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Policy Forum

April 2007 | Volume 4 | Issue 4 | e95

Genomic research has the potential to improve global health by elucidating basic
mechanisms of disease, susceptibility,
and resistance, thereby guiding
the development of preventive
interventions [1]. Recently developed
methods for exploring how human
genetic variation affects resistance are
likely to provide strategic clues about
vaccine development for researchers
working on malaria, HIV, tuberculosis,
and other diseases of the developing
world [2].

A key scientifi c challenge facing the
genomic epidemiology of common
diseases is the vast number of genetic
and environmental factors potentially
involved. Taken together with the fact
that certain genetic effects may be
more apparent in some populations
than others, this means that genomic
epidemiology studies must often
include large numbers of participants
across multiple populations. Such
studies pose not only scientifi c but also
ethical challenges, including how to
achieve valid consent for the collection
of large numbers of samples and
phenotypic information across a variety
of diverse, often resource-poor settings.

While there are many statements
setting out ethical principles for
biomedical research in developing
countries [3–5], there are few validated
methods by which to apply those
principles to large-scale genomic
studies. While the concept of “valid
consent” as codifi ed in the Declaration

of Helsinki has long been established
as a cornerstone of ethical research,
the interpretation of this concept in
practice is not straightforward [6–8]
and is further complicated by the fact
that what guidance there is on consent
tends to be biased towards clinical
trials and does not address novel issues
raised in genomic studies [8].

Drawing on experience gained
from a long-term programme of basic
and applied research on malaria in
Mali, including smaller-scale genetic
studies [9,10], and from current
efforts to bring together malaria
research groups across multiple centres
on four continents, we discuss the
practical challenges of defi ning and
obtaining valid consent for genomic
epidemiological research in developing
countries.

Ethical Issues Related to Consent

A number of guiding principles for
participation in research in developing
countries have been established
in guidelines, reports, and notes
from the fi eld [3,4,11–14]. While
these principles provide a helpful
framework, they leave unanswered a
number of important questions. For
example, several guidelines suggest
that unfamiliar concepts should be
explained using analogies—but provide
no guidance for how in practice one
might create useful analogies for, for
example, concepts such as “gene”,
“DNA”, or “genetic database”.

In what follows, and bearing in
mind that valid consent is a process
rather than a simple one-off matter
of signing a form, we consider a
number of challenges in relation
to the achievement of consent in
genomic epidemiology. We do so
under fi ve headings: (1) disclosure
and comprehension of information,
(2) voluntariness, (3) competence,
(4) “broad” or “open-ended” consent
for future use of samples, and (5)
community dimensions of consent
[15].

The discussion of these challenges
is made more concrete by the
accompanying Boxes 1–4, which
set out important principles that
could be included in an informed
consent form. Each principle includes
examples of the actual language
currently used in such consent forms.
In selecting these examples, we drew
on existing consent forms used for
genetic studies of malaria in Blantyre,
Malawi (a collaboration of Malawi
College of Medicine, Wellcome Trust
Research Laboratories, and Blantyre
Malaria Project), at Kilifi , Kenya
(a collaboration of Kenya Medical
Research Institute and Wellcome
Trust Research Unit), Banjul, The
Gambia (Medical Research Council
Laboratories), Navrongo, Ghana (a
collaboration of Navrongo Health
Research Centre and Noguchi
Memorial Research Institute), and in

Valid Consent for Genomic Epidemiology
in Developing Countries
Dave A. Chokshi*, Mahamadou A. Thera, Michael Parker, Mahamadou Diakite, Julie Makani, Dominic P. Kwiatkowski,

Ogobara K. Doumbo

Funding: The authors were supported by the Bill
and Melinda Gates Foundation, the Medical Research
Council, the Wellcome Trust, the National Institutes
of Health, the Rhodes Trust, and the Paul and Daisy
Soros Foundation.

Competing Interests: The authors have declared
that no competing interests exist.

Citation: Chokshi DA, Thera MA, Parker M, Diakite
M, Makani J, et al. (2007) Valid consent for genomic
epidemiology in developing countries. PLoS Med
4(4): e95. doi:10.1371/journal.pmed.0040095

Copyright: © 2007 Chokshi et al. This is an
open-access article distributed under the terms
of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.

Dave A. Chokshi, Mahamadou Diakite, and Dominic
P. Kwiatkowski are with the Wellcome Trust Centre
for Human Genetics, University of Oxford, Oxford,
United Kingdom. Mahamadou Diakite is also at the
Malaria Research and Training Centre, Department
of Epidemiology of Parasitic Diseases, University of
Bamako, Bamako, Mali, along with Mahamadou A.
Thera and Ogobara K. Doumbo. Michael Parker is
with The Ethox Centre, Department of Public Health,
University of Oxford, Oxford, United Kingdom. Julie
Makani is with the Department of Internal Medicine,
College of Health Sciences, Muhimbili University, Dar
es Salaam, Tanzania.

* To whom correspondence should be addressed.
E-mail: daveash@med.upenn.edu

The Policy Forum allows health policy makers around
the world to discuss challenges and opportunities for
improving health care in their societies.

Valid consent is a
process rather than a
simple one-off matter

of signing a form.

PLoS Medicine | www.plosmedicine.org 0637

Bandiagara, Mali (Malaria Research
and Training Centre, University of
Bamako). These examples show how
key elements of the consent form
have been addressed in practice. A
more detailed exposition of the role
of informed consent forms is also
included below.

1. Disclosure and Comprehension
of Information

To be valid, consent to participate in
research must be based on adequate
information and understanding.
Participants must have suffi cient
understanding of the purpose of the
research, of what participation in the
research means for them (and/or
their child), of what will happen
to samples and records during and
after the study, and of what steps are
being taken to ensure confi dentiality,
security, and privacy. In addition,
research participants must be aware

of the fact that they can withdraw
from the research at any time and
should know how to go about this.
Participants should, in our view, also
be informed about the benefi ts (if any)
that are likely to accrue to researchers,
individuals, and communities as
a result of the research. Each of
these elements presents signifi cant
diffi culty in research settings where
linguistic and cultural practices vary
considerably. In our experience, three
key challenges in this respect are:
linguistic and conceptual barriers to
conveying key concepts; the design and
provision of appropriate education
to help participants understand the
implications of involvement; and the
question of how best to convey the
purpose of the research and the value
of participation in it.

Linguistic and conceptual barriers.
Linguistic and conceptual barriers are
widely discussed in the literature [16].

In genomic research, one of the most
intractable challenges is how to convey
key genetic concepts in a clear and
understandable manner. Experiences
from the fi eld show that the process
of working out comprehensible
language is of crucial importance
in conveying such information,
whether in writing or verbally [17].
This process will involve researchers,
institutional review bodies, funders,
and communities jointly working out
commonly accepted language, oral
and/or written, for particular concepts.
It also means translating consent forms
and any accompanying information
and scripts for oral explanation into
local languages and ensuring that they
are independently back-translated for
validation. If discrepancies in back-
translations are found, researchers will
need to search for different channels of
communication within the community
to deal with them. For instance, in
genetic studies of malaria in Mali,
scientists work with school teachers in
the village. If teachers are involved in
the building of consent processes, they
can continue teaching and responding
to questions about the project when the
investigators are not present.

Educational activities. The
requirement for comprehensible
transmission of information to and
discussions about good practice with
participants must be tailored to the
local setting. In Mali, for instance,
researchers collaborate with translators
(who are not part of the scientifi c
investigation) in order to convey the
content of the consent forms and
information sheets in communities
with ancestral oral traditions. Having
investigators fl uent in local languages
serves as a safeguard to ensure accurate
translation. Messages recorded on
audio or video tapes and played during
the consent process have also been
useful. As a longer-term intervention,
researchers can work with linguists
in “word creation”. Word creation
involves relating a concept like
“gene” to attributes of heredity that
are already understood in the local
language. To increase understanding,
complementary creative approaches—
such as the use of drawings showing the
scale of how much blood is being taken
from a child’s body—may need to be
employed. Comprehension assessment
of consent should be used to both
validate and refi ne these methods.

What is the purpose of research?
The consent form and information

sheet, or their oral equivalents, will
include an accessible and easily
understandable explanation of the
purpose of the research, for example:

Malaria is caused by a germ that is
passed from one person to the other by
the bite of a mosquito that carries the
malaria germ. It can be particularly severe
in children and may cause death. We do
not know why some children become
severely ill with malaria or why some of
those children die from malaria. We think
that some children are born with a better
ability to resist malaria than others because
of their genetic makeup (the way they are
because of ancestry). To understand this
problem, we need to study children who
come to the hospital with severe malaria
and compare them to children who have
less severe malaria, to other children who
are feeling well, and in some cases, to their
healthy relatives.

What does participation involve?
The consent form and oral explanation

will provide a clear and accessible
description of what involvement in
the research will mean, for example:
What are the duration, procedures, and
risks of the study? Will participation
involve the taking of blood samples?

Will it require home visits or visits to
the clinic? Will participants be required
to answer questions about their child’s
health, or that of their relatives? How
will complications that arise during
research be handled? The distinction
between research being conducted and
treatment given should be made as clear
as possible and the section should affi rm
that treatment is not contingent upon
participation in the research project.

When a child is admitted to hospital,
it is usually necessary to take a blood
sample for testing to ascertain the best
treatment. This blood sample is not for
research purposes but to help in the
care of your child. In addition, we are
requesting from parents or guardians
of all children admitted to the hospital
permission to collect a small extra amount
of blood for research purposes. (Explain
here the amount involved for the child
in question—which may depend on
their size—e.g., if the quantity is 2 ml the
explanation might be “this will be about
half a teaspoon-full”.) This sample will be
collected at the same time as the blood
samples taken for normal investigations.
This will not harm your child in any way.
If you do not wish to provide this extra
blood sample, there are no negative
consequences. Your child will receive the
best possible treatment either way.

Box 1. Elements of an Informed Consent Form Addressing
Disclosure and Comprehension of Information

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Explaining the purpose and value of
the research. Researchers must aim to
develop, possibly using the techniques
described above, a clear, concise, and
simple way to explain why a study is
being performed and how it may add
to what is already known. Making
clear in what way participation has
the potential to contribute to a public
good—e.g., the knowledge required
to advance development of treatments
for disease—is important not just to
help explain the purpose of research
but also to assist comprehension of
why participation may be worthwhile.
Community-based genetic studies may
learn from vaccine trials: for instance,
in safety trials of a malaria vaccine in
Mali, researchers worked with a group
of adults who subsequently volunteered
for a genetic study after the study’s
aims were discussed with community
representatives and broadcast on
local radio stations. In this case, the
consent process started during the
screening period and continued
throughout the study with the purpose
of delivering information to local
administrative, health, and traditional
authorities. After every procedure with
volunteers, details on study conduct
were explained and questions were
answered. The most senior staff from
the research group visited the study
site and spoke with volunteers on a
regular basis. At the end of the trial, an
assembly—consisting of all volunteers
and the full research staff—was held to
receive feedback from volunteers on
how the study was conducted.

In addition, an offi cial ceremony
was organized to present preliminary
results (using non-technical language
and clear visual aids) and to publicly
acknowledge the participation of
volunteers as contributors to the on-
going development of a malaria vaccine.
It was conducted by the head of the
administrative authority in the district,
and was attended by international
co-investigators, regional and district
health authorities, traditional
authorities, and all volunteers. It was
found that public recognition and the
feeling of real partnership contributed
to the volunteers’ engagement with
the study and comprehension of its
purposes [14].

2.Voluntariness

In addition to being adequately
understood and informed, consent

must be voluntary—that is, free
from coercion [8]. This means that
participants must not come under
undue pressure to participate while
being informed about the potential
value of the research.

Voluntariness and the relationship
between research and clinical practice.
Consent may be coerced in a number
of ways. In resource-poor settings,
for example, the provision of health
care in research projects may act as
an inducement. If participation in
research is the only way for participants
to gain access to clinical care, or
if participants do not adequately
understand the difference between
research and clinical practice, this may
mean that the decision to participate
is not voluntary [18]. This can be
compounded in genetic association
studies of infectious diseases by the fact
that blood for DNA samples is often
collected during the acute clinical
episode, making it almost impossible
to clearly separate research from
treatment.

Nevertheless, while complete
separation of clinical practice from
research may be diffi cult to achieve
in such settings, it is vital that
researchers and those involved in
community engagement activities
take all steps they can to minimize
inducement effects [19]. This includes
making it clear (through repetition

and comprehension assessment)
to potential subjects that health-
care provision is not contingent on
participation and ensuring that a
similar level of health care is available
to non-participating patients.
Coercion could also occur as a result
of traditional respect for health
professionals, leading participants
to feel that it would be impolite or
that they are not “allowed” to refuse
participation. It will be important to
bear this possibility in mind in the
development of consent processes.

3. Competence

For consent to be valid it must also be
competently given. Where research is to
be carried out with young children,
very elderly people, people with mental
health problems, or people with
potentially impaired decision-making
ability for other reasons (such as
distress, infl uence of medication, or ill-
health), researchers must take special
precautions to ensure participants’
competence [20].

In cases of research on severe illness,
the role of researchers and practicing
clinicians may become blurred during
consent processes. Dividing the consent
process into two stages could help
ensure that a vulnerable patient’s
competence is not compromised by
their illness or by distress. Clinicians
might obtain consent for taking blood
when a patient comes in for treatment
during an acute clinical episode, but
wait until a later stage, when the patient
was not under immediate stress, to
seek permission to use the blood in
research. In remote settings, however,
follow-up consent can be diffi cult to
achieve as it may prove diffi cult to re-
contact patients once they have left the
hospital setting.

Another issue is obtaining consent
from older children and determining
the age at which it is appropriate for a
child to veto a parent’s consent. Rather
than specifying an age threshold,
it may be more appropriate for the
investigator (with review from a local
ethics board and following community
consultation) to assess on a case-by-
case basis the child’s maturity and
understanding.

4. Consent for the Future Use
of Genetic Information

Another issue arising in relation to
consent is the legitimacy of “broad”

Box 2. Elements of an Informed
Consent Form Addressing
Voluntariness
How can the participant withdraw
from research?

It will be made clear that the
participant has the right to withdraw
from research at any time and that this
will have no negative consequences,
particularly for treatment. This section
will include an explanation of how to
withdraw and, if applicable, a description
of the provisions for withdrawal from
future research.

Taking part in this study is entirely
voluntary. You can withdraw your child
from the study at any time. Not taking part
in the study will not affect current or future
medical care for your child in any way. If
you decide to withdraw from the study
later, please inform any member of staff or
make an appointment with the principal
investigator of the study.

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consent. Is it acceptable to ask
research participants to consent to
the long-term storage of their genetic
information for use in future, as
yet undetermined, research? Such
consent might be thought to be neither
voluntary nor informed. However, it
may be possible to impose limitations
to “broad” consent [21]. For example,
the scope of possible research could be
narrowed to a specifi c disease, even if
the exact nature of all possible future
experiments was not clear at that stage.
This could be complemented by an
ongoing opt-out process such that
participants can withdraw from any
study at any future point in time, which
would require appropriate processes
for withdrawal to be developed
beforehand.

Even with the “disease-specifi c”
constraint, however, it still could be
diffi cult to communicate the nature of
future, often highly technical research
projects to participants, particularly in a
developing-country context. In addition,
even a disease-specifi c constraint
might not be stringent enough to
preclude the misuse of genetic data.
For instance, genotyping haemoglobin
allelic variants—something that could
plausibly be done in a project related to
malaria—can also reveal whether or not
a child is biologically related to his or
her parents.

There are other arguments against
the disease-specifi c constraint. The
potential importance of clinical
and biological interactions between
different diseases (e.g., interactions
between nutrition, bacterial infection,
and parasitic infection) presents a
legitimate scientifi c rationale for
expanding the range of use for stored
samples beyond a single condition.
Understanding general mechanisms of
immune regulation (relevant both to
bacterial and parasitic infections, for
example) key to addressing malaria
would be a case in point. Samples
could also be useful for studying a vast
number of other diseases, regardless of
co-infection status.

Despite these problems, it is
important to bear in mind the potential
for previously collected genomic
data to facilitate medical research in
unforeseen ways. The potential value
of such data is an important and highly
signifi cant ethical consideration in its
own right. The reuse of samples also
allows researchers to collect fewer

additional blood samples from very sick
children. This would avoid the harms
to participants inherent in collecting
samples and the time and costs involved
in organizing such collections. From an
ethical standpoint, narrow approaches
to consent have disadvantages as well as
advantages.

The challenge is how to prevent
or lessen the likelihood of the abuse
of genetic data—say for paternity/
maternity testing or for research
that could result in discrimination
against an ethnic group—while still
permitting scientists to engage in
useful and ethical research. Alternative
approaches to the disease-specifi c
constraint on broad consent might be
categorized as (1) institutional and (2)
permissive.

Institutional approaches to broad
consent could rely upon a well-

developed ethics infrastructure
(including researchers’ ethics
committees, local Institutional Review
Boards, and funders’ oversight) to
ensure that genetic data will only be
used for projects that meet the criteria
set out by these overlapping bodies.
The International HapMap Project
has adopted this approach [22]. If
institutional capacity is not believed
to be suffi cient in a particular locale,
one might instead try to follow the
permissive approach to consent,
which describes all those things that a
participant’s sample will not be used
for, rather than restricting future use
to research of a specifi c disease. From
the perspective of protecting sample
populations, there are advantages
and disadvantages with each of
these approaches. The nature of the
research, characteristics of the sample

What steps are being taken to ensure
confi dentiality, security, and privacy?

The participant will be given an
explanation of how their confi dentiality
and privacy will be protected within the
study and of what measures are being
taken to ensure that data are secure.
This will include particulars about who is
granted access to personal information
and will state that medical information
collected will only be for the purposes of
research.

Once we take a blood sample, we
assign it a code number. By assigning your
sample a number, we separate the name
and any other personal information from
the sample. Therefore, information about
your child’s participation in this study
will remain confi dential. In any reports,
participants will be referred to by code
number only. Participants’ names will
not be used in any reports and will not
be shared with anyone except the study
investigators. All fi les with information
that could identify you will be kept in a
secure location, in case we need to talk to
you in the future, and will not be released
to anyone else.

What will happen to samples and
records during and after research?

The form and oral explanation will
include information about the time-
frame of research and whether genomic
information that is being sampled will

possibly be used for more than one
study. The extent of the participant’s
consent will also be explained, e.g.,
whether consent is limited to research
on a specifi ed disease or at a single
institution, or is permissive outside of
specifi cally prohibited uses. If samples
are to be stored after the end of the
current study, precise information on
how long and where samples will be
retained must be included. Forms and
explanations should separate the option
of consenting to future research projects
and consenting to the research project
being conducted at that time.

We will test your child’s blood to see
how it responds to malaria, and what
your child inherited from his/her parents
that may have affected his/her ability to
respond to malaria. There are other tests
to better understand malaria that we are
not aware of now that we might wish to
perform on your child’s samples. With your
permission, the blood taken from your
child’s arm will be kept and stored in our
laboratory locally and in the laboratories
of our partners abroad who are working
with us on this research project. If you
allow your child’s blood to be stored for
research, any future projects using the
blood sample would be approved by an
ethics review board. However, you may
choose not to have your child’s blood
stored for future research and still be part
of this study.

Box 3. Elements of an Informed Consent Form Addressing Future
Use of Patient Information

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populations, and the likelihood
that samples would be used for the
benefi t of sample populations in the
future should be used as criteria to
determine which approach is settled
upon. Identifying and addressing
these considerations appropriately will
require the development of innovative
ways of involving local communities.

5. Community Dimensions
of Consent

In our view, in many developing
country settings, consent may be
invalid if it does not have a familial or
communal dimension. In all cases this
will involve some level of community
involvement and consultation in the
research; in many cases, it will also
require appropriate processes of
community consent. However, tension
may arise between individual and
community consent; for example,
if community elders decide that
research should be participated in
but individuals are unwilling, or if
community leaders withhold consent
but individuals want to participate.
Community consent is no substitute for
individual informed consent [4], but
could be considered a precondition.

For example, in the stepwise
approach to consent utilized in malaria
trials in Mali, community consent
has been seen as the fi rst phase of
a continuous process [14,23]. Even
before seeking community consent,
investigators should identify relevant
offi cial and unoffi cial decision-
making structures that exist within
communities. If such a multi-step
approach is to work, each social unit
consulted must have veto power; that is,
only if all social units grant consent can
it be considered valid.

The role of consent forms. While it
is important to remember that valid
consent cannot be attained solely with
the completion of a consent form,
such forms can play an important
role. Among other things, a consent
form can help to ensure that consent
processes are comprehensive in
information conveyed to a research
participant. In large-scale genomic
research, the consent form has an
additional function: that of ensuring
that key elements of the consent are
standardized across research sites.
It has been demonstrated in the
United States that depending upon
local institutional review to ensure

uniformity of consent process in multi-
site research is problematic; such
diffi culties are likely to be much greater
in very diverse and resource-poor
settings [24]. It is important therefore
that such collaborations themselves
take on this responsibility. While a
standardized consent form is not by
itself suffi cient to ensure valid consent
across research sites, it can contribute
usefully to consistent practice.

The development of a consent
form for use in a range of diverse
sites needs to be fl exible enough to
take into account local community
and study-specifi c circumstances. The
form will also need to address—in a
relatively standard format—a number
of key issues [25]. These have been
broken out in Boxes 1–4 here and
include: the purpose of the research,
what participation involves, what will
happen to samples and records during
and after the research, what steps are
being taken to ensure confi dentiality,
security, and privacy, how participants
can go about withdrawing from
the research, and what benefi ts will
accrue to researchers, individuals, and
communities as a result of the project.

Conclusions

The tools of genomics have great
potential for developing sustainable
solutions to global health problems.
As researchers cover new ground
in understanding the fundamental
molecular mechanisms of disease, we
must make certain that sound ethical
practices keep pace with scientifi c
innovation. In this paper we have
explored practical ethical issues arising
in relation to the achievement of
valid, community-informed consent
in genomic epidemiological research.
The achievement of valid consent
for such research takes on particular
importance in developing countries,
both from the perspective of protecting
individuals and building trust between
communities and research groups.
While funders, research institutions,
and international policy makers have
an important role in achieving valid
consent, we have approached the issue
from the perspective of scientists in the
fi eld, for it is scientists who ultimately
manage the interaction between
laboratory and community.

Linking principles to practices at
the ground level is the most powerful
way to ensure that valid consent is
indeed realized. In this paper we have
highlighted a number of key areas
of practice and policy relating to the
achievement and understanding of
valid consent in genomic epidemiology
in developing countries. In turn, these
have suggested a number of areas of
practice in which embedded ethico-
social research would be of great value.
These include: research into models
of community consent and education
for genomic epidemiology; the
development of models for embedded
empirical research on obtaining valid
consent; research into the ethical and
social factors important in building
trust between communities and
researchers; and research into the use
of broad consent and the secondary
research use of data and archived
samples.

Acknowledgments
We thank Dr. Bill Rogers, Dr. Kojo
Koram, Prof. Terrie Taylor, Prof. Malcolm
Molyneux, Dr. Muminatou Jallow, Prof.
Kevin Marsh, Dr. Vicki Marsh, Dr. Tom
Williams, and many other colleagues for
discussion and for sharing information
about informed consent procedures
relating to genetic studies of malaria at

Box 4. Elements of an Informed
Consent Form Addressing
Community Benefi t
What benefi ts will accrue to
researchers, individuals, and
communities as a result of
participating in this project?

A discussion of group benefi ts
from research will be included, as
will compensation made available to
individual participants. An explanation of
the way in which the research is expected
to contribute to public knowledge will
be included, and, where relevant, a
statement of whether the research results
will be used commercially.

Although there are no direct benefi ts for
participating in this study, the knowledge
that will be gained will help us develop new
ways to control malaria that may benefi t
people living in areas where malaria is
a serious problem. It is hoped that our
research will help scientists develop new
treatments for malaria, although this may
not occur for many years. If this occurs,
neither researchers nor participants such
as you or your child are expected to receive
any fi nancial benefi ts.

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Malawi College of Medicine/Wellcome
Trust Laboratories/Blantyre Malaria
Project, Malawi; KEMRI/Wellcome
Trust Laboratories, Kilifi , Kenya; MRC
Laboratories, Fajara, The Gambia; Navrongo
Health Research Centre and Noguchi
Memorial Research Institute, Ghana; and
Malaria Research and Training Centre,
University of Bamako, Mali.

Author contributions. DAC, DPK, and
OKD conceived of the idea behind the
paper. DAC, MAT, MP, MD, JM, DPK, and
OKD contributed to writing the paper.
MAT, MD, and OKD coordinated the
genetic studies in Mali referred to in the
paper; JM did the same for the studies
conducted in Tanzania.

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April 2007 | Volume 4 | Issue 4 | e95