU Data Protecton Drectve provde that
no transfers of data to outsde the European Economc Area may be
made uness adequate protecton s guaranteed. Accordngy, f the
stated prncpes are not adhered to, ths coud consttute a barrer to
both transnatona research and access to research nformaton.
As a compromse n the above stuaton, an excepton exsts n both
the Act and Drectve to aow transfers to thrd countres f, among
others, a data sub|ect gves unambguous consent to a transfer - whch
consent must be freey gven, specfc and nformed - or the transfer s
on terms approved or authorsed as ensurng adequate safeguards. In
ths regard the European Commsson has deveoped prescrbed
standard contract terms for data transfer agreements (Commsson
Decson 2010/87/EU), as we as a method whereby a mutnatona
corporaton can deveop bndng corporate rues that, sub|ect to
approva through EU cooperaton procedures, woud ensure
acceptabty of a transfer (for more on ths, see |88|). Fnay, the USA
and EU have aso entered nto a so-caed Safe Harbour agreement
(Commsson Decson 2000/520/EC), whch encompasses a set of
vountary, sef-reguatory prncpes n order to assst n factatng data
transfer.
It woud seem that the prvacy concerns reatng to WGES research are
not overy probematc n most countres, as ong as the anonymty
thereof can be guaranteed. Forg et a. |89| pont out that ths s,
however, not so smpe, because t s necessary to keep an dentfabe
nk between a donor and hs genetc data to be abe to gve feedback
on reevant fndngs connected to the donors genetc data, and aso
when one takes nto account the unqueness of genetc data. As a
resut, true anonymsaton s not a vabe opton for genetc
research. Lowrance and Cons |19|, dentfy methods of mtgatng
ths, such as through mted reease of genome segments, but aso
ndcate how ths may pose ts own probems for research. Thus, t
woud seem that the most prudent route s st to obtan express
wrtten consent from research partcpants. Ths process does not
come wthout ts probems, as express consent s requred to be freey
gven, fuy nformed, and, wth reference to processng and transfer of
data, must be specfc n nature. Ths means that the use of nformed
consent forms that are overy broad or vague may end up creatng
nstances where researchers beeve themseves to be operatng
awfuy, when techncay they are not. Ths s further exacerbated,
both egay and ethcay, n the Afrcan context, where often research
s conducted usng partcpants who may not be terate or fuy
comprehend the nature and extent of the consent whch they purport
to gve.
Recommendatons for future genomc studes n Afrca
Future WGES studes n Afrcan popuatons need to consder the ponts
hghghted above n order to perform approprate research. Athough
not a-ncusve, ths woud be aded by the deveopment of oca
WGES-reated poces (ncudng the promoton of sharng nformed
consent documentaton), as we as the nvestment n reevant tranng
and the deveopment of educatona ads. A varety of usefu onne
resources for ethca and ega consderatons for WGES studes n
Afrcan popuatons can be found n Tabe 1.
Tabe 1
Usefu onne ELSI resources, especay reevant for performng
research n Afrcan popuatons
Development of local WE!"related policies
The deveopment of oca poces and egsaton that are reevant to
WGES research (e.g. nformed consent, data sharng, and the return of
resuts) w be essenta for performng successfu genomcs research
n Afrca. It s recommended, as far as possbe, that standardsed
methods to obtan nformed consent from research partcpants shoud
be deveoped n order to ensure that a generay appcabe and
recognsabe procedure s estabshed. It s advsabe not ony to have
these forms drafted n the ngua franca of research partcpants, but
aso n anguage whch s cear, succnct and easy to understand. Even
when not deang wth terate partcpants, t s generay best
practce to expan the nature and extent of the nformed consent
document n order to fuy ensure observance wth both the etter and
the substance of the aws surroundng research and data protecton. In
the nstance where one does dea wth terate partcpants, t s
techncay possbe to obtan wrtten consent through the use of a
thumbprnt or other dentfyng mark f one s abe to provde proof that
the sgned document has been adequatey expaned to the
partcpant. In ths regard, addtona nformaton provdng means,
such as vdeo recordngs, woud be advsed.
Gven that there s a movement towards greater and more open access
to WGES research and fndngs, t s n the best nterests of a nvoved
to share nove ways and best practces n order to deveop a
unversay appcabe standard n ths regard. Ths s partcuary
reevant for tempates of the nformed consent documentaton that
have been empoyed n WGES studes n Afrcan popuatons that have
successfuy been through the IRBs/RECs revew process.It has been
suggested that that ths coud be acheved through dedcated pubc
databases for such tempates and/or the ncuson n suppementary
matera |4|. Presenty, the ack of transparency n nformed consent
documentaton at the eves of ndvdua researchers and unverstes,
and that many |ournas do not appear to currenty have poces that
promote the avaabty of nformed consent tempates and standard
operatng procedures, may hamper researchers n resource-mted
settngs desgnng robust WGES nformed consent documents. Most
|ournas that pubsh genomc research nsst on studes that are ethcs-
compant; a further, postve step, however, woud be to request
tempates and documentaton of the nformed consent process to be
pubcy avaabe on pubcaton of the study. |ournas shoud therefore
encourage ths practce n a smar manner that t has been supported
for genomc genotype-phenotype and gene expresson datasets.
The sharng of ths documentaton shoud not, however, be an attempt
to create one-sze-fts-a or boerpate nformed consent
documents, snce ths woud not be feasbe for dverse Afrcan
stuatons; but rather as another resource for researchers to ad n the
desgn of approprate WGES research.Reevant, rapd assessment
processes n rura communtes pror to the commencement of genomc
studes n partcuar communtes can used to subsequenty taor the
consent process n a cuturay approprate manner |78,90|. Such
surveys coud ad future Afrcan WGES studes n the conceptuasaton
stages of genomc research.
The deveopment of WGES data sharng and data reease poces w
be essenta for future genomcs research on the Afrcan contnent and
shoud be performed n cose consutaton wth stakehoders. Afrcan
fundng agences, such as the South Afrcan Natona Research
Foundaton and the South Afrcan Medca Research Counc, do not
currenty requre genomc data to be made pubcay avaabe. Cear
WGES data sharng poces that are reevant for oca research shoud
therefore be drafted by such agences n the future, makng sure to
adhere to nternatonay accepted standards.
Data securty s of paramount mportance for WGES studes to prevent
surrepttous use of data and t s therefore essenta that such data be
protected n researchers persona as we as pubc databases. Hgh
standards of data protecton shoud therefore be commonpace for
genomc studes, ncudng those nvovng WGES. Further, databases
of borepostores shoud aso have adequate nfrastructure to prevent
data senstve nformaton from beng eaked as we as data
ntruson. The use of matera transfer agreements w hep prevent
sampes beng used for purposes not orgnay agreed upon and
therefore ad n avodng napproprate research when genetc sampes
are transferred between research groups, especay when the genomc
anayses of Afrcan sampes are beng performed abroad |53,64,91|.
Fnay, IRBs/RECs need to deveop quafed resuts dscosure poces
as we as crtera that ndcate what type of secondary/ncdenta
research fndngs, f any, need to be returned to research
partcpants. The knd of reatonshp that exsts between the
researchers and the research partcpants coud nfuence ths |35|.
#raining and educational materials
Provdng nfrastructure for varous eves of tranng n the reevant
concepts of the appcatons of NGS technooges n human research
w be mportant on the contnent of Afrca, especay snce there s a
need to mprove genetc teracy n sub-Saharan Afrca |92|. Workshops
for tranng members of IRBs/RECs as we as nterested researchers
w ad n ensurng nformed ethca revew processes for WGES
studes. Pubc ectures/nformaton sessons coud be used to educate
the communty and gauge the pubc percepton of WGES
studes. Internatonay, the ethca and ega concepts rased by WGES
studes n humans are ganng attenton |84,93|. Recommendatons
from the recent October 2012 US Presdenta Commsson for the
Study of Boethca Issues Report, "Prvacy and Progress n Whoe
Genome Sequencng" |84|, shoud be anaysed and used to ad n
draftng recommendatons for Afrcan stuatons.Low educatona eves
of research partcpants wth regards to genetc/genomc concepts may
requre the deveopment of unque educatona materas to be used
durng the nformed consent process. Interactve expanatons and the
use of nove technooges to expan compcated concepts to research
partcpants w be ntegra n ths regard. For exampe, the ntegraton
of emergng software appcatons (.e. apps), smar to the Iumna
MyGenome Pad app |94|, coud be used durng the recrutment stage
of WGES studes.
An encouragng sgn for future WGES studes n Afrca s the
nvestment n an Ethca, Lega, and Soceta Issues (ELSI) Research
Program by the H3Afrca Intatve, whch w make amost $2 mon n
fundng avaabe, over a perod of three years |95|. The Southern
Afrcan Human Genome Programme, whch w be nvoved n the
sequencng of Afrcan genomes and has receved provsona fundng
from the South Afrcan Department of Scence and Technoogy, aso
ams to hghght reevant ELSI topcs brought up by such research
|96|. Fnay, meetngs such as the Ethcs and Genomcs Research n
Afrca (EAGER-AFRICA) Conference |97| w postvey contrbute to the
fed by brngng researchers from across Afrca and the rest of the
word together and factate networkng and coaboraton.
Ethca, ega and soceta ssues (ELSI)-reated
research needs n Afrca
Whe a number of ELSI-reated research studes have now been
conducted n Afrca |for exampe, see Marsha et a. |77|, MaaraGEN
|81|, Tekoa et a.|62,78|, Nyka |69|, Marsh et a. |79||, more studes
are urgenty needed. Such ELSI research coud ncude:
Issues of nformed consent, data sharng, dentfabty and dscosure
of secondary/ncdenta fndngs n WGES studes n contrast to GWAS
or canddate gene studes n Afrca.
Studes of how genomcs fndngs are perceved n reaton to ethncty
and dentty n sub-Saharan Afrca.
Ethca and ega aspects of borepostores and ong-term
storage/dstrbuton of boogca matera for genomc studes.
Anayss of how IRBs/RECs n Afrcan countres and nsttutons
currenty revew WGES studes.
The reevance of oca Afrcan egsaton and governmenta poces n
the context of WGES studes n Afrcan popuatons.
These and some other ssues are hghghted n the 2012/13 H3Afrca
ca for appcatons for ELSI research programs (mentoned n the
prevous secton). A summary of varous ELSI ssues faced by WGES n
Afrca rased n ths study as we as potenta recommendatons to hep
address some of the aspects can be found n Tabe 2 .
Tabe 2
Chaenges and recommendatons for ethca and ega ssues for
performng WGES studes n Afrca

pagin 2
Chaenges and recommendatons for ethca and ega ssues for
performng WGES studes n Afrca
I!!$E C%A&&E'E REC())E'DA#I('
Informed
consent and
data sharng
Lmted avaabty of
nformed consent
documentaton tempates
for genomc studes n
Afrcan popuatons
|ournas and researchers
shoud promote the pubc
avaabty of these documents
Cutura and ethnc
dversty n Afrca
Communty engagement, rapd
assessment processes and
oca fed workers
Language dfferences Ensure the use of transators
who are aware of cutura
senstvtes
Lmted data on oca
vews on genomc data
sharng and reated
concepts (e.g. prvacy
and stgmatsaton)
Generate emprca data on
these concepts and opnons
through reevant research
Dssemnatn
g secondary
fndngs
Lack of oca poces and
gudenes
Perform studes on Afrcan
research partcpants atttudes
towards return of WGES
resuts. Encourage IRBs/RECS
to deveop such documentaton
Insuffcent genetc
counseors and
bonformatcsts
Tranng programmes and the
creaton of posts for these
professons
I!!$E C%A&&E'E REC())E'DA#I('
Lmted understandng of
the penetrance of genetc
varants n Afrcan
popuatons wth unque
genetc backgrounds and
envronmenta exposures
Investment n Afrcan WGES
medca research and reated
nfrastructure
Deveopmen
t of oca
egsaton
Current egsaton s not
drawn up wth medca
WGES research n mnd
The deveopment of oca
egsaton that s reevant for
WGES research and n ne wth
nternatona best practces
Numerous Afrcan
countres wth dfferent
egsaton
Conduct |ursprudence studes
that anayse reevant
egsaton n understuded
Afrcan countres
Lmted
resources
Poor educaton/teracy
eves
Deveopment of unque,
accessbe educatona
materas
Lmted numbers of
IRBs/RECs and many
members are not
famar wth genomc
prncpes
Perform tranng workshops and
ensure that fundng s aocated
to these groups
Abty to perform the
equvaent of CLIA-
vadaton n oca
aboratores may be
ackng
Anayse oca aboratory
standards and perform
vadaton n foregn
aboratores f necessary