The continuum of translation research in genomic
medicine: how can we accelerate the appropriate
integration of human genome discoveries into health
care and disease prevention?
Muin J. Khoury, MD, PhD, Marta Gwinn, MD, MPH, Paula W. Yoon, PhD, MPH, Nicole Dowling, PhD,
Cynthia A. Moore, MD, PhD, and Linda Bradley, PhD
Advances in genomics have led to mounting expectations in regard to their impact on health care and disease
prevention. In light of this fact, a comprehensive research agenda is needed to move human genome discoveries
into health practice in a way that maximizes health benefits and minimizes harm to individuals and populations.
We present a framework for the continuum of multidisciplinary translation research that builds on previous
characterization efforts in genomics and other areas in health care and prevention. The continuum includes four
phases of translation research that revolve around the development of evidence-based guidelines. Phase 1
translation (T1) research seeks to move a basic genome-based discovery into a candidate health application (e.g.,
genetic test/intervention). Phase 2 translation (T2) research assesses the value of a genomic application for
health practice leading to the development of evidence-based guidelines. Phase 3 translation (T3) research
attempts to move evidence-based guidelines into health practice, through delivery, dissemination, and diffusion
research. Phase 4 translation (T4) research seeks to evaluate the “real world” health outcomes of a genomic
application in practice. Because the development of evidence-based guidelines is a moving target, the types of
translation research can overlap and provide feedback loops to allow integration of new knowledge. Although it is
difficult to quantify how much of genomics research is T1, we estimate that no more than 3% of published research
focuses on T2 and beyond. Indeed, evidence-based guidelines and T3 and T4 research currently are rare. With
continued advances in genomic applications, however, the full continuum of translation research needs adequate
support to realize the promise of genomics for human health. Genet Med 2007:9(10):665–674.
Key Words: evidence-based medicine, genomics, public health, translation research
“I predict that comprehensive, genomics-based health care
will become the norm, with individualized preventive medi-
cine and early detection of illnesses.”1
discoveries to enter day-to-day clinical practice.”2
in human genomics and related fields (e.g., transcriptomics,
health care and disease prevention.1,3,4Currently, hundreds of
thousands of genetic variants are being evaluated for their as-
sociation with common chronic diseases.5Research is acceler-
proteomic, and other “omic” technologies.6The number of
genetic tests used in clinical practice and clinical research is
renewed attention as a genomic and public health tool for dis-
ease detection and prevention.8,9So far, however, few human
genome discoveries have led to evidence-based applications
for medicine and public health.4Moving scientific discoveries
into practice and the delivery of population-level health bene-
fit have always been slow and difficult at best. In a study of the
“natural history” of promising therapeutic or prevention in-
terventions over a 15-year period, Contopolous-Ioannidis et
al. showed that only 5% of “highly promising” basic science
findings were licensed for clinical use and only 1% were actu-
ally used for the licensed indication.10In 2003, Lenfant la-
mented that basic sciences and clinical research findings are
usually “lost in translation.”11He observed that 15 years after
successful clinical trials on ?-blockers for patients recovering
From the National Office of Public Health Genomics Centers for Disease Control and Pre-
vention, Atlanta, Georgia.
for Health Promotion, Centers for Disease Control and Prevention, 4770 Buford Highway,
Mail Stop K89, Atlanta, GA 30341. E-mail: email@example.com.
The findings and conclusions in this report are those of the authors and do not necessarily
represent the views of the US Department of Health and Human Services.
Disclosure: The authors declare no conflict of interest.
Submitted for publication May 16, 2007.
Accepted for publication July 9, 2007.
October 2007 ? Vol. 9 ? No. 10
r e v i e w
Genetics IN Medicine
for only 62% of patients. Furthermore, years after aspirin was
shown to be beneficial for treating unstable angina and for
secondary prevention of myocardial infarction, it was pre-
scribed for only one third of eligible patients.11Renewed calls
for enhancing the “translation” research enterprise have re-
cently emerged from the National Institutes of Health as part
of the Roadmap initiative,12as well as from the clinical, aca-
demic, and public health sectors.2,13–17Nearly all of these pro-
posals highlight the role of multidisciplinary research through
enhanced collaboration among researchers in the basic sci-
ences, clinical medicine, and public health.2,13–17
In this manuscript, we briefly review the continuum of
translation research that has been proposed for other areas of
medicine and public health and apply it to genomic medicine.
We propose a simple framework that classifies translation re-
search in genomics into four types or phases of multidisci-
plinary research, and we offer examples. We show that only a
small proportion of human genomics research has progressed
from gene discovery to an evidence-based health application
that has been effectively integrated into practice and has dem-
onstrated health impact, mostly in the realm of classical Men-
delian disorders. Recent findings from genome-wide associa-
tion studies will open the door in the near future to more
genomic applications for common complex disorders. For the
and gene-environment interactions. Although the ideas pre-
sented here are not unique, they have not been discussed pre-
viously in relation to genomic medicine. We hope that this
discussion provides a useful agenda for translating human
genomics from the “bench” to improved health outcomes for
individuals and populations.
THE FOUR PHASES OF TRANSLATION RESEARCH IN
Numerous terms have been used to describe parts of the
translation research enterprise, including outcomes research,
clinical research, and health services research13–19—so many,
in fact, that Kerner et al. commented, “the frequent use of the
terms translational research and research translation contrib-
utes to considerable confusion as to what is being done for
whom.”20Many basic scientists believe that translation re-
search means taking new discoveries from the laboratory to
develop applications (primarily drugs) for study in human
clinical trials.21–23Conversely, public health agencies tend to
view translation research as focusing on building the evidence
base for integration of applications into practice and demon-
strating health impact at the population level.24To distinguish
into clinical application) and “Type 2” (clinical application to
evidence-based practice guidelines).2,25Recently, Westfall et
al.2proposed that the evaluation of interventions in practice
can be called “Type 3 translation research.” To adapt this
framework to research translation in genomics, we prefer the
human genome epidemiology (HuGE)26and genetic test eval-
uation frameworks.27In this manuscript, we describe the gen-
eral characteristics and types of research at each phase and
provide examples (Table 1, Fig. 1). We recap definitions of
some translation research terms (Table 2), and in Table 3, we
summarize publication trends of human genetics and genom-
ics translation research from 2001 to 2006. We recognize that,
although the four phases of translation research can be viewed
phase can be overlapping or similar to research conducted in
T1 RESEARCH: FROM GENE DISCOVERY TO
CANDIDATE HEALTH APPLICATIONS
Gene discovery is the goal of most contemporary human
genomic research. Since the completion of the Human Ge-
The continuum of translation research in human genetics: types of research and examples
research phaseNotationTypes of researchExamples
TIDiscovery to candidate health
Phases I and II clinical trials; observational
Is there an association between BRCA
mutations and breast cancer?
T2Health application to evidence-based
Phase III clinical trials; observational
studies; evidence synthesis and
What is the positive predictive value
of BRCA mutations in at-risk
T3 Practice guidelines to health practiceDissemination research; implementation
research; diffusion research Phase IV
What proportion of women who meet
the family history criteria are tested
for BRCA and what are the barriers
T4Practice to population health impact Outcomes research (includes many
disciplines); population monitoring of
morbidity, mortality, benefits, and risks
Does BRCA testing in asymptomatic
women reduce breast cancer
incidence or improve outcomes?
Khoury et al.
Genetics IN Medicine
nome Project, many new methods and tools for identifying
disease susceptibility genes have become available, including
haplotype-tagging single nucleotide polymorphisms based on
the HapMap project28and high-throughput technologies that
allow examination of hundreds of thousands of genetic vari-
ants.5Collective efforts, including research networks, consor-
scale human population studies.
T1 research in genomics starts after gene discovery and has
as its goal the development of a candidate application to be
used in clinical and public health practice. In general, such
predictive testing, screening, diagnostic testing, prognostic
testing) or in the selection of the most effective therapeutic
options. Currently, genetic tests are used primarily for the di-
Increasingly, genetic tests are being developed for predicting
therapy (pharmacogenomics),33and developing prognostic
indicators for treatment of cancer and other diseases.34Family
test to identify individuals and families at risk for future dis-
ease.9Pharmacogenomics is an important source of new ge-
netic applications in health practice, such as the cytochrome
drugs for treating clinical depression and other disorders.35,36
In addition, therapeutic applications include drugs that use
genetic information to better target specific diseases—for ex-
ample, the use of Herceptin for treatment of breast cancer.37
The translation research pathway for therapeutics is relatively
straightforward, progressing from Phase I through Phase IV
clinical trials and will not be covered in depth here (Table 2).
However, the pathway is less clear for genetic tests, especially
because most genetic tests are still laboratory-developed (i.e.,
“home brew”) and, therefore, not regulated by the Food and
is often cited as an indicator for screening or intervention in
professional practice guidelines, there is no agreed-upon defi-
nition of family medical history or clear criteria that can be
used as an indication for screening that might deviate from
and clinical trials (Table 1). We have developed two research
by such studies: (1) human genome epidemiology26and (2) a
vational, population-based research that measures the fre-
quency distributions of alleles and genotypes in human popu-
lations, correlates genotypes with phenotypes, estimates
disease risks associated with human genetic variants, and as-
sesses gene-gene and gene-environment interactions.26This
sensitivity, specificity, and predictive values) of a diagnostic or
predictive genetic test. Currently, most published translation
research in human genomics is in the HuGE category, which
accounts for about 6% of all published articles, most of which
is devoted to adult common chronic diseases (Table 3). A ma-
gridlock—is the proliferation of small studies with inconsis-
tent results that fail to replicate initially promising find-
ings.38,39In collaboration with several journals, the Human
Genome Epidemiology Network40promotes collaborative ef-
of genetic associations; this approach can help evaluate the
robustness of such associations and arrive at more precise es-
timates of risk (HuGE reviews).41More than 500 meta-analy-
ses (including HuGE reviews) of gene-disease associations
have been published within the past 6 years.42
An important limitation of current T1 research is that it has
tended to reduce the genome to single genes/variants and has
focused on a tiny portion of genomic variation, potentially
Health Application Guideline
From Health Application From Guideline
Phase I Phase III
legal, and social issues. See text and Table 2 for definitions.
The continuum of translation research in genomic medicine. HuGE, human genome epidemiology; ACCE, analytic validity, clinical validity, clinical utility, ethical,
Continuum of translation research in genomic medicine
October 2007 ? Vol. 9 ? No. 10
missing the value of looking across the genome. Hence, an
undue emphasis on meta-analyses of published candidate
genes studies may miss the currently emerging data in high
current approaches have to be supplemented with genome-
wide approaches involving systems biology in large-scale well-
conducted epidemiologic studies.
An important application of HuGE research is for the eval-
discussed below). An emerging example of T1 research is the
construction of “genomic profiles” (e.g., “cardiogenomic”
profile, “osteogenomic” profile), testing combinations of ge-
potentially guide interventions.44Although most genomic
profiles are considered far from ready for clinical use,45some
companies have already developed and marketed them (in
some cases, directly to consumers) for use in disease preven-
tion and health promotion. Janssens et al. (personal commu-
that exist in this area. They examined genomic profiles mar-
least 73 different polymorphisms in 56 genes. No meta-analy-
and meta-analysis results were statistically significant for only
one third of the remainder, most finding relatively modest as-
sociations (odds ratios between 1 and 2) (Janssens et al., per-
sonal communication). A further limitation to the use of
genomic profiling is that meta-analysis of data on individual
the complex interaction between genetic variants and gene-
environment interactions. Paradigms for how to synthesize
this more complex information for health practice are only
random genetic markers from those used to establish func-
tional effects of individual identified variants. Of course, the
latter currently numbers no more than 50–100 variants. The
idea of testing (combinations or large panels of) markers is
inherently different (discovery tools) than testing functional
T2 RESEARCH: FROM HEALTH APPLICATION TO
The development and evaluation of genomic applications
for use in practice is a challenging and mostly unregulated
process. Government advisory groups have spelled out the
need for thorough evaluation of tests and development of evi-
dence-based guidelines for their use.32,46In 1997, the Task
evaluation of genetic tests based on the assessment of analytic
Secretary’s Advisory Committee on Genetic Testing added an
Glossary of certain types of “translation research” involving multiple
Many types of basic research efforts are needed to move a basic genome
discovery to a potential health application. Here we highlight only
those that involve observational or clinical trial studies in humans
Human genome epidemiology26
Research on prevalence of genetic risk factors, gene-disease
associations, and gene-gene and gene-environment interactions in
human populations to quantify contribution of genetic factors to
human diseases and magnitude of risks
Genetic test evaluation (ACCE components)27
A: Analytic validity. Research to measure the ability to accurately and
reliably measure the genotype of interest. The four main elements of
analytic validity include analytic sensitivity (or the analytic detection
rate), analytic specificity (or 1- the analytic false positive rate),
laboratory quality control, and assay robustness
C: Clinical validity. Research to measure the test’s ability to detect or
predict the associated disorder (phenotype)
C: Clinical utility. Research to define the risks and benefits associated
with a test’s introduction into practice. Specifically, clinical utility
focuses on the health outcomes (both positive and negative)
associated with testing
E: Ethical, legal, and social issues (some view this component as part of
clinical utility). Research to assess concerns specific to genetic
information, such as implications for relatives of the person
undergoing testing, the possibility of insurance discrimination, and
stigmatization based on genotype
Phase I: Research on a new drug or treatment in a small group of
people (20–80) for the first time to evaluate its safety, determine a
safe dosage range, and identify side effects
Phase II: The study drug or treatment is given to a larger group of
people (100–300) to see whether it is effective and to further evaluate
Phase III: The study drug or treatment is given to large groups of people
(1000–3000) to confirm its effectiveness, monitor side effects,
compare it to commonly used treatments, and collect information
that will allow the drug or treatment to be used safely
Phase IV: The postmarketing studies delineate additional information,
including the drug’s risks, benefits, and optimal use
Dissemination research: Systematic study of how the targeted distribution
of information and intervention materials to a specific health
audience can be successfully executed so that increased spread of
knowledge about the evidence-based interventions achieves greater
use and impact of the intervention24
Implementation research: Systematic study of how a specific set of
activities and designed strategies are used to successfully integrate an
evidence-based intervention within specific settings (e.g., primary
care clinic, community center, school)24
Diffusion research: Systematic study of the factors necessary for successful
adoption by stakeholders and the targeted population of an evidence-
based intervention that results in widespread use and specifically
includes the uptake of new practices or the penetration of broad-
scale recommendations through dissemination and implementation
efforts, marketing, laws and regulations, systems-research, and
Outcomes research: Research that describes, interprets, and predicts the
impact of various influences, especially (but not exclusively)
interventions on “final” endpoints that matter to decision makers.
Decision makers may include patients, families, individuals at risk,
provider, private and public payers, and so forth18
Khoury et al.
Genetics IN Medicine
sented by the acronym ACCE (for analytic validity; clinical
validity; clinical utility; and ethical, legal, and social implica-
tions).32This type of evaluation depends on research in multi-
ple disciplines, including clinical medicine, laboratory sci-
ences, economics, public health, ethics, and behavioral and
social sciences. The ACCE model project, sponsored by the
a framework for evaluation that incorporates the four pro-
posed components of evaluation to address T2 research. The
ACCE project has been discussed extensively elsewhere27,49
(Appendix); here, we summarize it only briefly.
The translation of a genetic test from research into practice
starts with identification of the disorder (or pharmacogenetic
effect) tested for, the specific test to be used, and the clinical
scenario in which the test will be used (e.g., diagnosis versus
predictive, population to be tested). A test must be evaluated
for each clinical application or intended use. Evaluation often
begins with establishment of analytic performance character-
relevant data are rarely published. Once a test is in use, addi-
tional data can sometimes be collected through proficiency-
Genetics.50Clinical validity is usually established in observa-
tional studies of genotype-phenotype association (which we
describe as T1 research); when correctly designed and con-
ducted, such studies can be used to estimate the clinical sensi-
tivity and specificity of a genetic test and—if the study is pop-
ulation-based—its positive and negative predictive value.
Genetic tests used to guide therapy (i.e., pharmacogenetic
tests) also may be evaluated in clinical trials (Table 2). In gen-
eral, T2 research on genetic tests begins once analytic validity
has been established and the early results of clinical validity
look promising to test developers.
T2 research—which for now is largely focused on the trans-
lation of new genetic tests, but may include family health his-
clinical utility of testing in the context of a wide range of ethi-
cal, legal, and social issues. The end result of such research is
systematic review and synthesis that will support the develop-
ment of evidence-based practice guidelines. This research
phase can take a long time, especially for rare genetic diseases,
for which it is difficult to accumulate and synthesize the evi-
dence. Currently, most T2 research in human genomics is in-
research publications in this field have been classified by the
National Library of Medicine (in PubMed) as reports of clini-
cal trials, most of which are not randomized trials. During the
same time period, only 0.5% of human genetic studies were
Library of Medicine listed 163 “guidelines” in human genetics
Guidelines on several genetic tests have been issued by diverse
groups, including professional societies, ad hoc consensus
groups, government agencies, and advocacy organizations. Of
course, the process of guideline development is not standard-
ized, and many guidelines are developed on the basis of expert
opinion, often in the absence of complete information. One
Task Force (USPSTF) hosted by the Agency for Health Care
Research and Quality.51,52From 2001 to 2006, the USPSTF
one on population- and risk-based testing for hereditary
hemochromatosis (HHC)53and one on BRCA1/2 testing for
hereditary breast and ovarian cancers.54To respond to the
need for evidence-based guideline development in genomics,
CDC launched in 2004 the Evaluation of Genomic Applica-
Numbers of publications related to human genetics and genomics, observational studies, clinical trials, practice guidelines, and research on genetic tests,
200154,521 2,398942 25119
200255,452 3,147 92721 213
200358,813 3,4601,242 23311
200463,251 4,3301,341 34379
200566,945 5,2431,586 26491
2006 64,1875,497 1,578 34462
Total363,169 24,0757,616 1631,975
Percentage 1006.62.10.04 0.5
aQuery conducted on PubMed April 16, 2007,47on genetics and genomics (limited to humans). Special online checkboxes were used to identify clinical trials and
practice guidelines using National Library of Medicine criteria without further review by the authors.
Continuum of translation research in genomic medicine
October 2007 ? Vol. 9 ? No. 10
tions in Practice and Prevention initiative, which is currently
based recommendations on seven genomic applications for
HHC, which is a useful example for illustrating the contin-
uum of T1 and T2 research, is the most common form of he-
reditary iron overload disease in the United States.56The HFE
gene and two common point mutations associated with HHC
on the value of population genetic screening for this disease,
in reducing the risk of adverse health outcomes.57Soon after
and promoted for use. During 1997, CDC and the National
Human Genome Research Institute jointly sponsored an ex-
for early detection of HHC. The panel concluded that popula-
tion screening for mutations in HFE could not be recom-
disease (especially age-related penetrance), optimal care for
asymptomatic persons who are found to carry mutations, and
the psychosocial and societal impact of genetic testing.58
Publication of the workshop report was followed by several
years of extensive T1 and T2 research. For example, a popula-
tion-based, nationwide survey established that almost 5% of
the United States’ non-Hispanic, white population was ho-
mozygous or compound heterozygous for the C282Y and
H63D mutations.59However, epidemiologic analysis of the
burden of disease using hospital records60and death certifi-
cates61found that the prevalence of diagnosed disease is much
association of HFE mutations with the risk of clinical disease
showed that homozygosity for the C282Y mutation was asso-
ciated with the highest risk of HHC, whereas risks associated
with other genotypes, including C282Y/H63D and H63D/
H63D, were much lower.62A large National Institutes of
Health-funded cohort study in the Kaiser Permanente South-
ern California health care network suggested that disease pen-
etrance for HFE mutations may be quite low63: only 1 of the
152 subjects who were homozygous for C282Y had HHC
in 2006 to recommend against routine population genetic
screening for hemochromatosis.53Thus, 10 years after the dis-
covery of the HFE gene and its mutations, intensive T1 and T2
research studies led to an evidence-based recommendation
against population genetic screening for HHC.
Lastly, family medical history tools have been evaluated
as a type of predictive test using the ACCE framework.9
Family history criteria (e.g., number of affected relatives,
age at disease onset) are being examined for their associa-
tion with common diseases and their ability to predict fu-
ture disease.64,65These criteria are then included in risk as-
sessment schemes or family history tools developed to
identify people at increased risk for common diseases such
as heart disease, diabetes, and cancer.9,66
T3 RESEARCH: FROM EVIDENCE-BASED GUIDELINES
TO HEALTH PRACTICE
one of the most challenging problems in health care and dis-
ease prevention. The Institute of Medicine focused on this
problem in its report “Crossing the Chasm: A New Health
of effective implementation and diffusion of proven health
care interventions.67This gap is especially problematic in pre-
ventive medicine, which is a growing focus of genomic re-
search.68Despite extensive public health research on the effi-
cacy and effectiveness of health promotion and disease
prevention strategies, methods for disseminating these inter-
ventions and encouraging their implementation and wide-
spread adoption are not well developed or evaluated.69T3 re-
search addresses such issues as increasing the spread of
knowledge about evidence-based interventions (dissemina-
tion research), integrating these interventions into existing
programs and structures (implementation research), and
widespread adoption of these interventions by stakeholders
(diffusion research)24(Table 2).
ics for public health, William Foege, a prominent public health
leader, expressed concern that genetics could exacerbate health
and not for all society.”70Policymakers, funding agencies, and
researchers are beginning to recognize the need for a translation
adigm.2,22,24Some people have called for public-private collabo-
rations to support this T3 research agenda, which has until now
workforce training, public health literacy, information systems,
throughout our health care system, are likely to worsen as new
Currently, few genetic and genomic applications are ready for
implementation in routine clinical practice. A notable exception
is breast cancer susceptibility gene (BRCA) mutation testing for
predicting breast and ovarian cancers, for which the USPSTF is-
sued two evidence-based recommendations during 2005.54First,
counseling or routine breast cancer susceptibility gene (BRCA)
testing for women whose family history is not associated with an
bility gene 1 (BRCA1) or breast cancer susceptibility gene 2
(BRCA2).” However, the USPSTF also recommended that
for deleterious mutations in BRCA1 or BRCA2 genes be referred
for genetic counseling and evaluation for BRCA testing.”54It is
noteworthy that in this particular guideline, the USPSTF spelled
Khoury et al.
Genetics IN Medicine
out clearly what family history criteria warranted the referral for
The story of BRCA1 illustrates the complex character of
translation research. Discovered in 1994, BRCA1 was the first
major susceptibility gene to be linked to a common disease. A
gene patent application was filed the same year, and a genetic
test became commercially available in 1996. T1 research was
conducted largely by the corporate laboratory holding the
patent, and the data are proprietary.71T2 research is unfin-
the USPSTF observed that “no data describe the range of risk
associated with BRCA [BRCA1 and BRCA2] mutations, ge-
netic heterogeneity, and moderating factors; studies con-
ducted in highly selected populations contain biases; and in-
formation on adverse effects is incomplete.”72T3 research
studies have been published in relation to various recommen-
dations for screening, counseling, and treatment for women
with these mutations.73During 2003, a pilot direct-to-con-
sumer marketing campaign for BRCA1 and BRCA2 testing
provided an opportunity to study diffusion of knowledge (al-
though not evidence-based guidelines).74A survey of approx-
imately 1000 randomly selected family physicians, internists,
obstetrician-gynecologists, and oncologists found that their
knowledge of genetic testing for susceptibility to breast and
city that received the pilot marketing campaign; however,
guidelines were significantly more knowledgeable than the
other health professionals in the survey.75Other controlled
clinical trials have reported on enhancing patient education
and information about options for genetic testing for breast
and ovarian cancers using various forms of decision aids.76–79
Kerner et al. points out that most dissemination research is
“conducted in the relatively resource-rich infrastructures of
How findings of such studies might apply to other popula-
tions—especially underserved populations—is largely un-
known. Westfall et al. identified several major challenges to
research in this area, including the heterogeneous character of
primary care; the lack of successful models for collaboration
among academic researchers, community physicians, and pa-
tients; and “the failure of the academic research enterprise to
research has focused largely on individual behavior change by
health care providers and patients, although, as McBride has
observed, “three decades of research in developing and testing
behavior-change interventions for risk reduction tell us it is
unlikely that a genetic test result alone will prompt behavior
change.”80Translation research also must address the integra-
tion of genetic testing with existing, evidence-based interven-
tions in specific settings (implementation research). Perhaps
systems (diffusion research), addressing such factors as the in-
fluence of marketing, laws and regulations, and policymaking
by professional organizations, insurers, and other stakeholder
groups. T3 research is inherently nonlinear, requiring wide-
ranging excursions down the collateral networks of the “blue
fer of genetic knowledge among individuals, providers, health
care systems, and the public health community.2T3 research
points to the complexities of compliance and education that
can ultimately affect the clinical utility of a genetic test in the
“real” world as opposed to the inherent clinical utility of the
test done under ideal scenarios of controlled clinical trials.
T4 RESEARCH: FROM PRACTICE TO POPULATION
tion of evidence-based recommendations and guidelines can
make an impact on real-world health outcomes. A workshop
sponsored by the National Cancer Institute suggested a broad
definition of “outcomes research” as that which “describes,
interprets and predicts the impact of various influences, espe-
cially (but not exclusively) interventions of ‘final’ endpoints
that matter to decision makers. The decision makers may in-
clude patients, families, individuals at risk, providers, private
and public payers and purchasers, regulatory agencies, health
care accrediting organizations, and society at large.”18In this
health outcomes as T4 research to distinguish it from research
focused on implementation processes (T3), although the two
which they label “macro,” “meso,” and “micro.”18For exam-
veillance of disease incidence, morbidity and mortality, and
by geographic and demographic categories. Meso-level out-
comes research includes clinical decision modeling and cost-
effectiveness analysis as well as studies monitoring quality of
care. Micro-level outcomes research examines individual in-
benefits outside the context of randomized clinical trials.18
We use newborn screening as an example to illustrate T4
research. In the United States, state-mandated programs have
tested all newborns for genetic conditions for several de-
cades.81This system has been increasingly under pressure as
states consider the addition of dozens of new “conditions” to
(tandem mass spectrometry [MS/MS]), make it technically
straightforward to do so.82A case in point is newborn screen-
ing for medium-chain acyl-CoA dehydrogenase deficiency
(MCADD), a disorder of fatty acid metabolism, for which the
impact of early detection has been debated.83A systematic re-
view and decision analysis that compared newborn screening
“screening consumes more resources than no screening but
They studied almost 2.5 million children born in Australia be-
tween 1994 and 2004; approximately one third of these chil-
Continuum of translation research in genomic medicine
October 2007 ? Vol. 9 ? No. 10
dren were screened for MCADD at 2–3 days of age. The study
found a clear reduction in mortality among children in the
screened group (4%) compared with children who were diag-
nosed through clinical presentation or after diagnosis of a sib-
ling (17%). Ideally, studies establishing the utility of an inter-
vention should be conducted and evidence-based guidelines
ing data collection and analysis can be valuable for filling in
We have presented an overarching framework for transla-
tion research for moving promising genomic applications to
clinical and public health practice for population health bene-
fit. We have discussed some types of research needed during
evidence-based guidelines. Although it is difficult to estimate
how many genetic studies examined in T1 research will be
sufficiently promising to be considered for further develop-
in this field so far focuses on T2 research and beyond. Indeed,
evidence-based guidelines and T3 and T4 research are very
rare. We urge government, academia, industry, public health,
and community groups to join forces in guiding the genomics
research translation enterprise, making optimum use of blue
highways (not just the fast lane) and avoiding the “myriad
al. cautioned against.2
Translation research questions related to the evaluation of genetic tests under the ACCE framework27
ElementComponent Specific question
Disorder/Setting1. What is the specific clinical disorder to be studied?
2. What are the clinical findings defining this disorder?
3. What is the clinical setting in which the test is to be performed?
4. What DNA test(s) are associated with this disorder?
5. Are preliminary screening questions employed?
6. Is it a stand-alone test or is it one of a series of tests?
7. If it is part of a series of screening tests, are all tests performed in all instances (parallel) or are only some
tests performed on the basis of other results (series)?
Analytic validity Sensitivity8. Is the test qualitative or quantitative?
9. How often is the test positive when a mutation is present?
Specificity 10. How often is the test negative when a mutation is not present?
11. Is an internal quality control program defined and externally monitored?
12. Have repeated measurements been made on specimens?
13. What is the within- and between-laboratory precision?
14. If appropriate, how is confirmatory testing performed to resolve false-positive results in a timely manner?
15. What range of patient specimens has been tested?
16. How often does the test fail to give a useable result?
17. How similar are results obtained in multiple laboratories using the same, or different technology?
Clinical validitySensitivity18. How often is the test positive when the disorder is present?
Specificity 19. How often is the test negative when a disorder is not present?
20. Are there methods to resolve clinical false-positive results in a timely manner?
Prevalence 21. What is the prevalence of the disorder in this setting?
22. Has the test been adequately validated on all populations to which it may be offered?
23. What are the positive and negative predictive values?
24. What are the genotype/phenotype relationships?
25. What are the genetic, environmental, or other modifiers?
Clinical utilityIntervention 26. What is the natural history of the disorder?
Intervention 27. What is the impact of a positive (or negative) test on patient care?
Intervention 28. If applicable, are diagnostic tests available?
Intervention 29. Is there an effective remedy, acceptable action, or other measurable benefit?
Khoury et al.
Genetics IN Medicine
1. Zerhouni E. National Institutes of Health (NIH) press release. NIH seeks input on
proposed repository for genetic information. August 30, 2006. Available at: http://
www.nih.gov/news/pr/aug2006/od-30.htm Accessed September 1, 2006.
road map. JAMA 2007;297:403–406.
Guttmacher AE, Collins FS. Realizing the promise of genomics in biomedical re-
search. JAMA 2005;294:1399–1404.
Burke W, Khoury MJ, Stewart A, Zimmern R. The path from genome-based re-
search to population health: development of an international public health genom-
ics network. Genet Med 2006;8:451–458.
Christensen K, Murray JC. What genome wide association studies can do for med-
icine. N Engl J Med 2007;356:1094–1097.
and private sectors working in partnership to improve the public health. Oncologist
Pagon RA. GeneTests: an online genetic information resource for health care pro-
viders. J Med Libr Assoc 2006;94:343–348.
Guttmacher AE, Collins FS, Carmona R. The family history: more important than
ever. N Engl J Med 2004;351:2333–2336.
Yoon PA, Scheuner MT, Khoury MJ. Research priorities for the evaluation of family
Contopolous-Ioannidis JP, Ntzani E, Ioannidis JP. Translation of highly promising
basic science research into clinical applications. Am J Med 2003;114:477–484.
N Engl J Med 2003;349:868–874.
Zerhouni EA. The NIH Roadmap. Science 2003;302:63–72.
Crowley WF Jr, Sherwood L, Salber P, Scheinberg D, et al. Clinical research in the
United States at a crossroads: proposal for a novel public-private partnership to
establish a national clinical research enterprise. JAMA 2004;291:1120–1126.
Sung NS, Crowley WF Jr, Genel M, Salber P, et al. Central challenges facing the
national clinical research enterprise. JAMA 2003;289:1278–1287.
Kerner JF, Guirguis-Blake J, Hennessey KD, Brounstein PJ, et al. Translating re-
search into improved outcomes in comprehensive cancer control. Cancer Causes
Control 2005;16(suppl 1):27–40.
Jones L, Wells K. Strategies for academic and clinician engagement in community-
participatory partnered research. JAMA 2007;297:407–410.
Lipscomb J, Donaldson MS, Hiatt RA. Cancer outcomes research and the arenas of
application. J Natl Cancer Inst Monogr 2004;33:1–7.
J Natl Cancer Inst Monograph 2004;33:178–197.
how can we close the gap? Health Psychol 2005;24:443–446.
Horig H, Marincola E, Marincola FM. Obstacles and opportunities in translation
research. Nat Med 2005;11:705–708.
Sonntag KC. Implementations of translational medicine. J Trans Med 2005;3:33.
Webb CP, Pass HI. Translation research: from accurate diagnosis to appropriate
treatment. J Trans Med 2004;2:35.
Centers for Disease Control and Prevention. Improving public health practice
through translation research (R18). Request for application. Available at: http://
www.cdc.gov/od/pgo/funding/CD07-005.htm#SectionII Accessed July 1, 2007.
Rohrbach LA, Grana R, Sussman S, Valente TW. Type II translation: transporting
Khoury MJ, Little J, Burke W. Human genome epidemiology: scope and strategies.
strategies. New York: Oxford University Press, 2004:13–16.
Haddow JE, Palomaki GE. A model process for the evaluating data on emerging
genetic tests. In: Khoury MJ, Little J, Burke W, editors. Human genome epidemiol-
ogy: scope and strategies. New York: Oxford University Press, 2004:217–233.
International HapMap Consortium. A haplotype map of the human genome. Na-
Hoover RN. The evolution of epidemiologic research: from cottage industry to big
science. Epidemiology 2007;18:13–17.
Seminara D, Khoury MJ, O’Brien TR, Manolio T, et al. The emergence of networks in
Public Population Project in Genomics (P3G). Available at: http://www.
tests. 2000. Available at: http://www4.od.nih.gov/oba/sacgt/reports/oversight_report.
Lyman GH, Kuderer NM. Gene expression profile assays as predictors of recur-
rence-free survival in early-stage breast cancer: a metaanalysis. Clin Breast Cancer
Agency for Healthcare Quality Research. Testing for cytochrome P450 polymor-
phisms (CYP450) in adults with non-psychotic depression prior to treatment with
gov/clinic/tp/cyp450tp.htm Accessed April 18, 2007.
Black JL 3rd, O’Kane DJ, Mrazek DA. The impact of CYP allelic variation on anti-
depressant metabolism: a review. Expert Opin Drug Metab Toxicol 2007;3:21–31.
Colozza M, De Azambuja E, Personeni N, Lebrun F, et al. Achievements in systemic
Intervention30. Is there general access to that remedy or action?
31. Is the test being offered to a socially vulnerable population?
Quality assurance32. What quality assurance measures are in place?
Pilot trials33. What are the results of pilot trials?
Health risks 34. What health risks can be identified for follow-up testing and/or intervention?
35. What are the financial costs associated with testing?
Economic36. What are the economic benefits associated with actions resulting from testing?
Facilities 37. What facilities/personnel are available or easily put in place?
Education 38. What educational materials have been developed and validated and which of these are available?
39. Are there informed consent requirements?
Monitoring40. What methods exist for long-term monitoring?
41. What guidelines have been developed for evaluating program performance?
ELSIImpediments42. What is known about stigmatization, discrimination, privacy/confidentiality, and personal/family social issues?
43. Are there legal issues regarding consent, ownership of data and/or samples, patents, licensing, proprietary
testing, obligation to disclose, or reporting requirements?
Safeguards44. What safeguards have been described and are these safeguards in place and effective?
Continuum of translation research in genomic medicine
October 2007 ? Vol. 9 ? No. 10
38. Bracken MB. Genomic epidemiology of complex disease: the need for an electronic Download full-text
evidence-based approach to research synthesis. Am J Epidemiol 2006;162:297–301.
Lohmueller KE, Pierce CL, Pike M, Lander ES, et al. Meta-analysis of genetic asso-
ciation studies supports a contribution of common variants to susceptibility to
common disease. Nat Genet 2003;33:177–182.
Centers for Disease Control and Prevention. Human Genome Epidemiology Net-
Accessed May 7, 2007.
thing HuGE. Am J Epidemiol 2000;151:2–3.
Lin B, Clyne M, Walsh M, Gomez O, et al. Tracking the epidemiology of human
genes in the literature: the HuGE published literature database. Am J Epidemiol
Wikipedia. The free encyclopedia. Clinical trial. Available at: http://en.wikipedia.
org/wiki/Clinical_trial Accessed April 18, 2007.
Eur J Epidemiol 2006;21:869–870.
prime time. Nat Genet 2003;34:347–350.
Holtzman NA, Watson M, editors. Promoting safe and effective genetic testing in
the United States: recommendations of the NIH-DOE task force on genetic testing
1997. Available at: http://www.genome.gov/10001733 Accessed July 1, 2007.
entrez/query.fcgi Accessed April 16, 2007.
Centers for Disease Control and Prevention. Genomics and Disease Prevention Infor-
mation System. Available at: http://apps.nccd.cdc.gov/genomics/GDPQueryTool/
Centers for Disease Control and Prevention. ACCE. Available at: http://www.cdc.
gov/genomics/gtesting/ACCE.htm Accessed April 17, 2007.
genetics. Clin Chem 2003;49:717–718.
Agency for Healthcare Research and Quality. U.S. Preventive Services Task Force.
Available at: http://www.ahrq.gov/clinic/uspstfix.htm Accessed May 7, 2007.
Whitlock EP, Garlitz BA, Harris EL, Beil TL, et al. Screening for hereditary hemo-
chromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann
Intern Med 2006;145:209–223.
U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation
testing for breast and ovarian cancer susceptibility. 2005. Available at: http://www.
ahrq.gov/clinic/uspstf/uspsbrgen.htm Accessed April 20, 2007.
Centers for Disease Control and Prevention. Evaluation of genomic applications in
practice and prevention (EGAPP). Available at: http://www.egappreviews.org/ Ac-
cessed May 7, 2007.
Waalen J, Beutler E. Hereditary hemochromatosis. Screening and management.
Curr Hematol Rep 2006;5:34–40.
Collins FS. Keynote speech at the Second National Conference on Genetics and
Public Health. Baltimore, MD, December 8–11, 1999. Atlanta: Office of Genetics
and Disease Prevention, 2000. Available at: http://www.cdc.gov/genomics/info/
conference/intro.htm Accessed July 1, 2007.
Burke W, Thomson E, Khoury MJ, McDonnell SM, et al. Hereditary hemochroma-
tosis: gene discovery and its implications for population-based screening. JAMA
Steinberg KK, Cogswell ME, Chang JC, Caudill SP, et al. Prevalence of C282Y and
H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA
Brown AS, Gwinn M, Cogswell ME, Khoury MJ. Hemochromatosis-associated
morbidity in the United States: an analysis of the National Hospital Discharge Sur-
vey, 1979–1997. Gene Med 2001;3:109–111.
Yang A, McDonnel SM, Khoury MJ, Cono J, et al. Hemochromatosis-associated
mortality in the United States from 1979 to 1992: an analysis of multiple-cause
mortality data. Ann Intern Med 1998;129:946–953.
63. Beutler E, Felitti VJ, Koziol JA, Ho NJ, et al. Penetrance of 845G3A (C282Y) HFE
hereditary haemochromatosis mutation in the USA. Lancet 2002;359:211–218.
Williams RR, Hunt SC, Heiss G, Province MA, et al. Usefulness of cardiovascular
family history data for population-based preventive medicine and medical research
(the Health Family Tree Study and the NHLBI Family Heart Study). Am J Cardiol
Scheuner MT, Whitworth WC, McGruder H, Yoon PW, et al. Expanding the defi-
nition of a positive family history for early-onset coronary heart disease. Genet Med
Centers for Disease Control and Prevention. Family history Web site. Available at:
http://www.cdc.gov/genomics/activities/famhx.htm Accessed May 7, 2007.
Institute of Medicine. Crossing the quality chasm: a new health system for the 21st
century. 2001. Available at: http://www.iom.edu/CMS/8089/5432/27184.aspx Ac-
cessed April 18, 2007.
Johnson JL, Green LW, Frankish CJ, MacLean DR, et al. A dissemination research
agenda to strengthen health promotion and disease prevention. Can J Public Health
Oldenburg BF, Sallis JF, French ML, Owen N. Health promotion research and the dif-
Foege W. How to effect change in the population. In: Institute of medicine. Impli-
cations of genomics for public health: a workshop summary. Washington, DC:
National Academy Press, 2005:25–27.
Centers for Disease Control and Prevention. ACCE review on BRCA1. Available at:
http://www.cdc.gov/genomics/gtesting/ACCE/fbr.htm Accessed May 7, 2007.
testing for breast and ovarian cancer susceptibility: systematic evidence review for the
Kutner SE. Breast cancer genetics and managed care: the Kaiser Permanente expe-
rience. Cancer 1999;86(suppl 11):2570–2574.
Mouchawar J, Hensley-Alford S, Laurion S, Ellis J, et al. Impact of direct-to-consumer
advertising for hereditary breast cancer testing on genetic services at a managed care
Myers MM, Chang MH, Jorgensen C, Whitworth W, et al. Genetic testing for sus-
ceptibility to breast and ovarian cancer: evaluating the impact of a direct-to-con-
sumer marketing campaign on physicians’ knowledge and practices. Genet Med
risk. Breast Cancer Res Treat 2007;Feb 27 [epub ahead of print].
sion aid on knowledge, perceptions, and intentions about genetic testing for breast
for women at increased risk of ovarian cancer. Med Decis Making 2006;26:360–372.
Lerman C, Bieseker B, Benkendorff JL, Kerner J, et al. Controlled trial of pretest
education approaches to enhance informed decision-making for BRCA1 gene test-
ing. J Natl Cancer Inst 1997;89:148–157.
disease. Prev Chron Dis 2005;2:1–5.
Feuchtbaum L, Faulkner L, Verghese S. Tandem mass spectrometry program im-
plementation challenges for state newborn screening programs: national survey of
barriers and issues. Pediatrics 2006;117(5 pt 2):S253–S260.
Grosse SD, Khoury MJ, Greene CL, Crider KS, et al. The epidemiology of medium
chain acyl-CoA dehydrogenase deficiency: an update. Genet Med 2006;8:205–212.
Tran K, Banerjee S, Li H, Noorani HZ, et al. Clinical efficacy and cost-effectiveness
of newborn screening for medium chain acyl-CoA dehydrogenase deficiency using
tandem mass spectrometry. Clin Biochem 2007;40:235–241.
Wilcken B, Haas M, Joy P, Wiley V, et al. Outcome of neonatal screening for me-
dium chain acyl-CoA dehydrogenase deficiency in Australia: a cohort study. Lancet
Grosse SD, Dezateux C. Newborn screening for inherited metabolic disease. Lancet
Khoury et al.
Genetics IN Medicine