v

Journal of
Prospective Health Care
Spring 2008 www.prospectivehealthcare.com

Prospective care in emergency departments • Interview: Geoffrey S. Ginsburg

Paleolithic diet and modern disease • RNA interference • and more
t

prә’spektiv
hel θ
pro•spec•tive health care

ke(ә)r
–noun
an emerging field of medicine that emphasizes
disease prediction and prevention, personalization of
treatment, and patient responsibility.

Prospective health care is intended to address the need to reduce costs

and improve patient care in the current health care system, especially
with chronic conditions.
Advances in the science behind health care—including the fields
genomics, proteomics, and bioinformatics—have fueled the
development of prospective health care.
However, a discussion of prospective health care would be incomplete
without contributions from other fields, including public policy,
economics, ethics, and journalism.
This Journal endeavors to raise awareness, promote discussion, and
encourage collaboration among students, professors, and professionals
from all fields to further the development of prospective health care.

Cover photo © iStockphoto.com/poco_bw

Volume 2, Issue 1 Journal of Prospective Health Care

Contents Spring 2008 / Volume 2, Issue 1

4 Interview: Geoffrey S. Ginsburg, Director, Duke IGSP Center for Genomic Medicine
by Jennifer Soung

6 Emergency Departments as Institutions of Prospective and

Preventative Health Services
by Jordan Kaylor

10 Paleolithic Diet and Modern Disease

by Maria E. Balzaretti

13 Targeted Genomic Medicine: RNA Interference

by Paul Fullerton

15 Racial Categories as a Proxy for Human Genetic Variation: History and Implications
by Lee Hong

19 Research Briefs: Prospective Health Care at Duke

by Josephine Li

Editorial Board
The Journal of Prospective Health Care is
Max Masnick, Editor-in-Chief, Trinity 2009 a publication of the undergraduate Duke
Prospective Health Care Club, and is an
Salman Bhai, Trinity 2010 independent publication of the Duke
Crystan Dowds, Trinity 2010 University Undergraduate Publications
Board. For more information about the
Sarah Grace King, Trinity 2011 Journal, including information about
submissions, please e-mail
Erica Jain, Trinity 2011
journal@prospectivehealthcare.com.
Josephine Li, Trinity 2010 Neither this publication nor any part
Jennifer Soung, Trinity 2008 of it may be reproduced without prior
permission from the Duke Prospective
Jessie Tang, Trinity 2011 Health Care Club.
3
Journal of Prospective Health Care
Interview: Geoffrey S. Ginsburg
By Jennifer Soung
Geoffrey S. Ginsburg, M.D., Ph.D., is the founding Director of the Center for Genomic Medicine in the Duke Institute
for Genome Sciences and Policy (IGSP) and Professor of Medicine and Pathology at the Duke University Medical
Center. He is a leading visionary in the movement to develop novel paradigms for translating genomic information
into medical practice. Journal of Prospective Health Care Editor Jennifer Soung spoke with Dr. Ginsburg about his
goals and opinions on how genomics is helping to shape the future of medicine.
Journal of Prospective Health Care:
Can you share your experiences in aca-
demia and in the private sector? What
was the motivation behind your decision
to choose one over the other?
Geoffrey Ginsburg: My research ca-
reer began in the area of molecular bi-
ology/genetics. As a cardiology fellow, I
became interested in the application of
genetic information to human disease. It
was clear that the Human Genome Proj-
ect was a technological revolution, and
I believed at that time that the biotech-
nology sector possessed the resources to
take full advantage of the large amount
of information being elucidated and
apply it on a grand scale to impact hu-
man health. My experience in indus-
try was a pivotal point in which I first
gained appreciation for the prospects of
prospective medicine. After the Human
Genome Project was completed in 2003,
I began to realize that academic health
centers were truly the best place to ap-
ply genomic medicine. Rich in resources
of clinical information and cutting-edge
technology, academic health centers are
front-runners in the personalized medi-
cine and prospective health care move-
ments.
JPHC: How does research conducted
in the private sector translate into thera-
peutic medications to treat the major
diseases of our time? How does academic
research differ?
GG: There exists a natural symbiotic
relationship between academia and the
private sector in the translation of re-
search into clinical practice. Academic
research—such as the research conduct-
4
Spring 2008
ed here at Duke—focuses on the molec-
ular mechanisms and pathways of disease
states. Industry cherry-picks information
elucidated from these research studies to
develop, manufacture, and deliver drugs
to treat or mitigate symptoms associated
with diseases. In this sense, academic re-
search serves as the springboard for the
development of therapeutic medications
to treat the major diseases of our time. In
industry, there is a five- to ten-year hori-
zon between an idea and its fruition. In
academic research, however, the focus is
on the patient, not on a long-term pipe-
line. Thus, it is possible to accomplish
things that will have an impact on pa-
tient care in a much shorter time frame.
JPHC: With the completion of the Hu-
man Genome Project in 2003, focus has Dr. Geoffrey S. Ginsburg
shifted toward the potential application Courtesy of the Duke IGSP
of genomics to medicine. How do you Genomic medicine is the application
think genomic medicine will contrib- of a wealth of genomic tools to enable
ute to the prospective health care move- such prospective health planning. The
ment? occurrence of disease can be attributed to
GG: The underlying concept of pro- many different factors other than genet-
spective health care is the ability to use ics, including an individual’s interaction
genomic and clinical information to with his/her environment (lifestyle, diet,
predict and/or prevent an individual’s exposure to harmful agents). Based on
susceptibility to future diseases. Cur- genetic information gathered at the level
rently, medical intervention is acute (re- of DNA, we can predict an individual’s
active)—focusing on the treatment of risk or susceptibility for a particular dis-
existing diseases at the time they come to ease, which can then influence the indi-
clinical attention and may be essentially vidual’s decisions about lifestyle choices
irreversible. Prospective health care pro- or medications. In essence, the goal of
poses to shift health care toward a more prospective health care is focused on pre-
predictive (preventive) intervention ventative medicine—developing predic-
model, in which diseases are detected tive tools to predict and prevent the oc-
in their earliest manifestations. In this currence of disease and to determine how
way, intervention is more likely to suc- best to treat disease. We are still in the
ceed and will result in lower costs for the early stages of this goal. Although many
health care system. disease variants have been discovered to
Volume 2, Issue 1
predict future diseases (heart disease, dia-
betes, cancer), these are only a subset of
the thousands of existing disease variants,
and further research is needed to confirm
replicability to the general population.
JPHC: How do the goals of the Center
for Genomic Medicine in the IGSP fit
into the overarching goals of prospective
health care?
GG: The Center’s mission is to develop
and translate novel therapies and pre-
dictive biomarkers into clinical research
and practice to optimize efficiency, ef-
fectiveness, and success in bringing the
right therapy to the right patient at the
right time. The research conducted here
will lead to insight about how one’s ge-
nome and its interaction with the envi-
ronment determine health and disease.
The ultimate goal is to incorporate this
information into the routine practice of
medicine and contribute to a more per-
sonalized approach to health care.
We are conducting several “first-in-
kind” genomic-guided clinical studies
that are addressing the questions, “Who
should be treated?” and “How should
patients be treated?” Last year, research-
ers discovered that genomic predictors
can significantly foretell the likelihood
of recurrences of lung cancer. Based on
genomic information from biopsies of
patient tumors, researchers identified
a unique molecular signature which
serves as a good predictor for the recur-
rence of lung cancer. We have designed
a landmark, multi-center research trial
with a cohort of 1500 patients that
will take effect later this year. By pro-
spectively identifying individuals who
are at a higher risk for more aggressive
stages of this disease, we can focus our
resources in treating these patients us-
ing chemotherapy. To answer the ques-
tion, “How should patients be treated?”
IGSP researchers are using information
from gene expression patterns of patient
biopsies to determine the best treatment
options and medications for patients.
We have identified molecular signatures
for the major chemotherapeutic agents,
and the responsiveness of these patients
to medication will be compared to the
responsiveness of those patients admin-
istered randomly-selected medications.
Together, these studies represent a semi-
nal prototype for how medicine will be
practiced in the future.
JPHC: What do you think are the big-
gest obstacles in implementing a pro-
spective approach to health care?
GG: With innovation comes obstacle:
anything new usually has a number of
resistances to overcome. The dissemina-
tion of innovation resembles an S-shaped
curve, with the “tipping point” occurring
when society accepts the new change.
Genetics and genomics are no different. I
believe that there are four major obstacles
in implementing a genomic and prospec-
tive approach to health care. First is the
educational barrier. Much of the pub-
lic and professional workforce has little
knowledge of genetics and genomics,
making it difficult for them to adopt this
new view. Physicians are in the unique
position to educate the public about these
advances, but there is currently a lack of
organized strategy for continuing medi-
cal education for medical students, phy-
sicians, and house staff. Second, govern-
mental regulatory agencies (FDA, CMS)
need to develop a unified set of rules and
regulations for genetic and genomic test-
ing. Without clearly articulated regula-
tory policies, the private sector is stagnat-
ed—devoid of a clear path for the future.
Third, the cost of technology is a major
obstacle. Who will pay for expensive new
genomic tests? Insurance companies are
demanding proof that these technolo-
gies improve health outcomes through
randomized trials, and this stringent
mindset will delay efforts to implement
personalized medicine on a grand scale.
Finally, privacy and confidentiality is-
sues arouse an infinite number of fears.
Will genetic and genomic information
be misused? Indeed, legislative initiatives
are needed to discourage such infringe-
ments. The adoption of research findings
into clinical practice will take time and
will occur only after a solid evidence base
is established. As both an employer and
provider of health care for a large work-
force, Duke has a unique opportunity to
Journal of Prospective Health Care
shape these public dialogues.
JPHC: Genomic medicine has the po-
tential to transform the way medicine is
practiced in the United States. Do you
believe that the current generation of
health care providers is prepared to deal
with the evolving genomics revolution?
If not, what should be done to address
this?
GG: I don’t think that the current gen-
eration of physicians and health care pro-
viders is well-versed in the genomics rev-
olution. I propose that a system should
be established to keep physicians up-to-
date with constantly-evolving informa-
tion. At Duke, the Genome Revolution
Focus Program is reaching out to college
students, but I think that genetics should
be taught at an earlier educational level
(high school). Imagine the ideal scenario
in which a high school student is able to
get a good sense of his/her “disease his-
tory family tree,” become cognizant of
the genetic component of disease, and
use this information to modify lifestyle
choices. In medical school, day-to-day
casework should focus on more practical
applications of genetics and genomics.
Courses in medical school are currently
taught at the level of mechanism and bi-
ology, as opposed to the actual applica-
tion to disease and decision-making. By
using relevant case examples that trans-
form abstract principles into real-life
scenarios, physicians will be trained to
use genomic information to better treat
patients. In this regard, the individuals
involved with developing continuing
medical education initiatives are in a
unique position to transform medicine.
Prospective medicine holds great prom-
ise, but I advise individuals to be appro-
priately cautious about its potential ben-
efits and applications. We are still in the
early days of this “grand experiment” and
need to fully understand all its implica-
tions before the results can be applied. In
the words of Mark Twain: “Be careful of
reading health books, you might die of a
misprint.”
Read the full interview online:
http://go.prospectivhealthcare.com/2-1-4
5
Journal of Prospective Health Care
Emergency Departments as
Institutions of Prospective and
Preventative Health Services
By Jordan Kaylor
Introduction
Emergency departments (EDs) are, by their very nature,
reactive elements of our current health care system. As their
name implies, EDs were designed to provide medical care to
victims of unforeseeable trauma and acute medical events. Giv-
en the large number and wide range of patients who visit EDs
to receive medical care, however, they also have the potential to
contribute greatly to both prospective and preventative health
care in the future. Each year, over 10% of the United States
population will visit an ED at least once,1 and annual ED visits
total over 100 million.2 EDs across the country provide care to
an immensely diverse population that includes a high propor-
tion of underinsured or uninsured patients, as well as those
with chronic health conditions.1 In terms of prospective health
care, this patient population makes EDs an ideal location to
assess disease trends and compile genetic data that could be
used to develop genetic testing for chronic diseases. EDs are
also the first point of contact with the health care system for
many patients, and as such, they might play a more integral
role in preventative health services by administering vaccina-
tions, educating patients on ways to live a healthier lifestyle,
and linking patients to existing community health services.
Prospective health care in the emergency
department
One of the most promising aspects of a prospective ap-
proach to health care is its ability to make personalized predic-
tions about everything from one’s risk of developing a chronic
disease to the efficacy of medications within specific patient
populations. Ideally, a patient would visit his or her primary
care physician and receive a comprehensive health analysis that
would include personalized advice and services based on his or
her unique genetic and biological markers. In order for these
predictions to be accurate and statistically robust, however, they
must be generated from massive amounts of data. Correlations
between thousands of genetic markers and patient medical his-
tories must be documented in many different patient popula-
tions. EDs across the country might serve as collection points
6
Spring 2008
for this information. Data collection for the development of
accurate genetic testing and prospective health services could
be integrated into patient care without compromising patient
privacy or increasing the hospital staff’s workload.
Contrary to what is seen on popular television shows such
as ER and Grey’s Anatomy, more than half of the patients who
visit EDs do not present with emergent or even urgent condi-
tions.3 Additionally, they tend to come from populations that
are traditionally underserved by the health care system for a va-
riety of reasons. In this sense, they would provide a large num-
ber of samples from populations that might otherwise be inac-
cessible to researchers. As part of the current ED standard of
care, patients are asked to provide nurses and physicians with a
detailed medical history, and many must also provide blood for
diagnostic and laboratory services.4 Genetic sampling could be
integrated into patient care by first identifying non-emergent
patients during standard triage procedures. These non-emer-
gent patients would be provided with consent forms and a brief
explanation of the study and its procedures, emphasizing that
their identifying information would be stripped from all sam-
ples and that no additional testing or follow-up visits would be
required. Then, if a blood sample is necessary for standard di-
agnostic testing, an extra tube would be drawn and used to se-
quence the patient’s DNA. The DNA sequence would later be
combined with the patient’s self-reported medical history with
patient-identifying information removed. These samples could
then be analyzed for any number of correlations between the
patient’s medical history and repeated genetic sequences, single
nucleotide polymorphisms (SNPs), or other genetic markers in
order to develop more effective tests to predict the likelihood of
developing a disease or condition based on a patient’s genome.
Emergency departments and preventative
care
Public health education
Health services are not limited to what is provided in pa-
tient care rooms. This is especially true in EDs, where the
amount of time a patient spends in the waiting room typically
Volume 2, Issue 1
exceeds the time spent with a physician. In 1996, the average
ED waiting time was three hours;1 this time might be used
effectively for self-directed education or consultations with
ancillary health care providers, such as social workers, nurses,
emergency medical technicians, or even volunteer health edu-
cators. Furthermore, as the emphasis of medicine slowly shifts
from the treatment of diseases (reactive) to the maintenance
of health (preventative and prospective), providers need ways
to distribute information about healthy lifestyles to the pub-
lic. ED waiting rooms could serve as information distribution
points by providing patients with information kiosks and bro-
chures that promote healthy behavior.
In a survey conducted at the North Shore University Hos-
pital in Manhasset, New York, researchers found that 96% of
the 878 respondents were interested in receiving information
about preventative health services while waiting in ED waiting
rooms.5 These services included breast cancer, prostate cancer,
stress reduction, exercise, depression, smoking, safe driving, re-
ferrals to primary care providers, tetanus and pneumococcal
immunizations, Pap smears, safe sex, obesity, youth violence,
alcohol and drug abuse, HIV screening, smoke detector use,
domestic violence, safe firearm use, and bicycle and motorcycle
safety. By providing this information at interactive computer
kiosks in the ED, hospitals could also collect patient e-mail ad-
dresses or phone numbers if patients provide them. This con-
tact information might then be used to send patients reminders
about future appointments, refilling prescriptions, or schedul-
ing other preventative health services.
Results of self-directed surveys at these information kiosks
could also bring risk factors to a patient’s attention or be passed
on to ED physicians to provide a more comprehensive medical
history. Patients tend to provide increasingly detailed descrip-
tions of their medical conditions each time they are asked to
report them, so waiting room surveys might have the added
benefit of improving a patient’s ability to accurately provide his
or her medical history when a physician is finally available.4 A
study published by Bernstein et al. (2007) confirmed the fea-
sibility of two similar computer kiosk systems.6 The study also
noted that female patients preferred computerized screening
over face-to-face conversations with physicians when reporting
intimate partner violence; the same might be true of patients
with socially stigmatized conditions, such as sexually transmit-
ted diseases, that they are not comfortable sharing with a physi-
cian.7
Presumably, patients might also be interested in receiving
referrals or counseling based on their responses to these surveys.
For example, a study by Boudreaux et al. (2005) found that the
majority of the 1461 patients surveyed at an urban Level 1
trauma center in New Jersey agreed that counseling for smok-
ing cessation should be available in EDs.8 Surveys could also
assess a patient’s thoughts about preventative health subjects
not necessarily related to the patient’s chief complaint—such
as eating habits, stress reduction and relaxation techniques, or
Journal of Prospective Health Care
genetic testing services—and provide personalized advice and
information that a patient could use to follow up with a spe-
cialist if desired.
In addition to surveys, ED waiting rooms might also pro-
vide live screening or advice to waiting patients. Bernstein et al.
(2007) highlighted the effectiveness of using ancillary health
care providers, such as peer health educators or substance abuse
counselors, to identify those in need of treatment for substance
abuse in EDs.6 These educators provided brief interventions
and referrals to substance abuse treatment during the patients’
ED visits. This setting may also promote the detection of other
disease processes. For example, many people live with type 2
diabetes for several years before learning that they have the dis-
ease.9 The only routine ED service to detect type 2 diabetes is
a simple blood glucose measurement, which is one of several
diagnostic tools that, in addition to a detailed patient history,
would be necessary to suspect type 2 diabetes.4 To educate pa-
tients about type 2 diabetes, a hospital staff member or volun-
teer could briefly screen patients while they sit in ED waiting
rooms; screening would include the discussion of detailed risk
factors, characteristic signs and symptoms of the disease, and
the suggestion of ways to lower one’s risk of developing the dis-
ease. These providers might even provide short (<10 minute),
repeated presentations about disease symptoms, ways to reduce
risk factors, or other health topics in rooms attached to ED
waiting rooms. The goal of such programs would be to increase
awareness, rather than to provide a definitive diagnosis. Llovera
et al. (2003) suggest that even volunteers with minimal train-
ing, such as pre-medical college students who are interested in
exposure to health care, would be able to provide this sort of
public health education in an ED setting.5 Once volunteers
bring the possibility of a condition to a patient’s attention, the
patient could immediately receive further advice and a defini-
tive diagnosis when he or she finally sees a physician in the
ED.
Emergency departments also present unique opportunities
to counsel patients about preventative services because of the
“teaching moment” phenomenon.10 Even patients who might
not normally be receptive to advice about health care or life-
style modifications tend to desire these services under the cir-
cumstances that bring them to EDs. For example, Kruesi et al.
(1999) found that “parents trained about adolescent suicide
risks during an ED visit for an adolescent behavior problem
were four times more likely to take steps to limit their child’s
access to guns and prescription drugs than parents without the
training.”11 Victims of drug overdoses or motor vehicle colli-
sions while intoxicated are also particularly receptive to ad-
vice and referral to treatment and rehabilitation programs.4,11
Therefore, information and advice presented to patients in an
ED setting may be more effective at changing patients’ habits
than when presented elsewhere.
7
Journal of Prospective Health Care
Vaccination programs
In actuality, EDs are already an integral (although certain-
ly not predominant) part of preventative health care efforts.
At the current standard of care in most EDs, every patient is
screened for hypertension and blood sugar abnormalities, and
is asked to provide a comprehensive medical history.4 Addi-
tionally, tetanus immunizations are usually given to patients
who present with lacerations or open skin wounds,10 and these
services might be expanded to include other vaccinations or
testing. For example, Slobodkin et al. (1998) explored the de-
livery of influenza and pneumococcal vaccinations to high-risk
patients at Cook County Hospital Adult Emergency Services
in Chicago, Illinois.12 Cook County Hospital was an ideal lo-
cation to explore the delivery of immunizations on a massive
scale and in a worst-case scenario because it is one of the larg-
est EDs in the country, is publicly funded, and receives pre-
dominantly uninsured patients.12 The authors determined that
providing both vaccinations to all ED patients in the United
States would save the health care system over $2.225 billion
each year. This cost reduction would result primarily from 1000
fewer hospitalizations, 4300 fewer premature deaths, a 2.25%
reduction of yearly incidences of influenza, and a 20% reduc-
tion of yearly incidences of pneumococcus after five years. The
study was performed in two stages, and in each, nurses received
rewards based on how many patients they screened and vacci-
nated. Vaccinating patients added a median time of only four
minutes to a patient’s ED visit, and results were so promising
that the vaccination of high-risk patients against influenza and
pneumococcus became part of Cook County Hospital’s perma-
nent standing orders for patient care.
A similar study, performed by Rimple et al. and the Univer-
sity of New Mexico Department of Emergency Medicine in Al-
buquerque, New Mexico, also found an ED-based vaccine pro-
gram to be effective at increasing influenza and pneumococcus
vaccination rates. The authors accurately summarized the value
of ED vaccination programs in their paper: “Vaccination can
be a low-cost, cost-effective, single-event, and minimal-risk
intervention that would potentially reduce the morbidity and
mortality associated with a number of vaccine-preventable dis-
eases in populations that are vulnerable and hard to reach in
traditional primary care settings.”1
Links to community care
In many cases, trauma and medical emergencies happen
without warning, and EDs serve the victims of these unpre-
dictable incidents without hesitation. Their function in emer-
gencies is based on the belief that medicine and health care
are public services to which everyone is entitled, but it is dif-
ficult to set boundaries for ED services so that they are able
to provide care in emergencies without becoming a financial
burden on society. An extension of the belief that health care is
a guaranteed public service is that EDs might serve as a valu-
able social welfare institution.13 They are often the first point of
contact for many patients who have no other means of obtain-
8
Spring 2008
ing health care as a result of various social, economic, and cul-
tural barriers to access. As such, they provide an indispensable
service to communities.
Patients who would otherwise receive no health care at all
are guaranteed necessary services at EDs; in fact, the Emergen-
cy Medical Treatment and Labor Act (EMTALA) requires that
EDs provide all patients with “an appropriate medical screening
examination” and stabilizing treatment if patients present with
an “emergency medical condition.”14 This wording is clearly
vague, but Dr. James Gordon, of the University of Michigan
Health System’s Department of Emergency Medicine, points
out that as a result of EMTALA, “the hospital emergency de-
partment is perhaps the only local institution where profes-
sional help is mandated by law.”13 Since EDs must see every pa-
tient who enters their doors, they might also link each of these
patients to ongoing preventative and primary care available in
the patient’s community. In this respect, EDs have the poten-
tial to serve as powerful elements of preventative medicine.
At Durham Regional Hospital’s ED in Durham, North
Carolina, for example, a licensed clinical social worker staffs
the ED along with physicians and nurses.4 Although the social
worker is not available around the clock, he or she meets with
patients when requested by an attending physician and discuss-
es the patient’s diagnosis and concerns. Afterwards, the social
worker arranges for follow-up and preventative care at com-
munity clinics, as well as any additional support services that
might be necessary or helpful. The social worker also provides
reimbursement for the patient’s transportation to and from
health appointments when necessary. Initial contact with the
patient is often reactive, but Durham Regional’s ED is an ex-
ample of how EDs might contribute to preventative medicine
by linking patients to more appropriate preventative care.
Conclusion
Although they are commonly considered reactive elements
of our health care system, emergency departments in the Unit-
ed States may also be useful institutions for prospective and
preventative health services. In terms of prospective medicine,
they are ideal places to collect a large and diverse sampling
of genetic data that will form the basis of future prospective
health services. EDs might also serve as sites that screen and
identify high-risk patients, provide health education and raise
awareness about disease processes, and administer vaccinations
and one-time treatments that will reduce long-term health care
costs. Finally, EDs may link patients who do not have primary
care physicians to community health services and more appro-
priate specialists, as well as ongoing care. These prospective and
preventative health efforts will ultimately improve the health of
millions of patients while placing particular emphasis on tra-
ditionally underserved and uninsured populations. This subset
of patients is especially costly to diagnose and treat, so target-
ing them has the potential to significantly reduce nationwide
health care costs over time. As demonstrated by programs al-
Volume 2, Issue 1
ready in place in EDs around the country,1,7,8,12,15 these efforts
can be directed at patients in ED waiting rooms and would not
significantly increase time spent at the hospital or overburden
hospital staff members.
Acknowledgements
The author would like to thank Varun Gokarn for his com-
ments and guidance during the house course entitled “Health
Disaster and Prospective Medicine”, which he taught at Duke
University during the fall semester of 2007.
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a public inner-city emergency department. Vaccine. Nov
1998;16(19):1795-1802.
13. Gordon JA. The hospital emergency department as a
social welfare institution. Annals of Emergency Medicine.
1999;33(3):321-325.
14. Emergency Medical Treatment and Active Labor Act, 42
USC §1395dd (1986).
15. Kruesi MJ, Grossman J, Pennington JM, Woodward PJ,
Duda D, Hirsch JG. Suicide and violence prevention:
parent education in the emergency department. J Am Acad
Child Adolesc Psychiatry. Mar 1999;38(3):250-255.
9
Journal of Prospective Health Care Spring 2008

Paleolithic Diet and Modern

Disease
By Maria E. Balzaretti

C
ulture has played a significant role in the evolution of
humans as the main strategy for adaptation and sur-
vival in a changing environment. As humans adapted
to environmental conditions, selective factors resulted in the
genetic change of populations over millions of years. Through
biocultural evolution, both environment and culture continue
to propel the evolutionary process, and human variation has
responded by means of physiological, genetic, and cultural
change. A crucial cultural change occurred about 10,000 years
ago with the emergence of agriculture, which altered the nutri-
tion of humans considerably. Nutrition has always been a focus
for the growth, development, and maintenance of the body.1
The discrepancy between the nutritional intake before and af-
ter agriculture has had a severe consequence on contemporary
health.
The diet of Paleolithic humans, inhabiting Earth between
1.5 million and 10,000 years ago, has influenced our genetic
evolution by establishing the nutritional requirements for our
bodies.2 Many cultural changes since then, including the Neo-
lithic Revolution (agriculture) and the Industrial Revolution,
have modified the human diet. Yet genetic adaptation has not
kept pace with these cultural advances.3 Our genome has only
undergone minor changes since Paleolithic times, and there-
fore, the dietary patterns of that era are relevant today: we still
have the same nutritional requirements as our hominin ances-
tors.
In 1985, S. Boyd Eaton and Melvin J. Konner developed
the Discordance Hypothesis, which states that the mismatch
between contemporary and ancestral diets has had negative im-
plications on today’s health.4 They argued that the prevalence
of modern chronic diseases is the result of the discrepancy be-
tween the nutritional requirements set by Paleolithic hunter-

General paleolithic nutrition Paleolithic nutrition

Nutrient Typical Variation with Latitude Paleolithc1 Current US2 Ratio
Protein (mg/d) (mg/d)
Animal Very High Positive MINERALS
Vegetable Moderate Negative Calcium 1622 920 1.8
Fat Copper 12.2 1.2 10.2
Total Moderate to High Positive Iron 87.4 10.5 8.3
(~ Mediterranean vs.
Magnesium 1223 320 3.8
E. Asian)
Manganese 13.3 3.0 4.4
C20 & Very High Positive
C22 LCPUFA1 Phosphorus 3223 1510 2.1
n-6:n-3 Ratio ~1 Positive Potassium 10500 2500 4.0
Serum Cholesterol Sodium 768 4000 0.2
Raising FA Low Positive Zinc 43.4 12.5 3.5
Cholesterol High (~ US levels) Positive VITAMINS
Carbohydrate Ascorbate 604 93 6.5
Cereals None to Minimal Negative Folate 0.36 0.18 2.0
Vegetabvles & Fruits Very High Negative Riboflavin 6.49 1.71 3.8
Dairy Foods None After Infancy - Thiamin 3.91 1.42 2.8
Refined Sugars None (Honey) - Vitamin A 17.2 7.8 2.2
Fibre Very High Negative Vitamin B 32.8 8.5 3.9
Micronutrients Very High Negative 1
based on 3000 kcal/d, 35% animal: 65% plant subsistence
2
average of US men and women; Food and Nutrition Board, 1989
Phytochemicals (Probably High) (Probably Negative)
1
long-chain polyunsaturated fatty acids
Figure 1. Comparison of Paleolithic and Modern Nutrition. Adapted from Eaton et al., 2000.
10
Volume 2, Issue 1
gatherers and the foods consumed today. Since humans have
evolved to subsist on a single, Paleolithic diet, they concluded
that following the nutrition of our ancestors could help reduce
many of these “new” diseases.5 Many comparative studies of
traditionally living humans that have been conducted then
demonstrate a wide variety of diets and none of the modern
chronic diseases. Through these analyses we can better under-
stand the role of Paleolithic and contemporary nutrition in
these diseases, and potentially find a way to prevent and even
cure them.
Human nutritional requirements have coevolved with the
types of food available to us, and date back to our earliest an-
cestors. For instance, the first primates were probably insec-
tivores, and therefore, we have the ability to process animal
protein.1 The diets of our Paleolithic ancestors also affected our
nutritional requirements. Their diet was high in animal meat
and fish, vegetables, and fruits. However, it avoided dairy prod-
ucts, margarine, oils, refined sugar, and cereals.2 Meat was their
source of protein, and fruit and vegetables were their main
source of carbohydrates, rather than the cereals, refined sugars,
or dairy products consumed today.6 Figure 1 provides a good
comparison between Paleolithic and modern diets.
A pre-agricultural diet provided much more fiber and 2-
10 times the micronutrients of a contemporary diet. It also
provided more calcium, despite the lack of dairy consumption,
and other minerals, except sodium. Sodium is the only mineral
that is consumed at higher levels in modern diets, which has
proven to be deleterious to modern health. The Paleolithic diet
also had a higher intake of vitamins and showed evidence of the
more active lifestyle of hunter-gatherers.7 These comparisons
demonstrate that, regardless of our cultural and technological
advances, modern society is failing to fulfill the nutritional re-
quirements of the past.
The repercussions on modern health are what Eaton calls
the “diseases of civilization” because they emerged only after
the Neolithic revolution. These include the following: cardio-
vascular diseases, such as atherosclerosis, hypertension, and
stroke; cancer; the malfunction of insulin receptors and insulin
resistance, including type 2 diabetes; obesity; chronic obstruc-
tive lung disease, such as emphysema and chronic bronchitis;
hearing loss; and dental caries.4, 6, 2 All of these diseases can be
alleviated through environmental factors and many by dietary
changes. Awareness of these health risks and analysis of indi-
vidual genetic predisposition can lead to the successful preven-
tion of these chronic conditions.
A case study of hypertension, (high blood pressure, usually
above 140/90) provides an interesting example.8 Hypertension
itself is not deadly, but it can contribute to heart attacks, kid-
ney failure, stroke, and atherosclerosis.4 Although hypertension
has genetic factors, it is not considered a genetic disease be-
cause of the environmental-dietary component that can help
control it.9 According to several studies, there is a strong cor-
relation between hypertension and high sodium consumption.
Journal of Prospective Health Care
This is not surprising considering that our Paleolithic ancestors
consumed ¼ the amount of sodium that Western society cur-
rently consumes.10 According to the Discordance Hypothesis,
this mismatch in sodium intake should have health implica-
tions, and indeed it has—hypertension.
The increased sodium intake of many populations today is
not only due to the increase of sodium-rich food sources, but
also to cultural advances. Only 10% of modern sodium con-
sumption is due to the food itself; nearly 90% of it is from food
processing.4 Through technology we have developed a way to
conserve food and protect ourselves from disease caused by the
bacteria found in rotting food, yet this technology also has in-
creased the sodium content of preserved food. Our genome has
not adapted as quickly to this cultural change, demonstrated
by the emergence of cardiovascular diseases like hypertension.
The genes for hypertension have not yet been identified, but
a recent study found a correlation between hypertension and
populations originating in warm climate.8 Because this environ-
ment causes higher salt loss through sweating, salt is retained
longer in the kidneys before excretion as an adaptive measure.
These populations also experience a greater rise in blood pres-
sure on a high sodium diet, which could lead to hypertension
depending on salt intake.8 While this is considered a problem
in today’s society, it may have once been a benefit because sodi-
um was not readily available for the majority of hominin evolu-
tion. Thus, retaining salt in the body for a longer period of time
was a way to increase survival and reproductive success. There
would have been selection for this trait, and it would have been
passed down through generations because of the advantage it
provided to survive through episodes of sodium loss.8 This trait
would only have been detrimental when salt became routinely
available in food, as it is today. Therefore, though our genome
has not adapted to the shift in sodium availability, some popu-
lations are genetically adapted to sodium deficit, and in turn
will be more inclined to develop hypertension.
However, comparative studies of contemporary hunter-
gatherer societies demonstrate a wide variety of diets, not just
the single Paleolithic diet, and none of the modern chronic
diseases. Since the diseases were absent in our Paleolithic ances-
tors and they appear to be absent in these traditionally-living
populations today, there is an apparent link between the two.3
A study conducted by Lindeberg et al. surveyed foragers of
the populations of Kivata, Trobriand Islands, and Papua New
Guinea. From these societies, the average blood pressure for
males at the age of 40 was 105/65, well below the value con-
sidered normal in Western societies of 120/80. Not only were
these people virtually free of hypertension, they also lacked
stroke, obesity, type 2 diabetes, and malnutrition.2 Similari-
ties to Paleolithic diet include low intake of sodium and fat,
and high fiber consumption. The average sodium consump-
tion of contemporary hunter-gatherer societies is 700 mg per
day, which is less than the recommended amount of 1000 mg
a day. The modern American diet consists of 2,300 to 6,900
11
Journal of Prospective Health Care Spring 2008

VARIOUS DIETS can satisfy human nutritional requirements. Some populations subsist almost entirely on plant foods;
others eat mostly animal foods. Although Americans consume less meat than do a number of the tradionally living
people described here, they have on average higher cholesterol levels and higher levels of obesity (as indicated by
body mass index) because they consume more energy than they expend and eat meat that is higher in fat.
Population Energy Intake Energy from Energy from Total Blood Body Mass Index
(kilocalories/day) Animal Foods (%) Plant Foods (%) Cholesterol (weight/height
(milligrams/deciliter) squared)
HUNTER-GATHERERS
!Kung (Botswana) 2,100 33 67 121 19
Inuit (North America) 2,350 96 4 141 24

PASTORALISTS
Turkana (Kenya) 1,411 80 20 186 18
Evenki (Russia) 2,820 41 59 142 22

AGRICULTURALISTS
Quechua (Highland Peru) 2,002 5 95 150 21
INDUSTRIAL SOCIETIES
U.S. 2,250 23 77 204 26
Note: Energy intake figures reflect the adult average (males and females); blood cholesterol and body mass index (BMI) figures are
given for males. Healthy BMI = 18.5-24.9; overweight = 25.0-29.9; obese = 30 and higher.

Figure 2. Comparison of Different Types of Modern Diets. Adapted from Leonard, 2002.

milligrams of sodium per day.4 The low salt intake is one of
the few similarities between our Paleolithic ancestors and the
populations of hunter-gatherers today.
While the foragers’ food sources may be nutritionally ben-
eficial, there are not enough wild foods to feed the growing
human population, making it impossible for modern societies
to all follow the hunter-gatherer or Paleolithic way of living to
obtain food resources. Instead, we must rely on agriculture, do-
mesticated animals, and processed foods that are not as healthy
as the wild resources. Without the wild resources, how are we
supposed to prevent and cure the diseases of civilization?
Eaton et al. 2000 suggest restructuring our modern diet to
resemble the nutrition of the Paleolithic diet. This includes re-
ducing sodium intake, eating more fruits and vegetables, and
increasing exercise. They also discourage a diet based on grains
like those of the nutritional pyramids because it is out of line
with primate and hominin evolutionary nutrition.6 Instead,
our diet should focus on the nutrients, minerals, and vitamins
consumed by our ancestors.
William Leonard has recently proposed an alternative to
the dietary dilemma. He believes that the comparative studies
conducted on the contemporary traditionally-living popula-
tions demonstrate that humans can meet nutritional require-
ments through a variety of diets, and should not rely on exactly
what our Paleolithic ancestors ate. Therefore, if humans have
evolved the ability to be “flexible eaters,” a single, optimal diet
does not exist.5 Instead, we can minimize health risks by bal-
ancing the energy we consume with the energy we expend by
avoiding calorie-packed foods. Figure 2 shows Leonard’s com-
parison between the different types of diets in the world. All of
these diets are able to meet the metabolic requirements of each
population.
Humans today cannot change the nutritional requirements
set by our Paleolithic ancestors or our genetic predisposition
to certain diseases. We are not able to rely on evolution to
eradicate these diseases of civilization because these diseases do
not affect our survival before reproduction, and thus, they will
not be selected as disadvantageous.11 Our only option left is
to change our diets according to personal needs. For instance,
individuals with genetic predisposition to hypertension should
have a lower intake of sodium than those individuals not at
risk. But those not at risk should strive to consume the recom-
mended one gram per day of sodium since they also are at risk
for developing hypertension. Our genetic predispositions en-
able us to predict our individual nutritional needs and health
risks in order for us to develop a more personalized health plan
that will allow for targeted disease prevention.
Even though we cannot control our predisposition to dis-
eases, we can attempt to prevent them by leading a healthy
lifestyle. Humans have evolved to subsist on a variety of diets,
so a healthy lifestyle is not one set diet. The valuable examples
of our Paleolithic ancestors and contemporary hunter-gatherer
populations can lead us to focus on the minerals and vitamins
that have kept them free from the diseases of civilization. Even
though we lack their healthier, wild resources, we can still avoid
the calorie-packed foods available today. Not one diet of those
from Figure 2 is optimal because they all meet each population’s
metabolic needs. Humans today must choose a diet that best
meets their nutritional requirements and complements their
own genetic predispositions to modern chronic diseases.
References are available online at:
http://go.prospectivehealthcare.com/2-1-10

12
Volume 2, Issue 1 Journal of Prospective Health Care

Targeted Genomic Medicine: RNA

Interference
By Paul Fullerton
RNA interference (RNAi) is a natural cellular mechanism involved in the regulation of gene expression. It is a powerful
genomic tool for sequence-specific gene silencing and holds immense potential as a highly individualized therapy.
While research has shown RNAi to be promising in treating and preventing various physiological diseases, the
delivery and effectiveness of the treatment are still in need of improvement.

I
n 2001, the completion of the Human Genome Project
ushered in a new era in medicine. For the first time, scien-
tists had the opportunity to study the entire genome and dsRNA + dicer
to ultimately elucidate the relationship between an individual’s
genes and his expressed phenotypes. This genome revolution
is resulting in a newfound understanding of diseases as well
siRNA
as the development of treatments tailored to an individual’s + proteins
unique genomic profile. Individualized treatments can allow
for diseases to be combated even before they strike. One such
method of prospective treatment is RNA interference (RNAi).
Although it must overcome challenges in mode of delivery and
treatment effectiveness, RNAi contributes substantially as an assembly of RISC
effective method for preventing tissue damage, repressing vi- siRNA unzips
ruses, treating neurological conditions, and fighting cancer.
RNAi is a naturally occurring mechanism in cells that in-
hibits gene expression. Although it is still being studied, RNAi
is known to be initiated by the enzyme dicer (Figure 1), which
cuts double-stranded RNA (dsRNA) into fragments 20-25 base activated RISC
pairs long called small interfering RNA (siRNA). The siRNA + targeted mRNA
fragments are incorporated into the RNA-inducing silencing
complex (RISC), which is activated by the unzipping of siR-
NA. The RISC then employs the unwound siRNA fragments
as guides to the targeted messenger RNA (mRNA) strand by
complementary base pairing of the siRNA to the mRNA. The siRNA-mRNA cleavage of mRNA by
duplex RISC
siRNA-mRNA hybrid that results is cleaved by enzymes found
on RISC.1 Thus, RNAi prevents translation of target mRNA
by degrading it before it reaches the ribosome. The function of gene silencing
RNAi in the cell is not fully understood, but researchers believe
Figure 1. Overview of RNA interference
that it plays a role in the immune response to viruses, con-
tributes to genome maintenance, and affects gene regulation. For example, siRNA has been used to inhibit overexpression of
Research has confirmed that RNAi is involved in modulating the gene Fas caused by autoimmune hepatitis.3 By silencing
the expression of genes during development and exercises reg- this gene, liver fibrosis, which leads to liver failure, was sup-
ulatory control over cell division.2 By harnessing this natural pressed in transgenic mice after they received an intravenous
mechanism of gene regulation, scientists hope to specifically injection of Fas siRNA. The inhibition of the gene persisted
inhibit protein production to treat tissue damage, viruses, neu- without any diminution for ten days after the initial treatment,
rological conditions, and cancer. while the control mice died of liver failure within three days.4
Tissue damage is caused by overactive host responses to in- Additionally, the local delivery of Fas siRNA by low-volume
fection or injury, which can be successfully combated by RNAi. renal vein injection effectively protected mice from renal isch-
13
Journal of Prospective Health Care
emia reperfusion injury. The ability to temporarily suppress the
cell death that occurs when blood supply is restored to the tis-
sue after an unnatural restriction5 can be used to limit the effect
of strokes and prevent inflammation.
RNAi also holds considerable promise for the treatment of
viruses including HIV, Influenza A, Respiratory Syncytial vi-
rus (RSV), Parainfluenza virus (PIV), and Hepatitis B (HBV).
In an attempt to prevent HIV-1 replication, siRNA has been
used in trials to interfere with the viral Nef gene, which causes
T-cell activation and establishes a persistent state of infection.
Although it was initially successful, viruses with nucleotide
substitutions or deletions in the Nef gene appeared after a few
weeks, ending the usefulness of the RNAi treatment. While
RNAi has the potential to be a useful tool in the fight against
HIV/AIDS, HIV’s mutability prevents RNAi from being a
cure.6 Positive results have been achieved in trials targeting In-
fluenza A, RSV, PIV, and HBV, in which siRNA fragments
succeeded in inhibiting virus replication in mice.7, 8, 9 In one
study, siRNA instilled intranasally in the mouse prevented
as well as inhibited joint and individual RSV and PIV infec-
tions. These results suggest that low doses of inhaled siRNA
may prove to be an excellent anti-viral treatment method for
humans.9 However, RNAi has its limits in virus treatment; re-
spiratory syncytial virus, hepatitis delta virus, and rotavirus are
all resistant to RNAi. Both tight shielding of the virus’s ge-
netic material by proteins and self-sequestration of the virus in
cell compartments can render the virus inaccessible to siRNA.
Other viruses, such as HIV/AIDS, can develop resistant strains
to avoid targeting by siRNA.10 Nevertheless, RNAi’s ability to
repress virus replication demonstrates its capacity as an effec-
tive antivirus treatment.
RNAi may be an answer for otherwise untreatable neuro-
logical conditions like Huntington’s disease. Huntington’s dis-
ease is caused by a single trinucleotide repeat expansion in the
HD gene coding for Huntington protein (Htt) on chromo-
some four. RNAi targeting of the expression of the HD gene
in trials using a Huntington’s disease transgenic mouse model
have shown improvements in motor and neuropathological
abnormalities.11 Because of its relatively simple genetic cause,
treatment for Huntington’s disease appears to be one of the
most promising targets for RNAi. Furthermore, RNAi may
also be valuable in treating more complex neurological diseases
like Alzheimer’s, once their genetic causes are understood.
RNAi has the ability to become a vital tool in the fight
against cancer by specifically targeting tumors. RNAi can sup-
press cancer by blocking genes associated with tumor growth,
vascularization, and spread of glioma tumors.12 RNAi gene
therapy has also been directed against the human epidermal
growth factor receptor (EGFR), which plays an important on-
cogenetic role.13 This treatment has succeeded in prolonging
the survival of mice with human brain cancer by 88%. RNAi
has been used to knock out the M-BCR/ABL fusion site, caus-
ing leukemia cells to undergo apoptotic cell death.14
14
Spring 2008
Before RNAi can reach its full potential, concerns about
its delivery must be addressed. There are two basic methods
for the delivery of siRNA into the RNAi infrastructure of the
cell, viral and nonviral, each of which presents a different set
of difficulties. Viral delivery vectors involve the creation and
injection of a virus that carries the siRNA fragments into the
organism. The advantage of this system is that the virus per-
sists for several weeks, which lengthens the time between each
subsequent treatment.10 However, viral delivery carries the
challenges of ensuring efficient transduction of targeted cells
and maintaining sustained gene expression of transduced cells.
Negative side effects and risks must be minimized and include
the danger of oncogenesis from insertional mutagenesis, the
risk of recombination with endogenous retroviruses, and toxic-
ity from immune or inflammatory responses to the viral vec-
tor itself.15 Nonviral methods using siRNA based drugs avoid
the dangers of viruses, but instead have a very short half-life
and poor uptake. This leads to reduced effectiveness and causes
each treatment to last less than a week.10 If RNAi is to become
a feasible method of treatment, considerable advances in the
delivery process must be made.
Although the method of delivery is an issue, a more fun-
damental concern is that any particular siRNA may have a
broader impact on gene expression than originally thought.
Recent experiments have shown that individual siRNA frag-
ments can work to regulate multiple genes instead of simply
silencing a single target. If a therapeutic siRNA is imperfectly
designed or mutates during replication, it may silence some-
thing in addition to the target, which may have negative re-
percussions. For example, in high concentrations, siRNAs may
induce an interferon response that could potentially result in
global suppression of protein translation.16 These challenges in
RNAi targeting might be overcome by careful design of siRNA
fragments.17
Finally, because RNAi based therapy uses the cell’s own nat-
ural RNAi mechanisms and molecular machinery, there is the
possibility that introduction of too many additional siRNAs
might displace endogenous RNAi mechanisms and prevent the
cell from performing its normal functions.1 Although this is
still a theoretical concern, any tinkering with the natural work-
ings of the cell raises the specter of unknown side effects.
Despite the challenges it has to overcome, RNAi therapy’s
ability to specifically target and silence gene expression holds
immense potential for the treatment of many diseases. As re-
search reveals more about the mechanics of gene expression,
medicine will become more individualized and target-specific.
Because of its ability to silence individual gene expression,
RNAi can become a promising and powerful tool of personal-
ized genomic medicine.
References are available online at:
http://go.prospectivehealthcare.com/2-1-13
Volume 2, Issue 1 Journal of Prospective Health Care

Racial Categories as a Proxy for

Human Genetic Variation:
History and Implications
By Lee Hong
There is a significant controversy around the implications of using racial categories to analyze human biological
differences, with many stakeholders—policymakers, health care professionals, research scientists, the media, and
society at large—in the continued use of such categories. While some argue that race is a purely social construct
and not legitimate in biomedical research, others argue that race is indeed biological.
Though genomics research can access and measure the extent of genetic variation within and among human
populations, many researchers continue to use traditional racial and ethnic categories to describe and predict
susceptibility to disease. Developing a new classification system that accurately includes both disparities and
genetic clustering without social stigmatization may resolve this issue, but the broader interpretations of
genomics studies in the media, health care, and policy are also pertinent.

Background
The U.S. Census has consistently been used as a tool for
data analysis on the U.S. population. However, the census has
also changed every decade, particularly in its questions about
identifying race and/or ethnicity—the categories, specificity,
and wording of the questions have changed with each census as
American society has changed with regard to peoples’ identifi-
cation with racial and ethnic groups.
In an analysis of the 1990 U.S. Census, the ambiguity of
race and ethnicity as classification systems was further revealed.
To identify race, the Bureau of the Census has used “the enu-
merator’s observation and self-identification;” persons were
also asked to “report the one race with which they most closely
identified,” though the Bureau did not provide a definition of
race.1 This format brought about objections from persons who
were “confused as to how to report because national origin
groups were listed in the race item.”1 Other respondents viewed
race and ethnic questions as asking for “the same identity.”1
To make things even more confusing, McKenney and
Bennett (1994) also noted that the data from the 1990 U.S.
Census and public health surveillance data have discrepancies
when used in conjunction with each other due to “different
data collection methods, different content and format of the
questions, and different definitions and classifications for race
and ethnicity.” While the authors did not mention whether
these discrepancies affected disease intervention or treatment,
it is easy to see how confusing defining one’s race or ethnic-
ity really is. Nevertheless, the authors noted that “the need to
improve the quality of the race and ethnic data is driven by the
many important uses of the data, such as redrawing political
boundaries, implementing legislation and programs, and fund-
ing governmental programs,” specifically for minimizing the
socioeconomic differences and health disparities between racial
groups.1
The problems that arose from the 1990 U.S. Census reflect
the complexity in using racial and ethnic categories to clas-
sify human populations. Such categories carry with them heavy
social, political, and cultural weight. Unfortunately, many sci-
entists throughout history have conducted studies mired in
stereotypes on analyzing human differences in character traits,
i.e. behavior and cognition. These studies that have described
broad character traits across racial and/or ethnic populations
without sound scientific evidence have consistently been used
to justify the continued discrimination of human population
groups.
Such “scientific” studies may be condoned today, but the
continued use of racial and ethnic categories in biomedical re-
search to describe and predict susceptibility to disease is a seri-
ous issue that has not been resolved. The reactions from scien-
tists and non-scientists have varied in tone and severity. Some
argue that race is a purely social construct, is not a legitimate
category for biological research, and reinforces stereotypes.
Others argue that race serves a good proxy for geographic an-
cestry, includes cultural and socioeconomic factors important
for clinical research, and illuminates disparities with the inten-
tion of eliminating such disparities.
15
Journal of Prospective Health Care
The focal point of misunderstanding between scientists and
nonscientists is in the impact of scientific data and results on
the current social paradigm. While many scientists study racial
groups with the goal of alleviating disparities that exist between
groups, they do not understand why they are being accused
of racism when examining complex trait differences such as
behavior and cognition. On the other hand, many social scien-
tists and nonscientists are aware of the historical and cultural
complexities of race but may not understand the significant
and real differences that exist between populations of different
ancestries.
Beyond the scientific realm, however, there are many
stakeholders in how the perception of race is changed or not
changed. Ethicists, clinicians, policymakers, the media, and the
public all have varying benefits and risks from learning about
how genetic variation translates into phenotypic variation and
predisposition to disease. All stakeholders are affected by the
turbulent history of analyzing human biological differences, a
history deeply embedded in Western culture since the eigh-
teenth century.
Cultural and scientific history
The notion to classify humans in scientific thought was not
always commonplace in European literature. Rather, most eth-
nographic literature by the beginning of the eighteenth century
focused on the “relative sophistication” of other countries based
on their political and social systems,2 not the notion of race.
Likewise, European explorers perceived themselves as superior
to all the peoples they encountered because of their achieved
level of civilization.2
However, Europeans underwent a shift in attitude during
the early years of the Enlightenment as Locke and other natu-
ralists acknowledged that humans were no longer considered
unique for their rationality or reason. Scientists acknowledged
that humans are subject to the same biological and evolutionary
forces as other species—and thus, humans should be described
and analyzed as another biological species. Thus, writers from
this era tended to dismiss national differences as insignificant
and instead chose to describe the “general physiognomy and
intellectual capacity” of entire races “with essentially common
traits of body and mind.”2 Likewise, as European countries be-
gan to colonize and expand their empires, the influence of im-
perialism and slavery stripped non-European peoples of their
national identities and were described as innately inferior to
Europeans.2
In the nineteenth century, “scientific” evidence in the fields
of anthropology, biology, craniometry, and medicine served to
further distinguish races.3 Many findings in these fields reiter-
ated the idea that such distinguishable behavioral, cognitive,
and social traits were inherited and that these traits directly af-
fected each race’s susceptibility to disease.3 Before 1930, racial
divisions were not just made between light and dark-skinned
groups; immigrant groups were also distinguished from the
United States’ “White founders,”3 though the original Consti-
16
Spring 2008
tution granted such immigrant groups the same rights as all
other white Americans. Nevertheless, immigrant groups were
ranked and distinguished by a “visual economy” using cues
such as skin color, head size and shape, and physiognomy.4
Such stereotypes translated to class structure, for these charac-
teristics were “economic assessments that had economic con-
sequences”.4
Once the term “race” had been established as “the biological
subdivision of humanity,” it was later “rejoined with ‘nation’
in a new and explosive mixture”2—as evidenced in the Nazi
regime. The doctrine of Nazi medicine—to achieve biological
superiority through the elimination of traits considered un-
favorable in the gene pool of the favored peoples—stemmed
from the eugenics movement of the early twentieth century.
The eugenics movement was warmly embraced in America,
where officials and politicians used the language of “undesir-
able” traits, “useless” races, and the importance of “breeding”
on a national scale to convey problems on immigration and
intermarrying.4 It would be interesting to further study the eu-
genics movement and its impact on policy, genomics research,
and society at large in the context and relevance of race.
Today, as research in human variation continues in various
fields and generalized therapies are introduced to individual
patients, it is important to acknowledge the cultural and sci-
entific history—and ultimately the context—of scientific re-
search grounded in the idea that humans are innately different.
Scientists, as history has shown, work within the social, cul-
tural, and political norms of their time and will continue to do
so. Ultimately, the interpretation of scientific studies and the
spread of common knowledge about human variation can im-
pact society, culture, politics, and medicine. In this context, it
is important to analyze the current scientific research in popu-
lation genomics and where the research is headed
Population genomics and genetic variation
Four evolutionary forces are responsible for most of the
genetic variation found in humans.5 The first is mutation, a
random event that is a source of genetic diversity within and
among populations. The second is genetic drift, in which al-
leles change their frequencies by chance; genetic drift can cause
a decrease in genetic diversity and a differentiation between
different local populations. The third is gene flow or genetic ex-
change, which involves migration to and from different popu-
lations; this decreases genetic diversity both within and among
populations. The fourth evolutionary force is natural selection,
“a powerful homogenizing force” for different populations
adapting to the same environments.5 Each of the forces, when
at work within and among populations, reflects the dynamics
of genetic drift and gene flow between such populations.5
Some general patterns that biologists have discovered be-
tween population dynamics and genetic variation are straight-
forward. Because there is more genetic drift in smaller popu-
lations, the variance of neutral polymorphism frequencies
increases among groups.6 The polymorphisms that arose in one
Volume 2, Issue 1
group are more likely to be restricted to this group.6 Thus, the
frequencies of genetic differences vary among populations of
all kinds.
However, there are limitations in using single nucleotide
polymorphisms (SNPs) to examine human genetic diversity.
SNPs limit the size of case-control studies and could be mis-
leading—as Goldstein and Weale (2001) noted, “a SNP variant
could also be associated with the condition not because it is
biologically causal, but because it is statistically correlated with
a causal variant.” Furthermore, most polymorphisms that differ
in frequency between groups and thus distinguish such groups
are “neutral, functionally insignificant and probably of little
relevance to phenotypic differences between individuals.”6
Thus, population geneticists are increasingly using a dif-
ferent indicator of genetic variation between human popula-
tions—linkage disequilibrium (LD). LD is the non-random
pattern that arises when alleles at different loci are found to-
gether more or less often than expected.7 By measuring the
variance of linkage disequilibrium as a function of distance be-
tween the sites of genes along with the average extent of linkage
disequilibrium across the genome, population geneticists can
more accurately describe the genetic variants that contribute to
phenotypic variation.7
So what have population geneticists discovered so far
about human genetic variation? Because the human species is
young on an evolutionary scale, the overall genetic variation
between humans is low—the human FST, a measure of the
relative amounts of diversity within and among populations,
is only about 0.15, when the standard quantitative threshold
for FST for other species is 0.25-0.30.5 While all humans share
the “adaptive traits” that define the human species,5 the genetic
variation that does exist in the human species is considerable—
due to how humans sexually reproduce, all gene variants are
unique to individuals.8
Because of this phenomenon, there can be no “sharp genet-
ic boundaries” drawn between human populations.8 In fact, 93
to 95% of all genetic variation occurs within populations9—in
essence, “the vast majority of common genetic variants present
today existed in our common ancestral pool.”8 However, there
has been substantial evidence that genetic variation is associ-
ated with geographical ancestry. It is true that individuals can
be allocated to groups representing geographical regions us-
ing a couple multilocus genotypes,6 and that two people from
different racial groups, regardless of which racial group they
belonged into, were more different than two individuals from
the same racial group approximately two-thirds of the time.6
In fact, many population geneticists argue that it is possible to
analyze multilocus genotypes and infer genetic ancestry with-
out prior knowledge of sampling location.9
Nevertheless, this point is ambiguous when reconstructing
population structure. When some use strictly genetic informa-
tion to create population clusters, geographic origins and racial
categories proved unreliable for determining population struc-
Journal of Prospective Health Care
ture. For example, Bamshad et al. (2004) noted that two such
studies “failed to accurately allocate individuals from Central
or South Asia into a genetic cluster that corresponded to com-
mon concepts of race, presumably because these populations
are historically admixed with populations from both Europe
and Asia” (p. 601). Thus, in such populations where there has
been a significant history of admixture and migration, using
genetic ancestry can be misleading.
Along these lines, Wilson et al. (2001) concluded that eth-
nic labels are also “insufficient and inaccurate descriptions of
human genetic structure” in a study evaluating drug safety and
efficacy. Not only did they discover extreme differentiation be-
tween two commonly labeled ethnic clusters, the researchers
noted that “the ethnic labels never show[ed] sharp differentia-
tion that is not observed in the clusters.”10 Racial categories,
in terms of phenotypic variation, are decidedly not enough to
accurately categorize people by their population genetic struc-
ture: “…although facial features and skin pigmentation are
routinely used to group people by race, populations that share
similar physical characteristics as a result of natural selection
can be very different genetically.”10
In light of discrepancies in using geographic ancestry, eth-
nicity, and race as categories for human genetic variation, one
may ask if there is any legitimate category to describe human
genetic variation in the first place. Indeed, measuring the net
effect of genetic influences in a given population will require
an analysis of the frequencies of the susceptibility alleles in
all genomic regions, while taking into account the environ-
mental factors that are either difficult to measure or entirely
unknown11—a seemingly impossible task. Thus, the ultimate
direction of population genomics seems to be, according to
many population geneticists, in personalized medicine, where
one can analyze individual genotypes in comparison to overall
population structures.
Discussion
Outside the scientific realm, there are many implications for
the continued use of racial categories in biomedical research.
One main concern is from health care professionals, who can
most directly use information from population geneticists to
develop treatments and therapies for individual patients. Some
are not convinced that scientists that use racial categories have
justified their use in terms of “demonstrable benefits to pa-
tients.”12 However, racial classifications continue to be used in
clinical practice because they continue to have practical clinical
utility12—in the United States, as well as in other countries,
there is substantial variation in health status that corresponds
to racial and ethnic categories.11
It is also unclear whether information gleaned about pa-
tients’ health from geographic ancestry is useful or reliable in
terms of developing a personalized health plan designed to
prevent disease at the earliest point of onset.12 For example,
although studies on polymorphisms in drug-metabolizing en-
17
Journal of Prospective Health Care
zymes showed significant variation according to race, neither
racial categories nor genetic clusters were accurate enough to
make them clinically useful in choosing drugs.11 Due to many
other environmental, social, and economic factors related to
health, categories based on differences in allele frequencies are
not the same as apportioning human diversity into medically
relevant categories.11
Policymakers must also carefully consider research in pop-
ulation genomics as they consider policies on immigration,
health care, education, and criminal justice and the constituen-
cies affected—especially in the alleviation of health disparities
between racial and ethnic groups. Minority groups, in particu-
lar, are sensitive to fears of genetic discrimination as studies
continue to emphasize differences in these minority groups. It
would be interesting to further explore the dynamics between
policymakers and scientific researchers on the issues of race and
ethnicity.
For the media, there is a pressing danger for the oversim-
plification of results from scientific studies on human genetic
variation. Headlines such as “Racial Component is Found in a
Lethal Breast Cancer” and “Race: A Risk Genetics Must Run,”
and the language and metaphors used when communicating
topics on race convey that racial categories are entirely accu-
rate in predicting susceptibility to disease—a concept that is,
as previously mentioned, not accurate in the least. When com-
municating complex topics to the public, there is a need for
discernment and comprehension.
18
Spring 2008
Finally, for the public and society at large, the main point of
contention with researchers is in how individuals understand
genetic variation and disease risk, whether these understand-
ings are legitimate or not. As Carlson (2005) noted, “there is
a real peril that lowbrow theories wrapped in tendentious and
oily slogans will get the public’s ear and gain even footing with
scientific proof as worthy of belief.” Another important impli-
cation is the influence understanding of genetic variation has
on behavior, such as with the patient-doctor dynamic, support
or opposition to policy, and reactions to the media. Ultimately,
studies on population genomics could affect how individuals
identify themselves in the context of biological, environmental,
social, and economic factors. These identities could affect how
individuals approach their relationships with their health care
providers—from the kinds of health care providers to which
they can relate to the selection and application of health care
plans.
Acknowledgements
The author would like to acknowledge the mentorship of
Dr. Robert Cook-Deegan, Professor Lauren Dame, and Dr.
Subhashini Chandrasekharan.
References are available online at:
http://go.prospectivehealthcare.com/2-1-15
Volume 2, Issue 1
Research Briefs: Prospective
Health Care at Duke
By Josephine Li
Duke University has consistently been at the forefront of the prospective health care transformation, partly because
of ongoing research that works toward the realization of a health care system that is predictive, preventative,
personalized, and patient-involved. Here are some of the current research discoveries that contribute to the four
goals of Prospective Health Care.
Prediction
Researchers led by Edward Patz, Jr.,
M.D. have discovered four serum bio-
markers associated with lung cancer.
Higher levels of these proteins have been
found in patients with cancerous nodules
as compared with patients with benign
lesions. A classification tree has been cre-
ated to determine the probability of ma-
lignancy of suspicious nodules based on
an individual’s biomarker levels. These
blood proteins serve a clinical benefit by
permitting early detection of lung cancer
in a non-invasive manner.
Joseph Matthew, M.D. led a team
of researchers in identifying two gene
polymorphisms involved in inflamma-
tion regulation that are associated with
cognitive decline in patients after cardiac
surgery. An understanding of the genetic
factors that contribute to cognition not
only allows for prediction of patients at
higher risk for postoperative cognitive
dysfunction (POCD) but also advances
the development of perioperative thera-
pies that aim to reduce this complica-
tion.
Prevention
Researchers led by Johanna L. John-
son, M.S. have studied the effect of exer-
cise on metabolic syndrome, defined as
the presence of several risk factors that
increase an individual’s chance of devel-
oping diabetes and cardiovascular dis-
ease. They have discovered that 30 min-
utes of moderate exercise per day lowers
one’s risk of metabolic syndrome even
in the absence of dietary changes. These
findings emphasize the importance of
a proper exercise regimen in achieving
long-term health.
According to a study led by Todd D.
Green, M.D., children are exhibiting
signs of peanut allergy at an earlier age.
Because the cause of the decline in aver-
age age of peanut allergy onset is pres-
ently unknown, the accepted method of
preventing allergic reactions is to avoid-
ance of peanut products altogether. How-
ever, ongoing research is currently testing
whether early introduction of peanuts
may promote desensitization and trigger
an immune response that prevents the al-
lergy.
Personalization
HIV treatment can be rendered in-
effective by the presence of multiple
drug-resistant strains. Researchers led by
Fangping Cai, M.D. have developed an
assay that efficiently tests for drug-resis-
tant HIV strains in patients, even at low
levels in the blood, and provides linkage
analysis of resistant mutations. Under-
standing the mechanisms underlying
HIV drug resistance as well as the various
mutations that cause resistance is perti-
nent to tailoring effectual treatments to
each individual.
Jed E. Rose, Ph.D. has worked with
researchers from the National Institute
on Drug Abuse to identify 221 gene vari-
ants that distinguish people who success-
fully stop smoking from those who have
Journal of Prospective Health Care
trouble quitting. Genes contributing to
nicotine vulnerability have been found
to overlap with features that affect other
substance addictions. Knowledge of the
heritable factors contributing to nicotine
dependence may further the design of
treatments based on individual’s genetic
makeup.
Patient Responsibility
Researchers led by Truls Ostbye,
M.D., Ph.D. have found a positive
correlation between body mass index
(BMI) and the number of worker com-
pensation claims. This study stressed the
importance of work-based programs that
focus on physical activity and healthy
eating. Because employers often shift in-
creases in health care costs to their em-
ployees, participation in these programs
provides employees with the incentive
of lower premiums, copays, and deduct-
ibles.
Pao-Hwa Lin, Ph.D. and other re-
searchers have found lifestyle interven-
tion programs to be effective in helping
participants adhere to dietary regiments
that prevent hypertension. Participants
kept food diaries and attended weekly
sessions with trained dietitians and
health counselors. These findings high-
light the importance of self-monitoring
and awareness in producing behavior
changes.
References are available online at:
http://go.prospectivehealthcare.com/2-1-19
19
Sponsors The Duke Prospective Health Care Club would like to thank the
following sponsors for their support of the Journal.

Duke Center for Research Duke Department of

on Prospective Health Care Biomedical Engineering

Duke Institute for Genome Duke Department of

Sciences and Policy Biology

John Spencer Bassett

Memorial Fund

Journal of Prospective Health Care

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