[House Hearing, 111 Congress]
[From the U.S. Government Publishing Office]
HOW CAN NIST BETTER
SERVE THE NEEDS OF
THE BIOMEDICAL RESEARCH
COMMUNITY IN THE 21ST CENTURY?
SUBCOMMITTEE ON TECHNOLOGY AND INNOVATION
COMMITTEE ON SCIENCE AND TECHNOLOGY
HOUSE OF REPRESENTATIVES
ONE HUNDRED ELEVENTH CONGRESS
FEBRUARY 24, 2010
Serial No. 111-79
Printed for the use of the Committee on Science and Technology
Available via the World Wide Web: http://www.science.house.gov
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COMMITTEE ON SCIENCE AND TECHNOLOGY
HON. BART GORDON, Tennessee, Chair
JERRY F. COSTELLO, Illinois RALPH M. HALL, Texas
EDDIE BERNICE JOHNSON, Texas F. JAMES SENSENBRENNER JR.,
LYNN C. WOOLSEY, California Wisconsin
DAVID WU, Oregon LAMAR S. SMITH, Texas
BRIAN BAIRD, Washington DANA ROHRABACHER, California
BRAD MILLER, North Carolina ROSCOE G. BARTLETT, Maryland
DANIEL LIPINSKI, Illinois VERNON J. EHLERS, Michigan
GABRIELLE GIFFORDS, Arizona FRANK D. LUCAS, Oklahoma
DONNA F. EDWARDS, Maryland JUDY BIGGERT, Illinois
MARCIA L. FUDGE, Ohio W. TODD AKIN, Missouri
BEN R. LUJAN, New Mexico RANDY NEUGEBAUER, Texas
PAUL D. TONKO, New York BOB INGLIS, South Carolina
STEVEN R. ROTHMAN, New Jersey MICHAEL T. MCCAUL, Texas
JIM MATHESON, Utah MARIO DIAZ-BALART, Florida
LINCOLN DAVIS, Tennessee BRIAN P. BILBRAY, California
BEN CHANDLER, Kentucky ADRIAN SMITH, Nebraska
RUSS CARNAHAN, Missouri PAUL C. BROUN, Georgia
BARON P. HILL, Indiana PETE OLSON, Texas
HARRY E. MITCHELL, Arizona
CHARLES A. WILSON, Ohio
KATHLEEN DAHLKEMPER, Pennsylvania
ALAN GRAYSON, Florida
SUZANNE M. KOSMAS, Florida
GARY C. PETERS, Michigan
JOHN GARAMENDI, California
Subcommittee on Technology and Innovation
HON. DAVID WU, Oregon, Chair
DONNA F. EDWARDS, Maryland ADRIAN SMITH, Nebraska
BEN R. LUJAN, New Mexico JUDY BIGGERT, Illinois
PAUL D. TONKO, New York W. TODD AKIN, Missouri
DANIEL LIPINSKI, Illinois PAUL C. BROUN, Georgia
HARRY E. MITCHELL, Arizona
GARY C. PETERS, Michigan
BART GORDON, Tennessee RALPH M. HALL, Texas
MIKE QUEAR Subcommittee Staff Director
MEGHAN HOUSEWRIGHT Democratic Professional Staff Member
TRAVIS HITE Democratic Professional Staff Member
HOLLY LOGUE Democratic Professional Staff Member
DAN BYERS Republican Professional Staff Member
VICTORIA JOHNSTON Research Assistant
C O N T E N T S
February 24, 2010
Hearing Charter.................................................. 2
Statement by Representative David Wu, Chairman, Subcommittee on
Technology and Innovation, Committee on Science and Technology,
U.S. House of Representatives.................................. 5
Written Statement............................................ 5
Statement by Representative Adrian Smith, Ranking Minority
Member, Subcommittee on Technology and Innovation, Committee on
Science and Technology, U.S. House of Representatives.......... 6
Written Statement............................................ 7
Dr. Thomas M. Baer, Executive Director, Stanford Photonics
Research Center, Ginzton Lab
Oral Statement............................................... 8
Written Statement............................................ 10
Ms. Sharon F. Terry, MA, President and CEO, Genetic Alliance
Oral Statement............................................... 14
Written Statement............................................ 16
Dr. Daniel Sullivan, Professor and Vice Chair, Research in
Radiology, Duke University Medical Center and Science Advisor,
Radiologic Society of North America
Oral Statement............................................... 20
Written Statement............................................ 21
Appendix: Additional Material for the Record
Testimony of Dr. Karen Mann, PhD, President of the Association
for Molecular Pathology........................................ 37
HOW CAN NIST BETTER SERVE THE NEEDS OF THE BIOMEDICAL RESEARCH
COMMUNITY IN THE 21ST CENTURY?
WEDNESDAY, FEBRUARY 24, 2010
House of Representatives,
Subcommittee on Technology and Innovation
Committee on Science and Technology
The Subcommittee met, pursuant to call, at 2:10 p.m., in
Room 2318 of the Rayburn House Office Building, Hon. David Wu
[Chairman of the Subcommittee] presiding.
U.S. HOUSE OF REPRESENTATIVES
COMMITTEE ON SCIENCE AND TECHNOLOGY
SUBCOMMITTEE ON TECHNOLOGY AND INNOVATION
How Can NIST Better Serve the
Needs of the Biomedical Research
Community in the 21st Century?
wednesday, february 24, 2010
2318 rayburn house office building
On February 24, 2010, the Subcommittee on Technology and Innovation
will hold a hearing to examine ways in which NIST could better serve
the needs of the biomedical community. This hearing is a follow-up
hearing to the hearing held on September 24, 2009, entitled: The Need
for Measurement Standards To Facilitate Research and Development of
Dr. Thomas M. Baer is the Executive Director of Stanford Photonics
Research Center at Ginzton Lab.
Sharon F. Terry, MA is the President and CEO of Genetic Alliance.
Dr. Daniel Sullivan is a Professor and Vice Chair for Research in
Radiology at Duke University Medical Center and Science Advisor to the
Radiologic Society of North America.
On September 24, 2009, the Science and Technology Committee for the
House of Representatives, Subcommittee on Technology and Innovation,
held a hearing to examine the need to develop measurements, reference
materials, reference standards, standard processes, and validation
procedures to improve the research, development and regulatory approval
of biologics.\1\ In the September 24th hearing, industry and the FDA
expressed that there is a need for NIST to perform basic measurement
science research to support the growth of the biologics industry.
\1\ Hearing available at: http://science.house.gov/publications/
Additional initiatives in the biomedical field have been proposed
by NIST, including performing metrology research to support better
diagnostic testing and the development of personalized medicine.
Developing reference standards and materials in each of these areas
could potentially lead to a substantial savings in the cost of
healthcare, supporting innovation in the biomedical field, leading to
job creation. For example, in the area of personalized medicine, the
development of basic measurement science, particularly in the area of
proteomics and biomarker discovery, could enable small biotech
companies to utilize their more limited resources to develop therapies
targeted to specific populations of patients. This, in turn, could lead
to the growth of the biotech industry which has traditionally fostered
innovation through small and start-up biotechnology companies.
As another example, interpreting the results of diagnostic tests
can be inconsistent and inaccurate, leading to the need for multiple
testing of the same patient and/or the use of less effective treatment
options. In the area of imaging tools, such as x-rays, magnetic
resonance imaging (MRI) and positron emission tomography (PET),
interpretation of the results is a subjective task; however the
treatment of disease is an increasingly objective process given the
multiple options available to patients. In addition, medical imaging
devices vary from hospital to hospital, thus increasing the likelihood
that results obtained from different machines using different standards
and methods will not be comparable. Hence, better reference standards
are needed to assist doctors in interpreting diagnostic medical imaging
results objectively and consistently to improve patient treatment
In a third example, as recently as 1980, the measurement
uncertainty for cholesterol tests was more than 10 percent. This wide
margin of uncertainty meant that large numbers of people were
misdiagnosed as needing treatment when they did not, or not needing
treatment when they did. After an investigation by the Subcommittee,
NIST, in collaboration with the Centers for Disease Control and
Prevention, developed a Standard Reference Material, which reduced the
uncertainty level of these tests to 5 percent saving millions of
dollars per year in unneeded treatment costs and improving the quality
of health care for patients.\2\
\2\ See http://www.nist.gov/public-affairs/techbeat/
All of the initiatives proposed by NIST in the biomedical field
will require a substantial investment of resources and funding. As
suggested in the September 24th hearing, in addition to providing
increased funding to NIST for these programs, structural and managerial
improvements would also be desirable to help NIST accomplish its goals
in the biomedical area.\3\ The National Research Council, while
approving of the efforts of NIST in the biomedical area, has indicated
that improvements may also be made to NIST, and particularly to the
Chemical Science and Technology Laboratory (CSTL), in order to maximize
the impact of these efforts on the advancement of biomedical
\3\ The Potential Need for Measurement Standards to Facilitate the
Research and Development of Biologic Drugs, Hearing before the
Subcommittee on Technology and Innovation, Committee on Science and
Technology, House of Representatives, 111th Congress, 1st Session
(September 24, 2009), Ser. No. 111-53 at p. 86.
\4\ The National Research Council, for example, suggested that:
GThe Biochemical Science Division should identify what it
considers to be success in the context of NIST. There may
be too many small efforts to make a major impact. An
overarching strategy should be articulated and priorities
set, based on identifying what kinds of activities can best
be done in the NIST environment. Many of the groups have
done this, but a top-down alignment of research with the
division mission is missing. Once this is achieved, the
management team will have less difficulty in sifting
through the projects to determine which are the most
important to pursue going forward.
An Assessment of the National Institute of Standards and Technology
Chemical Science and Technology Laboratory, Fiscal Year 2009, Panel on
Chemical Science and Technology Laboratory Assessments Board, Division
on Engineering and Physical Sciences, National Research Council of the
National Academies (p. 17).
The Subcommittee will examine ways in which the NIST Director could
improve biomedical research at NIST to accurately and effectively
reflect the needs of the biomedical community. In particular,
biomedical research at NIST should be structured to achieve the
following: (1) increase NIST's technical expertise through
collaborations with academic institutions, private industry and
nonprofits; (2) increase and improve NIST's outreach efforts to
industry, academia and nonprofits; and (3) develop mechanisms that
allow for NIST to obtain effective and targeted input and feedback from
industry, academia and nonprofits.
As examples, the Subcommittee, with input and comments from experts
in the biomedical field, will examine whether the following proposals
may improve the ability of NIST to serve the needs of the biomedical
1. Development of an advisory board or panel of experts,
largely from industry, in the biomedical field to provide
guidance on focal areas and to discuss CSTL's official
2. Proving for the establishment of joint NIST university
centers for biomedical research at universities with strong
reputations for their biotechnology programs.
3. The establishment of a user facility at NIST that could be
used by industry and academia, similar to the NIST Center for
Further, the Subcommittee has asked witnesses to provide comments
on any additional changes that the NIST Director may implement that
would improve NIST's ability to achieve the goal of providing the most
effective service to the biomedical community, patients and doctors.
4. Witness Questions
The following questions were asked of each witness:
If NIST expands its involvement in performing
measurement science to develop measurements, reference
materials, reference standards, standard processes, and
validation procedures in the biomedical area, what future and
nascent areas of biomedicine will be most affected and how?
Would the following elements assist NIST in
ascertaining current and future metrology needs for the
biomedical community? If so, how?
an advisory board for CSTL.
a NIST university center for biomedical research.
a user facility at NIST that could be used by
industry and academia.
What other recommendations would you make regarding
the implementation of these or other elements?
Chairman Wu. This hearing will come to order. Good
afternoon. I would like to welcome everyone to today's hearing
on improving the biomedical program at NIST [National Institute
of Standards and Technology].
This is the second hearing of this Subcommittee to examine
how NIST can better serve the needs of the biomedical
community. Our first hearing focused on what NIST could do to
meet the metrology needs of the biologics industry.
Today, the Subcommittee will hear testimony on how NIST can
better respond to the metrology needs of the broader biomedical
community, including performing research support, not just
biologic drug development, but also personalized medicine and
We all know that people across the country have recently
been engaged in an ongoing debate over healthcare reform. We
will not be debating that issue today, but that debate has
focused, in part, on who should bear the costs for providing
healthcare. This Subcommittee will take the discussion further
and examine how we can use science to potentially reduce our
healthcare costs, while improving care for patients.
The growth of the biomedical sciences is essential to
providing better care for patients, and better treatment
options for doctors. Earlier, more accurate diagnoses of
chronic diseases, such as heart disease and cancer, would save
billions of dollars each year in medical costs. Moreover,
better diagnostic tools, and the use of personalized medicine
can lead to more effective treatments that are tailored to a
In short, advancing the biomedical sciences promotes
patient health and will lead to job creation in biotechnology
and healthcare industries. We have heard from the biomedical
community that metrology research is necessary to take
biomedical science to the next level, and that NIST needs to be
more connected to industry and academia to innovatively respond
to the demands of this rapidly changing industry.
That is the focus of today's hearing: innovation. Today, we
will hear about new, innovative biomedical treatments, and how
NIST may develop new, innovative processes to better provide
service and support to this growing industry.
I want to thank our witnesses for being here, for making a
long trip on the part of many, and we plan to act on their
guidance in the process of reauthorizing the America COMPETES
And now, I would like to recognize the ranking member, Mr.
Smith, for his opening statement.
[The prepared statement of Chairman Wu follows:]
Prepared Statement of Chairman David Wu
Good afternoon. I'd like to welcome everyone to today's hearing on
improving the biomedical program at NIST.
This is the second hearing the Subcommittee has held to examine how
NIST can better serve the needs of the biomedical community. Our first
hearing focused on what NIST could do to meet the metrology_or
measurement_needs of the biologics drug industry. Today the
Subcommittee will hear testimony on how NIST can better respond to the
metrology needs of the broader biomedical community, including
performing research to support not just biologic drug development, but
also personalized medicine and diagnostic testing.
We all know that people across the country have recently been
engaged in an ongoing debate over health care reform. That debate has
focused in part on who should bear the costs for providing health care.
This Subcommittee will take the discussion further and examine how we
can use science to reduce our health care costs while improving care
The growth of the biomedical sciences is essential to providing
better care for patients and better treatment options for doctors.
Earlier and more accurate diagnoses of chronic diseases, such as heart
disease and cancer, would save billions of dollars each year in medical
costs. Moreover, better diagnostic tools and the use of personalized
medicine can lead to more effective treatments that are tailored to a
In short, advancing the biomedical sciences promotes patient
health, saves medical costs, and will lead to job creation in the
biotechnology and health care industries.
We have heard from the biomedical community that metrology research
is necessary to take biomedical science to the next level and that NIST
needs to be more connected to industry and academia to innovatively
respond to the demands of this rapidly changing industry.
That is the focus of today's hearing_innovation. Today we will hear
about new, innovative biomedical treatments and how NIST may develop
new, innovative processes to provide better service and support to this
I want to thank our witnesses for being here. We plan to act on
their guidance in the process of reauthorizing the America COMPETES
Mr. Smith. Thank you, Mr. Chairman, Chairman Wu, for
calling today's hearing to examine ways in which the National
Institutes of Standards and Technology can better serve the
needs of biomedical researchers.
At our first hearing on this topic last September, we had
the opportunity to hear from NIST and the Food and Drug
Administration [FDA] regarding what they believe to be their
appropriate roles in supporting biomedical research, and about
new initiatives NIST would like to implement to support this
rapidly advancing field of research.
It is clear from past experience there is a constructive
role for NIST to play as a standard-setting body in biomedical
research. Past advances by NIST have improved the accuracy and
comparability of medical research and testing in numerous
fields, and as diagnoses and treatments become more and more
individualized, the need for such criteria will certainly only
As we work to ensure NIST's authorization meets the
evolving needs of the biomedical research community, we must
also remain mindful of our responsibility to ensure NIST's
standardization efforts enhance and ease ongoing research, but
actually do not replace it. Although this has not often been an
issue, we would be remiss to not continue monitoring this
We must also address how expanded activities at NIST will
be funded. One idea discussed at our last hearing was whether
benefiting agencies such as FDA and NIH [National Institutes of
Health] should fund NIST's work in these areas from their
budgets. Although shifting funding from these agencies to NIST
may appear less than ideal, if NIST's work catalyzes these
agencies' efforts, it may be an option worthy of pursuit, as
such arrangements are not without precedent.
Thank you again, Mr. Chairman. I am looking forward to a
constructive session with today's witnesses, and I yield back
the balance of my time.
[The prepared statement of Mr. Smith follows:]
Prepared Statement of Representative Adrian Smith
Thank you, Chairman Wu, for calling today's hearing to examine ways
in which the National Institute of Standards and Technology can better
serve the needs of biomedical researchers.
At our first hearing on this topic, last September, we had the
opportunity to hear from NIST and the Food and Drug Administration
regarding what they believed to be their appropriate roles in
supporting biomedical research and about new initiatives NIST would
like to implement to support this rapidly advancing field of research.
It is clear from past experience there is a constructive role for
NIST to play as a standards-setting body in biomedical research. Past
advances by NIST have improved the accuracy and comparability of
medical research and testing in numerous fields, and as diagnoses and
treatments become more and more individualized, the need for such
criteria will only increase.
As we work to ensure NIST's authorization meets the evolving needs
of the biomedical research community, we must also remain mindful of
our responsibility to ensure NIST's standardization efforts enhance and
ease ongoing research, but do not replace it. Although this has not
often been an issue, we would be remiss to not continue monitoring this
We must also address how expanded activities at NIST will be
funded. One idea discussed at our last hearing was whether benefiting
agencies such as FDA and NIH should fund NIST's work in these areas
from their budgets. Although shifting funding from these agencies to
NIST may appear less than ideal, if NIST's work catalyzes these
agencies efforts, it may be an option worthy of pursuit, as such
arrangements are not without precedent.
Thank you again, Mr. Chairman. I am looking forward to a
constructive session with today's witnesses and I yield back the
balance of my time.
Chairman Wu. Thank you very much, Mr. Smith. Other Members
who wish to submit additional opening statements, your
statements will be added to the record at this point.
Now, it is my pleasure to introduce our witnesses. First,
Dr. Thomas Baer is the Executive Director of the Stanford
Photonics Research Center at the Ginzton Lab, and is a
consulting professor in the Applied Physics Department at
Now, I would like to recognize the gentlelady from
Illinois, Ms. Biggert, to introduce our next witness.
Ms. Biggert. Thank you, Mr. Chairman, and I am honored to
introduce Sharon Terry, who is the President and CEO of the
Genetic Alliance, a network that is transforming health by
promoting an environment of openness, centered on the health of
individuals, families, and communities.
I have had the opportunity to work with her for quite a few
years, on what we consider as a very important bill. It is
called GINA, that is the Genetic Information Nondiscrimination
Act, which passed two years, and I think the regs have just
come out. But it was something that Louise Slaughter of New
York and Ted Kennedy and Olympia Snowe and I worked on, and it
took over ten years. And it passed out of the House with about
420 to 2 votes. You wonder why it took that long, but there was
a lot of work that it went into it, and it really is going, I
think, to change healthcare, and I am very proud of that.
And Sharon put it all together, with her enthusiasm, and
her way of bringing together advocates and, diverse advocates,
and get them all to work together.
I welcome her here.
Chairman Wu. Thank you very much, Ms. Biggert.
And our final witness is Dr. Daniel Sullivan, who is
Professor and Vice Chair for Research in Radiology at Duke
University Medical Center, and Science Advisor to the
Radiological Society of North America [RSNA].
You will each have five minutes for your spoken testimony.
Your written testimony will be included in the record in its
entirety, and when you complete your testimony, we will begin
with questions, and each Member of the panel will have five
minutes to question the panel.
Dr. Baer, please proceed.
STATEMENT OF DR. THOMAS M. BAER, EXECUTIVE DIRECTOR, STANFORD
PHOTONICS RESEARCH CENTER, GINZTON LAB
Dr. Baer. Thank you, Chairman Wu. And I would like to thank
you and the rest of the Committee for the opportunity to
testify about how NIST can better serve the needs of the
biomedical research community in the 21st Century.
I am a physicist, but I have worked in the biomedical area,
primarily in the private sector, for the last twenty years,
developed instrumentation and technology for HIV and AIDS
diagnosis, as well as bone marrow transplant quality control,
and breast cancer diagnostics, and know very well the
importance of accurate measurement for precise diagnosis.
I also have a background with NIST. I served for six years
on the NRC [National Research Council] panel for both the
Physics Lab and Chemistry Science and Technology Lab, as well
as served for the last four years on the Visiting Committee for
Advanced Technology [VCAT], and chaired the Biosciences
Healthcare Subcommittee as a part of my VCAT responsibilities.
Today, I will be presenting my personal perspective, and
not speaking for the VCAT Committee, but of course, my opinion
has been shaped by many discussions with my colleagues on the
VCAT Committee, and they share many of the opinions that I will
be presenting today.
My long history with NIST has instilled in me a great
respect for what NIST can accomplish when it focuses its effort
to support U.S. industry through world-leading measurement
research and standards development.
I am very pleased to be here with my colleagues, Sharon
Terry and Dan Sullivan. Sharon is going to present, very
eloquently, a patient point of view, and Dan, a clinical point
of view. And I thought I would take my time to present my
perspective on the industry, the biomedical and bioscience
industry, and the exciting potential that new technology offers
We are here today because of a technological revolution
that has occurred over the past several decades. In general,
new products bring benefit to society through creating new
industries, and these new products are based on innovative
engineering. And engineering usually has its foundation in the
quantitative sciences, which have traditionally been
mathematics, physics, and chemistry.
However, over the last 30 years, there has been tremendous
progress in the life sciences, and it has entered into this
regime of quantitation. Through remarkable advances in
technology, which allow very precise measurements of DNA, RNA,
and proteins. Many of these advances were developed here in the
United States, based on research funded by the U.S. Government,
the polymerase chain reaction, DNA microarrays, four color
sequencing, all evolved here in the United States.
There are many industries that depend on this industry,
besides the healthcare industry, and they are listed here, but
the healthcare industry, which we are focusing on today is a
$2.5 trillion industry. It represents 20 percent of the U.S.
gross domestic product, and it employs ten million people. And
it is truly an enormous industry here in the United States.
It is a rapidly growing industry. It is not only big, it is
one of the fastest growing. It is one of the largest areas of
investment in Silicon Valley for venture capital. Dozens of
companies are formed each year, creating thousands of new jobs.
The goal of these companies, and of this industry, is to
improve the quality of healthcare and save lives. It is to
reduce the cost of healthcare, to create new jobs, and to keep
the U.S. biomedical healthcare industry competitive worldwide.
As an example of the types of advances that have occurred,
here is one illustration. In 1975, if you used a sequencing
instrument back then, you could generate about a nucleotide
sequence of about 2,000 base-pairs. And if you printed out this
data, it would take up one half a page in a book. To sequence
the human genome using a single instrument from that technology
would have taken 4,000 years. In 1990, when lasers were
introduced as a part of the instrumentation in capillary
electrophoresis, you could generate data on 100,000 base-pairs
per day, and to sequence the human genome would have taken
about 80 years. To print out all this data would have taken a
chapter in a book. Today, a single instrument can generate two
billion base-pairs of data in a single day, and that data would
fill ten encyclopedia's worth, to print out all of that data.
Chairman Wu. Dr. Baer.
Dr. Baer. Yes.
Chairman Wu. Let me interrupt you just for a second. Your
slide says, it takes--it would take one day to sequence a
single human genome.
Dr. Baer. Yes.
Chairman Wu. You mean, like, the entire genome of a human
Dr. Baer. Yes. A single human genome has three billion
base-pairs in it, and one of these instruments now_one of the
state of the art instruments_can do that process in a single
Chairman Wu. You have to understand that, given that I am a
child of the mid to late '70s doing biochemistry, I was in a
basement lab at Stanford, at Stanford Medical School. This is
just jaw-dropping. Sorry to interrupt.
Dr. Baer. Not a problem. And to put it in perspective, some
of the testimony from Sharon Terry, her accomplishment,
searching for the PXE [pseudoxanthoma elasticum] gene, would be
like looking for one misspelling in a word within that ten
encyclopedias. It is a phenomenal accomplishment that she and
her husband worked on. Yes. So, this example is one of the
challenges facing medical science today, what to do with this
enormous amount of data.
As another example, the type of data that is generated by a
high resolution CT [CAT/computer tomography] scan that Dr.
Sullivan will be talking about, that CT scan generates a
comparable amount of data, about two billion data points.
So, the role of NIST is to make sure that this data is high
quality, to be able to develop the technology and software to
extract from this data the critical elements that can be used
in diagnosing diseases.
Currently, NIST is primarily organized by discipline. It
has a number of very high quality laboratories, primarily
focused around the traditional areas of mathematics, physics,
and chemistry. It does not have a life science laboratory
focused on the biomedical and healthcare industry, or the
technology that has evolved over the last several decades. And
I think, it is clear to us that NIST needs to expand its
efforts in the biomedical area, and to do so effectively, and
optimize its interface to the biomedical industry. It may be
necessary for NIST to consider forming a separate operating
unit and laboratory in the bioscience and healthcare area.
Let me close my remarks by commenting on the strong
leadership provided by the current director of NIST, Dr.
Patrick Gallagher. Dr. Gallagher indicated at the last VCAT
meeting that we had in February that he is working with the
NIST lab directors and senior managers to develop a new NIST
structure that will improve NIST's ability to address the
pressing needs of U.S. industry and fellow government agencies.
NIST can best be organized to service its many diverse
stakeholders, I believe, and capitalize on this great
opportunity to reorganize and expand NIST resources, by
potentially introducing a new biomedical and healthcare
laboratory. I look forward to working with Dr. Gallagher to
bring about these types of changes.
Thank you very much, Mr. Chairman.
[The prepared statement of Dr. Baer follows:]
Prepared Statement of Thomas M. Baer
Chairman Wu, Congresswoman Edwards and Biggert, and Committee Members:
Thank you for this opportunity to testify before the Technology and
Innovation subcommittee on How NIST Can Better Serve the Needs of the
Biomedical Research Community in the 21st Century.
My name is Tom Baer, and I am the Executive Director of the
Stanford Photonics Research Center and a Consulting Professor in the
Applied Physics Department at Stanford University. Although my early
training and scientific research was in Physics, I have spent most of
my career working in the fields of biotechnology and biomedicine,
primarily in the private sector. I have been a research scientist,
founder, CEO, and senior manager in several biomedical companies in
Silicon Valley and have developed technology used in the diagnosis of
AIDS, quality control of bone marrow transplants, and the molecular
analysis and diagnosis of breast and lung cancer.
I have a long association with NIST, having worked with several
directors and lab managers, serving six years in the 1990s on the NRC
review panels for both the Physics and Chemical Science and Technology
Laboratories. I have also served for the past four years on the
Visiting Committee for Advanced Technology (VCAT). I want to clearly
state that in my testimony today I am presenting my own perspective on
the topics being discussed, and I am not speaking on behalf of the VCAT
committee. However, my perspective has been influenced by many in-depth
discussions held with my colleagues on the VCAT, and we share similar
views on many of these issues.
My long association with NIST has instilled in me a deep respect
for this government agency, its personnel, and its unique mission.
NIST's world class measurement science and standards development
activities can form an important framework for innovation, enhancing
competitiveness of US industry, and supporting job creation. This is
particular true in the area we are discussing today of bioscience and
As one of the largest sectors of our economy, estimated at $2.5
trillion, healthcare makes up 20% of the total US gross domestic
product and employs approximately ten million Americans. These workers
provide services essential to our quality of life in this dynamic,
rapidly growing sector. In spite of the recession, US venture capital
firms clearly foresee tremendous growth potential in biomedicine and
biotechnology. Venture capital firms in Silicon Valley continue to fund
life science startups, creating dozens of companies each year,
employing thousands of workers. Startup companies translating
scientific advances into important, new therapeutic and diagnostic
medical procedures have been one of the largest areas of venture
capital investment in Silicon Valley for the last ten years. This area
is clearly one of the most important, dynamic sectors of our economy,
and one in which NIST can and must play a vital role.
What is causing this tremendous growth? Technology innovation and
new product engineering historically have been based on a foundation
provided by the quantitative sciences: physics, chemistry and
mathematics, strong areas of focus at NIST. However over the past 30
years tremendous advances in instrumentation and new technologies have
stimulated extraordinary progress in the life sciences. Innovative
instrumentation has opened up unprecedented capabilities for precise
measurement of biological macromolecules such as DNA and proteins.
Thirty years ago, using an instrument of that era, it would have taken
several thousand years to sequence a human genome. The newest
generation of high throughput gene sequencing instruments can sequence
a human genome in less than one day. Similarly, 3 decades ago measuring
the expression level of a single gene in a tumor would have taken
several days or weeks in a biomedical research lab. Today we can
measure the expression levels of thousands of genes simultaneously in
under an hour. These measurements provide the possibility for more
precise classification of cancer tumors and much more effective methods
for quickly and effectively choosing optimal drug therapy. These
advances make possible personalized medicine where custom therapies are
developed and prescribed based on a patient's individual genetic
makeup. Medicine is being transformed by these developments, moving
from a primarily observational science to a truly quantitative
discipline, hopefully soon to fully join the ranks of physics,
chemistry and mathematics.
This progress presents tremendous potential for lowering medical
costs by reducing the number of tests necessary to diagnose disease and
by helping physicians choose the best therapies and thus helping
patients avoid unnecessary medical procedures. However, capitalizing on
these therapeutic and diagnostic opportunities presented by recent
advances in biotechnology requires the development of standardized
procedures, new reference materials, instrument calibration protocols,
and a much better understanding of the science underlying these new
technologies, areas where NIST can make critical contributions.
Despite the introduction of many new, effective diagnostic tests
numerous challenges remain: the lack of standards, cross platform
inconsistencies, and lab-to-lab variability are significant barriers to
optimizing their impact. Two examples of current problems are
illustrated by tests performed millions of times each year in the US:
measuring levels of prostate specific antigen (PSA) to diagnose
prostate cancer and thyroid stimulating hormone (TSH) essential to
diagnose and treat thyroid disease. Results of PSA or TSH tests cannot
be reliably compared if they are performed at different diagnostic
laboratories using different measurement methods. A recent laboratory
report had the following warning in a footnote ``PSA values from
different methods cannot be used interchangeably.'' Patients are warned
to be careful about interpreting TSH laboratory results if they have
moved to a new location or change laboratories. This lack of
reproducibility in test results confuses patients, causes much concern
in medical practitioners, makes appropriate therapeutic intervention
much more difficult, and often increases medical costs by creating a
demand for multiple, repeated testing. NIST, specializing as it does in
measurement science and standards development, could help to vastly
improve test consistent and accuracy, substantially reducing medical
Translating the tremendous advances in quantitative biology
instrumentation into effective diagnostic tests will require developing
standard reference materials, reproducible consensus protocols, and
understanding the basic measurement science underlying these new
quantitative biomedical instruments. Much of this work has yet to be
done and lack of this standards framework is impeding the translation
of these new technologies into medical practice, affecting the lives of
many critically ill US citizens who could benefit from accelerated
introduction of these breakthrough technologies. NIST can play a
pivotal role in accelerating deployment of these remarkable new
instruments and procedures. Other government agencies, such as the FDA
and NIH focus, on different aspects of health care, regulatory affairs
and disease research respectively. Both of these agencies have strongly
encouraged greater involvement by NIST in supporting the health care
industry by developing standards and by expanding its ongoing research
efforts bioscience and healthcare.
As part of my VCAT responsibilities I chaired the Subcommittee on
Bioscience and Healthcare. This Subcommittee included fellow VCAT
members Lou Ann Heimbrook and James Serum, two highly experienced
senior executives from the pharmaceutical and biotechnology industries.
We have been working with several of the laboratory directors at NIST
to help guide formation of a strategic plan to address the wide ranging
needs of the Biomedical Health Care industry and research communities,
as well as coordinate this program with the ongoing efforts at NIST to
develop electronic medical records standards. I have found working with
NIST senior management to formulate a roadmap for NIST in biomedical
and healthcare to be a challenging but rewarding task, and it is still
a work in process. NIST does not have a completely conceptualized and
articulated a vision for how to best serve US industry needs in this
area. I do feel strongly, however, that NIST management recognizes that
there is an urgent need to complete this process and that there is a
very exciting, critical role for NIST to play in the rapidly expanding
arenas of healthcare and bioscience. One of the results of this
planning was a conference designed to initiate a dialogue between NIST
and stakeholders in the Biomedical Industry. The proceedings of this
conference have been published in a document summarizing the opinions
of the participants.
NIST is at present organized by discipline with very strong
laboratories in the traditional quantitative sciences. The Physics,
Chemical Science and Technology, and Information Technology
laboratories provide essential support to many US industries.
Unfortunately NIST does not have a laboratory devoted specifically to
supporting the biomedical and healthcare industry. In my opinion, NIST
currently needs to add more staff familiar with the challenges facing
the pharmaceutical, diagnostic and medical device industries. NIST also
needs additional resources for expanding its facilities and acquiring
the equipment to develop the research programs necessary to meet the
needs of these industries. Currently there are several excellent groups
within NIST making very important contributions, focused on research
impacting significant, specific biomedical problems. However, the VCAT
has commented in past annual reports that these groups are often
isolated from one another in different NIST laboratories, their efforts
are not well coordinated, and they often lack sufficient resources to
optimize their impact. I believe that to be truly effective NIST needs
to be provided with additional resources to expand efforts in this area
and establish an operating unit or laboratory specifically focused on
servicing the needs of the US Biomedical/Healthcare industry.
For over a century NIST has played a very important role in many
areas of quantitative science and technology providing standards and
world-leading measurement science for precise reproducible measurement
of many physical constants, chemical analytes, and important
information on material properties. The standards and technologies
developed by NIST have led to many very important and diverse advances
such as GPS navigation, microelectronics and software standards, and
critical standards for building materials which are integral parts of
US fire codes. It is thus very appropriate for NIST to develop the
expertise and facilities to play a comparable pivotal role in the 21st
century in this new era of quantitative biomedicine.
Let me close my remarks by commenting on the strong leadership
provided by the current director of NIST, Dr. Patrick Gallagher. Dr.
Gallagher indicated at the last VCAT meeting in February, 2010 that he
is working with NIST lab directories and senior managers to develop a
new NIST structure that will improve NIST's ability to address the
pressing needs of US industry and fellow government agencies. He is
formulating a significant, exciting new vision for how NIST can best be
organized to service its many, diverse stake holders. I believe that
this is a great opportunity to reorganize and expand the NIST resources
supporting the US biomedical and healthcare industry, and I look
forward to working with him to bring about these changes.
In my testimony, Mr. Chairman, you asked me to address several
If NIST expands its involvement in performing measurement science
to develop measurements, reference materials, reference standards,
standard processes, and validation procedures in the biomedical area,
what are the current, future and nascent areas of biomedicine that
could be best served by NIST and how?
The areas where I see NIST providing the greatest service are:
1. Diagnostic medicine
In particular developing standards, consistent
protocols, and advancing measurement science in
applying quantitative molecular analysis technology to
Supporting the application of the newest generation
of quantitative imaging instruments (CT, MRI,
2. Working with the drug development industry to accelerate
the drug development process
Improving our understanding of the technology needed
to perform the measurements necessary to provide
accurate assessment of the safety and efficacy of new
3. Working with universities and private industry to
development methods for new classes of therapy enabled by
advances in stem cell science. With applications, in diseases
such as diabetes and organ replacement
4. Providing a sound basis for measurement science in the area
of neuroscience and neuromedicine. With applications in
Parkinson's disease and Alzheimer's disease.
Would the following elements assist NIST in ascertaining current
and future metrology needs for the biomedical community? If so, how?
An advisory board made up of industry experts.
I recommend that NIST develop several advisory boards comprised of
experts from the private sector and other government agencies
representing different sectors of the biomedical industry. For example,
separate panels could be formed with experts from molecular
diagnostics, imaging diagnostics, drug development, medical devices and
biomedical materials. These advisory panels should meet regularly with
NIST personnel working in these areas to help identify the critical
problems that need to be addressed and to establish the most effective
strategic and tactical focus for biomedical programs at NIST.
A university center for biomedical research
University collaborations and joint institutes have played an
important and very successful role in other NIST programs, and I
believe this approach would work extremely well in the biomedical
healthcare area. Specifically a university center focused on research
into the fundamental measurement science underlying biomedical
instrumentation and a joint institute studying the measurement science
challenges inherent in the measurement of complex biological systems.
A user facility that could be used by industry and
A separate operating unit or laboratory would provide a critical
central focus for research at NIST in biomedicine. Such a facility
could support visiting scientists from industry to provide input to
NIST research activities, as well as physical location for NIST
researchers, postdocs, and graduate students to associate with
multidisciplinary teams working in similar or related biomedical areas.
Biography for Thomas M. Baer
Thomas Baer is the executive director of the Stanford Photonics
Research Center. He has been active in many scientific areas employing
optics: atomic and molecular spectroscopy, optical metrology, ultrafast
lasers, pulse compression, solid-state lasers, laser scanning
fluorometry of blood cells, laser capture microdissection of biopsy
samples and microgenomics. He has worked in industry and academia, and
has participated in a number of successful collaborations with academic
and government research groups, resulting in numerous commercial
products that incorporate lasers and optics.
Tom graduated with a BA in physics from Lawrence University and
received his PhD in 1979 from the University of Chicago, where he
studied atomic physics with Isaac Abella and Ugo Fano. After that, he
worked with John Hall at JILA on high resolution spectroscopy and co-
invented new techniques for frequency stabilizing lasers.
In 1981, he joined Spectra-Physics (SP), where he held positions as
vice president of research and Spectra-Physics Fellow. His research
there focused on ultra-fast lasers, pulse compression, diodepumped
solid-state lasers and non-linear optics. His group developed and
patented the first commercial optical pulse compressor, high power,
fiber-coupled diode-pumped solid-state lasers, and mode-locked Ti-
Sapphire lasers. His commercial products received several industry
awards for design innovation.
After leaving SP, he joined Biometric Imaging (BMI) and changed his
research focus to biophotonics. At BMI, he led an interdisciplinary
group that developed the scanning laser instruments used in diagnostic
tests for bone marrow transplant therapy and immune system monitoring
in AIDS patients.
Following his departure from BMI, Tom founded Arcturus Bioscience
and served as CEO and chairman until 2005. Arcturus Bioscience
pioneered the area of microgenomics_the precise molecular analysis of
microscopic tissue samples. Arcturus technology is widely used in life
science research laboratories and in molecular diagnostic tests for
cancer. He left the company in 2005 and joined Stanford University,
where he is the executive director of the Stanford Photonics Research
Center and a member of the Applied Physics department. Tom has co-
authored scientific publications in the fields of atomic physics,
quantum electronics, laser applications and biotechnology.
He is an inventor on over 60 US patents and a co-author on many
scientific papers. He was named Entrepreneur of the Year for emerging
companies in Silicon Valley in 2000 by the Silicon Valley Business
Journal. He is an alumnus of Harvard Business School, and has received
the Distinguished Alumni Award from Lawrence University. Tom also
serves on visiting committees and advisory groups with NIST, NIH and
the Physical Sciences Division of the University of Chicago. He is a
Fellow of The Optical Society and the American Association for the
Advancement of Science. He served as President of the Optical Society
of America in 2009 and is currently serving as Past President.
Chairman Wu. Thank you very much. Thank you very much, Dr.
I think that many of us are very excited about Dr.
Gallagher's installation at NIST, and look forward to a long
and stable administration there.
And thank you very much for this perspective on the
progress of gene sequencing. I don't know if I am more
gratified about the progress made, or more concerned about how
long it has been since I was a college student.
Ms. Terry, please proceed.
STATEMENT OF MS. SHARON F. TERRY, MA, PRESIDENT AND CEO,
Ms. Terry. Thanks very much, Chairman Wu, and thank you
very much, Congresswoman Biggert, for your introduction.
Congresswoman Edwards, and to the Committee.
Today, you are hearing from accomplished researchers and
leaders in the fields of their study, from Stanford and Duke.
These individuals are scientists, entrepreneurs, biotechnology
innovators, and certainly great leaders.
I come here primarily as a mom. I am here today to address
the critical link between my experience as a mother, striving
for treatments for my kids and millions of others, and the
question before this Committee, how could NIST be more
effective in influencing innovation in the life sciences?
I begin with a plain statement about NIST and its
activities. It can appear to be boring, non-interesting, and
terribly esoteric. NIST suffers from being hidden, embedded in
the foundational infrastructure of the scientific and early
commercial enterprise of innovation, as well as having the
thankless task of creating measurement standards for a whole
array of scientific disciplines. However, it is precisely
because of these elements that this Committee needs to champion
a more active role for NIST in the life sciences.
Some have quite convincingly argued that the next century
of scientific and technological innovations will be the most
profound in the life sciences. NIST is critical to a robust
medical, biomedical enterprise, and must contribute high
quality materials, methods, and expertise for the field to
advance on a platform of certainty and high quality
My two children were diagnosed with a genetic disease,
pseudoxanthoma elasticum, 15 years ago. As a result, I chose to
leave my career as a college chaplain, and become involved with
the life sciences and biotechnology in search for a solution
for their disease. I started a foundation called PXE
International, organized patient populations around the world,
created a bio-bank, isolated the disease gene, developed a
commercial diagnostic, created animal models, and have
supported clinical interventions for adults living with the
We still do not have a treatment intervention for my
children or any of the individuals with this disease, and we
are still hard at work. This is typical of most diseases. We
have been stymied by a number of measurement and experimental
roadblocks in advancing clear understanding of the disease, and
the function of the altered protein that causes pseudoxanthoma
elasticum. We have run smack into the wall of both scientific
and technological limitations.
My foundation's research work has been written about in
prestigious journals as a model of innovation, and an example
of the power of patient-driven translational research. Some
have said our work will change the field. But I am telling you
that we are limping toward the finish line of our objective,
because of the current limitations in measurement science. This
science has real world impact on patients, families, and
At this time, each provider of biomedical tests and
therapies is creating their own system, leading to widespread
inconsistencies between these practices. Americans believe they
are receiving healthcare that is high quality, accurate, valid,
and consistent. They do not realize that a PSA [prostate-
specific antigen] test from one lab cannot be compared to
another lab. They have no idea that the four million newborns
who are screened every year are subjected to different
screening cutoffs in every state program, for the somewhere
between 29 to 54 tests. The states count the number of screens
they conduct differently from one another, because there are no
standards. The 2,700 genetic tests that are now protected by
GINA, thanks to Congresswoman Biggert and others, listed in
gene tests, are purported to be actually hundreds of thousands
of tests, because of the variability across labs performing
these tests. No one knows how many tests there are, and there
are only standards for 35 of the analytes used in all these
Every technology manufacturer applies relevant measurement
technology with their own standard references and controls. For
example, housekeeping genes and control agents. The FDA, as a
regulatory agency, is challenged with ascertaining the accuracy
and precision of these technologies based on the manufacturer-
supplied standards. Ultimately, they must trust the
Just this morning, I was at NIH, where Secretary Sebelius
announced a collaboration between NIH and FDA, and Drs. Collins
and Hamburg announced that they will be doing regulatory
science and the study of that science. Very seriously, there is
not any way they can do it without the standards that NIST
needs to produce, and a collaboration in that regard is
NIST must take a leadership role in creating the standards
necessary to integrate new technologies into medicine. These
technologies, in genetics, genomics, laboratory science and
imaging, are migrating into healthcare, sometimes to the point
of care. It is critical that patients know that these
healthcare services are based on the certitude that only
standards can bring.
With Congress' increased support, I believe NIST should
create a life sciences infrastructure catalog and distribution
system for reference materials and standards for quality
assurance for all clinical diagnostic tests, integrate
measurement standards and technologies into the FDA regulatory
regime, partner with the National Institutes of Health on
resolving the measurement challenges at the intersection of
patient care, and conduct a comprehensive analysis of the life
sciences to determine the highest needs for measurement
In this age of emerging personalized medicine, delivered
through new technologies to patients today, we cannot wait any
longer, having far outstripped the standards available to
biomedical enterprises. Leading Genetic Alliance and feeling
the urgency of the hundreds of millions of people who need
answers today, I know we need excellent leadership in an
Let us take this charge seriously. Every one of us has a
role to play, and NIST is poised to do great things.
Thank you for the opportunity to contribute to the
important work of your Committee.
[The prepared statement of Ms. Terry follows:]
Prepared Statement of Sharon F. Terry
My name is Sharon Terry, I am the mother of two children with a
genetic disease, pseudoxanthoma elasticum (PXE). If it takes its
course, they will loose their vision at about age 40. They both already
experience moderate to severe wrinkling of the skin, another
manifestation of the disease. I was catapulted into the world of
genetics and biomedical research when they were diagnosed 15 years ago.
I now run not only a genetic disease foundation for PXE, but also
Genetic Alliance. Relevant to this testimony, I also serve on the
Health and Human Services Office of the National Coordinator's
Standards Committee for Health Information Technology.
Genetic Alliance is the world's leading nonprofit advocacy
organization committed to transforming health through genetics. We
bring together diverse stakeholders to create novel partnerships in
advocacy; we integrate individual, family, and community perspectives
to improve health systems; we revolutionize access to information to
enable translation of research into services and individualized
decision-making. Genetic Alliance's network includes more than 10,000
organizations, including disease-specific advocacy organizations as
well as universities, private companies, government agencies, and
public policy organizations. The network is a dynamic and growing open
space for shared resources, creative tools, and innovative programs.
Over the past 24 years, Genetic Alliance has been the voice of advocacy
in health and genetics.
Advocacy in the 21st century, however, requires new definitions and
new focus. We dissolve boundaries to foster dialogue that includes the
perspectives of all stakeholders: from industry professionals,
researchers, healthcare providers, and public policy leaders to
individuals, families, and communities. In a rapidly changing world,
Genetic Alliance understands that nothing short of the transformation
will suffice to transform health.
My world revolves around the hundreds of millions of men, women and
children in the US and throughout the world that wait, and sometimes
die, for tests and therapies. It is my passion to accelerate
translation of the phenomenal explosion of information surging through
the biomedical research pipeline today. I grow more certain each day
that the outcomes we seek, better health for all, are dependent on a
solid foundation. That foundation is standards that allow high quality
diagnostics and therapeutic development.
I have witnessed enormous waste and disparities in test and drug
development. I will give some examples and recommendations that
illustrate the enormous payoff we would have as a nation with increased
participation of NIST in the biomedical enterprise.
The National Institute of Standards and Technology is the premier
standards agency in the world. The success of the biomedical research
enterprise, and America as a leader in innovation depends on NIST
providing standards upon which to build personalized medicine.
At this time, each provider of biomedical tests and therapies is
creating their own system, leading to widespread inconsistencies
between these practices. American's believe that they are receiving
healthcare that is high quality, accurate, valid, useful and
consistent. They do not realize that a PSA test from one lab, cannot be
compared to another lab. They have no idea that the 4 million newborns
who received screening at birth this year, are subjected to different
screening cutoffs in each of the 51 programs in the states and
territories. Most measurements are relative, internal to one lab, or
one state, or one company. Every manufacturer applies relevant
measurement technology with their own standard references and controls,
for example in housekeeping genes and general control reagents. The
Food and Drug Administration, as a regulatory agency, is challenged
with ascertaining the accuracy and precision of these technologies
based on the manufacturers supply control and references. Ultimately
they must trust the manufacturers' standards.
These technologies, in genetics, genomics, laboratory science and
imaging, are migrating into clouds of care. At this point, the
iterative cycle is over because a static product is being introduced
into healthcare. We absolutely need new standards. They can be called
clinical standards, but this should be a regulatable gray clinical
standard in which all technology is measured if it's going to be used
to treat patients. NIST needs to take a leadership role in creating the
standards necessary to integrate new technologies into medicine.
Metrology can be considered less than exciting science, because it
is thankless and invisible in the medical system. The valiant work of
NISTs scientists produce incredible standards of temporal and spatial
value with little recognition.
I have witnessed public health laboratories and companies develop
precise measurements, and have them eschewed by their peers. However,
the community won't use them because they are not independently judged
or assessed, and because they would create the opportunity for
comparisons that might be good for public health, but are generally not
welcome by industry or laboratories. The community will use the least
expensive alternative. If NIST standards, underpinned FDA requirements,
the industry would be incentivized to improve life science measurement.
Then companies and academic labs would not be differentiating
themselves against the least expensive alternative. They'd be
differentiating themselves against a performance standard, which is a
completely different exercise.
The highest standard for laboratory performance is Clinical
Laboratory Improvement Amendment (CLIA). CLIA is structured in such a
way that it avoids standards because it doesn't have them to use. Labs
just need internal standards for the laboratory, the machines, the
operators, and the protocol. At the present time, every single standard
for every single test is unique to the test provider. This has created
an untenable morass. The 2700 genetic tests currently listed in
are actually somewhere in the hundred thousands tests because of the
variability across the labs performing these tests in the US and
Current, future and nascent areas of biomedicine that could be best
served by NIST if it expands its involvement in performing measurement
science to develop measurements, reference materials, reference
standards, standard processes, and validation procedures in the
In the future, schizophrenia, rheumatoid arthritis, asthma,
attention deficit disorder, autism and other spectrum disorders may be
treatable if there were control standards to measure various attributes
of phenotype. At present, these all rely on subjective patient
Linearity studies can be conducted that show standards are accepted
and work well for the technologies. This is the challenge for substrate
microarrays for DNA measurement. There is a need an artificial control,
a ladder control. It would create a benchmark for accuracy in
measurement that would bring biomedical research and technologies a
level of evidence it sorely needs to move to personalized medicine.
In all cases, handling, storage, preparation all have influence on
the accuracy of a laboratory measurement. It is difficult to control
for all these variables in a measurement science. NIST at times appears
paralyzed because of the large number of variables, wondering where to
start, and seeming to be overwhelmed. If the biomedical universe is too
big for one to tackle everything, then NIST should begin by producing
We need measurement standards of controls for pseudoxanthoma
elasticum (PXE). The gene, ABCC6 has a 99% homology fossil gene that
can produce erroneous test results for patients. In addition, at least
17 other genes that have similar profiles and there are no controls.
How many of these scenarios exist in the humane genome? Many, perhaps,
but the genome is a fixed repository. It's a recipe and a cookbook for
biological processes that has 23,000 functioning genes and probably
100,000 alternate transcripts that could be mapped today and easily
catalogued. These could have standards created for them. NIST could
collaborate in a much more effective way with the FDA in the
submissions they receive and integrate standards more frequently into
the regulatory regime. Certainly at first we would be demanding more of
a perfection standard from new technologies than what was cleared in
the predicate standard, but one hopes science improves medicine. A good
point for the intervention of high standards can be the point where
something migrates into a regulatory schema for clinical use.
Genetic Alliance submitted a citizen's petition for the creation of
a genetic subspecialty under the Clinical Laboratory Improvement Act
(CLIA). CLIA's response indicated that there were few standards for the
2700 hundred tests that are being offered to patients. They indicated
that they would be able to create a specialty when there were
standards. This was in 2002, and there has been no progress since.
Assisting NIST in ascertaining current and future metrology needs for
the biomedical community:
Advisory board of industry experts
I believe advisory boards can be very effective, provided they are
given authority to make recommendations and the leadership of the
agency is receptive. I am serving at this time on the HIT Standards
Advisory committee and am impressed with the level of commitment of the
members from industry and academia alike. We feel urgency and we feel
like we are having an impact. A body with these attributes would be
very good for NIST.
University center for biomedical research
The creation of multiple standards in many disciplines may be too
broad a waterfront for NIST to tackle alone. A granting mechanism would
be very effective. For example, academic groups could reply to RFPs
that asks for referencing control standard for the biology of the
highest priority cancers for NIH, including the encyclopedic genome of
these cancers; for standards for all of the conditions in the current
recommended panels for newborn screening, and/or the 2700 or so
Mendelian disorders. Another RFP could ask for standards that would
allow comparison of the fidelity of one machine to the next for
Other recommendations for implementing these elements (advisory board,
university center and/or user facility) or others?
It may be beneficial to set up a laboratory network dedicated in
part to standards. The Collaboration Education and Test Translation
program of the Office of Rare Disease Research at the National
Institutes of Health has such a network associated with it.
Laboratories share reference standards and controls for rare diseases.
These could be codified in a standards based system at NIST. The model
of this network might be deployed to other problems.
NIST must take a leadership role in creating the standards
necessary to integrate new technologies into medicine. These
technologies, in genetics, genomics, laboratory science and imaging,
are migrating into health care, sometimes to point-of-care. It is
critical that patients know that these healthcare services are based on
the certitude that only standards can bring.
With Congress's increased support, NIST should:
1. Create a life sciences infrastructure, catalog, and
distribution system for reference materials and standards for
quality assurance for all clinical diagnostic tests
2. Integrate measurement standards and technologies into the
FDA regulatory regime
3. Partner with the National Institutes of Health on resolving
the measurement challenges at the intersection of patient care
4. Conduct a comprehensive analysis of the life sciences to
determine the highest needs for measurement science
In this age of emerging personalized medicine, delivered through
new technologies to patients today, we cannot wait any longer, having
far outstripped the standards available to biomedical enterprises.
Leading Genetic Alliance, and feeling the urgency of the hundreds of
millions of people who need answers today, I know we need excellent
leadership in an exceptional age. Let us take this charge seriously.
Every one of us has a role to play, and NIST is poised to do great
things. Thank you for the opportunity to contribute to the important
work of this committee.
Biography for Sharon F. Terry
Sharon F. Terry is President and CEO of the Genetic Alliance, a
network transforming health by promoting an environment of openness
centered on the health of individuals, families and communities. She is
the founding Executive Director of PXE International, a research
advocacy organization for the genetic condition pseudoxanthoma
elasticum (PXE). Following the diagnosis of their two children with
pseudoxanthoma elasticum (PXE) in 1994, Sharon, a former college
chaplain, and her husband, Patrick, founded and built a dynamic
organization that enables ethical research and policies and provides
support and information to members and the public.
She is at the forefront of consumer participation in genetics
research, services and policy and serves as a member of many of the
major governmental advisory committees on medical research, including
the HIT Standards Committee for the Office of the National Coordinator
for Health Information Technology, liaison to the Secretary's Advisory
Committee on Heritable Disorders and Genetic Diseases in Newborns and
Children and the National Advisory Council for Human Genome Research,
NHGRI, NIH. She serves on the boards of GRAND Therapeutics Foundation,
the Center for Information & Study on Clinical Research Participation,
The Biotechnology Institute, National Coalition of Health Professional
Education in Genetics, and the Coalition for 21st Century Medicine. She
is on the steering committees of Genetic Association Information
Network of NHGRI, the CETT program, the EGAPP Stakeholders Group, and
the editorial boards of Genetic Testing and Biomarkers, and
Biopreservation and Biobanking, and the Google Health and Rosalind
Franklin Society Advisory Boards. She is the chair of the Coalition for
Genetic Fairness that was instrumental in the passage of the Genetic
Information Nondiscrimination Act. She is a member of the IOM
Roundtable on Translating Genomic-Based Research for Health. In 2005,
she received an honorary doctorate from Iona College for her work in
community engagement and haplotype mapping; in 2007 received the first
Patient Service Award from the UNC Institute for Pharmacogenomics and
Individualized Therapy; and in 2009 received the Research!America
Distinguished Organization Advocacy Award. She has recently been named
an Ashoka Fellow.
Ms. Terry is a co-founder of the Genetic Alliance Biobank. It is a
centralized biological and data [consent/clinical/environmental]
repository catalyzing translational genomic research on rare genetic
diseases. The BioBank works in partnership with academic and industrial
collaborators to develop novel diagnostics and therapeutics to better
understand and treat these diseases. Along with the other co-inventors
of the gene associated with PXE (ABCC6), she holds the patent for the
invention. She co-directs a 33-lab research consortium and manages 52
offices worldwide for PXE International.
Terry is committed to bringing together diverse stakeholders that
create novel partnerships in advocacy; integrating individual, family,
and community perspectives to improve health systems; and
revolutionizing access to information to enable translation of research
into services and individualized decision making. She lives with her
husband Patrick and their two children in Maryland.
Chairman Wu. Thank you very much, Ms. Terry. Thank you for
your work as an advocate. I think that many children would
benefit from your work.
Your testimony has already opened eyes on this panel, in
that I don't think any of the Members knew that no two PSA
tests are comparable. That is really quite stunning.
Dr. Sullivan, please proceed.
STATEMENT OF DR. DANIEL SULLIVAN, PROFESSOR AND VICE CHAIR,
RESEARCH IN RADIOLOGY, DUKE UNIVERSITY MEDICAL CENTER AND
SCIENCE ADVISOR, RADIOLOGIC SOCIETY OF NORTH AMERICA
Dr. Sullivan. Thank you, Chairman Wu and Members of the
Committee. Thank you for this opportunity to offer brief
testimony on how NIST could help better serve the needs of the
biomedical research community in the 21st century.
It is increasingly clear that the value of medical scans
would be significantly greater if we could extract more
objective, quantitative information from scans, rather than
relying on radiologists' subjective, qualitative
This is an important priority for the RSNA, and we have
several related activities, including the Quantitative Imaging
Biomarkers Alliance, which brings together representatives from
the medical scanner manufacturers, the pharmaceutical industry,
and academicians, to work with manufacturers, to have them
engineer medical scanners to be accurate measuring devices and
not simply imaging devices. And also, the Imaging Biomarkers
Roundtable, which facilitates communication among many
In my brief testimony today, I would like to show you three
examples of common diseases, using three different scanning
methods, to illustrate why standards for extracting
quantitative information are critically needed. First, the CT
scan of a patient with chronic obstructive pulmonary disease,
or emphysema. All digital images are made up of numbers. Here
are some of the numbers behind the pixels in this scan. These
numbers carry tissue information, but to be useful in medical
care, these numbers have to be standardized, so that we know,
for example, what tissue quality each number signifies on a
given scanner, and what it means when that number changes.
Right now, such standardization does not exist.
For example, here, the red areas are areas of destroyed
lung tissue, identified by a computer analyzing these numbers.
A percentage number is what the treating physicians want to
know, so that they could determine from future scans whether
the patient is responding to therapy or not. If the patient is
not improving, or getting worse, physicians have other
treatment options they could use.
However, right now, we radiologists cannot provide this
kind of objective information about the actual percentage of
lung destroyed, or other measurements, because the numbers are
The second example is cancer. These are PET [positron
emission tomography] scans of a patient with lymphoma. PET
scans show a radioactively tagged glucose that is being used in
the body. In these scans, yellow is the highest level of
glucose uptake. Because tumor cells are growing so rapidly,
they take up much more glucose than normal cells, and the
yellow areas represent tumor. If this glucose activity
decreases after a couple of weeks of therapy, as shown here, it
is a good sign the therapy is working. Oncologists need to know
this early, because if the therapy is not working for a
particular patient, there are usually alternatives that can be
However, there are insufficient standards for PET scanners
to ensure that you would get the same number for the amount of
glucose measured in a tumor on one scanner as on another
scanner, or even on the same scanner after an interval of a few
My third example is Alzheimer's disease. We desperately
need objective measures to determine whether lapses of memory
are due to the ordinary stresses of everyday life or early
dementia. Without objective markers for diagnosis, or to
determine whether the disease is responding to new drugs or
not, it will be impossible to develop effective therapies.
One objective measure that could be used is the volume of
the hippocampus on MRI [Magnetic Resonance Imaging] scans, as
shown here. However, subtle volume differences in this small
brain structure cannot be discerned by radiologists
subjectively reading MRI scans. The scans have to be done on
scanners that are calibrated with appropriate reference objects
so that computer algorithms would calculate the same accurate
and reproducible hippocampal volume no matter which scanner was
These are just a few examples where clinicians clearly need
more objective diagnostic tests. NIST can be a critical
participant to help manufacturers meet this need. We need NIST
to develop reference materials, standards, and validation
procedures in the biomedical imaging area, especially for CT,
PET, MRI, and medical optical imaging.
To determine the metrology needs for the biomedical imaging
community, NIST should appoint an advisory board made up of
both industry experts and representatives of the imaging device
users, such as patient advocates and professionals.
Prior collaborations between scientists at NIST and
university centers have been very productive. Such
collaborations should be fostered by establishing one or more
NIST academic centers for biomedical research. The private
sector will continue to be a source of innovative reference
objects, algorithms, and other devices for quantitative
imaging. A NIST managed user facility that could be used by
industry and academic developers to test their devices under
standardized, controlled conditions would be an important
Finally, and very importantly, there is a critical need for
a neutral broker, trusted by the public, to develop an
accreditation and performance levels program, with associated
policies and procedures. NIST is ideally suited to perform this
Thank you again, Mr. Chairman and Members of the Committee,
and I appreciate this opportunity to express the imaging
community's view on this important topic.
[The prepared statement of Dr. Sullivan follows:]
Prepared Statement of Daniel Sullivan
Chairman Wu and Members of the Subcommittee_Thank you for this
opportunity to offer brief testimony on How NIST Can Better Serve the
Needs of the Biomedical Research Community in the 21st Century.
I am Daniel Sullivan, Professor and Vice Chair for Research in
Radiology at Duke University Medical Center, and Science Advisor to the
Radiological Society of North America (RSNA). RSNA is an international
organization with more than 40,000 members (http://www.rsna.org/). Its
mission is to improve patient care through education and research. RSNA
hosts one of the world's largest annual medical meetings, publishes two
highly respected peer-reviewed journals, offers opportunities to earn
CME, and provides research and education grants to young investigators.
It is not a lobbying organization and has no government relations
office or staff. My area of expertise is in diagnostic radiology and my
remarks will therefore focus on that topic.
Statement of the Problem:
The quality and cost of health care are major issues facing all
Americans. In the past decade, discoveries about the basic biology of
disease and technological advances in computers, imaging devices and
laboratory methods have made it possible to imagine treatment plans
that are individualized and optimized for each patient's unique pattern
of disease. The term ``Personalized Medicine'' is used frequently these
days. Of course, physicians have always, probably from the time of
Hippocrates, tried to personalize their approach to treating patients
based on the information available. What's different now is that we can
get basic molecular information from each patient about the genetic and
biochemical basis of their disease. Using each patient's unique
biochemical signature of disease to individualize treatment is what the
modern use of the term ``personalized medicine'' refers to.
However, there are some major roadblocks on the path toward that
vision. One is that diagnostic medical tests suffer from a lack of
standards_in far too many cases we do not know whether test results are
either accurate or comparable over space and time. Even though
approximately 70 percent of health care decisions are based upon
results from a test performed in a clinical laboratory, standards exist
for only about 10 percent of the 700 most commonly ordered clinical
tests. In the area of medical imaging, where it is estimated that U.S.
healthcare consumers spent a combined $50 billion on medical imaging
tests (MRI, CT scans, etc.) in 2008, the software and standards needed
to enable physicians to extract and compare relevant data and to make
definite determinations as to whether or not a tumor actually shrank or
grew do not exist. These measurements and standards shortcomings result
in repeat testing, misdiagnosis, and ineffective treatment decisions--
all of which contribute to a second major roadblock on the path toward
personalized healthcare, the dramatic rise in health care spending.
These dramatic cost increases are being driven by multiple
inefficiencies throughout the health care system. One area in which
significant improvements could be made, which would both decrease costs
of and improve the overall quality of healthcare, is in developing and
implementing better validated standards for laboratory medicine and
medical imaging. Although modern clinical imaging methods are widely
used, it is increasingly clear that the value of clinical imaging would
be significantly enhanced if we moved toward extracting more objective,
quantitative information from scans rather than relying on
radiologists' variable, subjective, qualitative interpretations, which
is the norm now. My comments today are focused on the need to develop
measurements and standards infrastructure for medical imaging.
In addition to its high standing in the professional communities,
RSNA enjoys a reputation as trusted, neutral party for industry. My
role with the RSNA is to develop and coordinate programs to move
radiology from subjective interpretations to objective, quantitative
interpretations (i.e., ``imaging biomarkers''). In November 2006 the
RSNA convened a group of stakeholders to advise the organization on
what role it could most constructively play with regard to imaging
biomarkers. The RSNA subsequently launched, and continues to sponsor,
multiple initiatives to promote the quantitative, objective extraction
of information from clinical images, focusing on imaging in clinical
trials as an appropriate approach to establishing the necessary
groundwork to support the use of imaging as biomarker.
Among our various activities I would like to highlight just two:
the Quantitative Imaging Biomarkers Alliance (QIBA) explicitly brings
together representatives from the medical device imaging companies,
representatives from the pharmaceutical industry and academicians to
improve the accuracy and reproducibility of numbers extracted from
medical scans (http://www.rsna.org/Research/giba-intro.cfm).
Current scanners can be thought of as elaborate cameras, designed to
produce exquisite pictures. They are not engineered to make precise
measurements. A ``sound bite'' version of QIBA's mission is to
encourage the vendors to produce measuring devices rather than just
The second activity to mention today is the Imaging Biomarkers
Roundtable, which brings together representatives from any and all
organizations with an interest in or activities related to improving
quantitative imaging biomarkers (http://www.rsna.org/Research/
roundtable.cfm). These activities were in fact started by a joint
meeting including various government agencies, with a particularly
important workshop in 2005 hosted by the NIST. Although I am not
speaking on behalf of all these organizations today, my remarks are
informed by the opinions of a diverse array of stakeholders. The
Imaging Biomarker Roundtable and the technical committees formed under
QIBA together comprise a collaborative enterprise addressing the need
for quantitative imaging methods. Over the last two years, it has
convened regular working groups for specific actions needed for
specific imaging biomarkers, and proposed an organizational context
that has potential to be self-sustaining to move the industry forward.
In my brief time for testimony today I would like to show you three
examples of common diseases, using 3 different scanning methods, where
standards for extracting quantitative information are critically
needed. NIST's participation in this endeavor is essential.
First, some technical background. All digital images, whether on
your digital cameras, your computer screens, or a medical scanner, are
made up of numbers. Every pixel or voxel has a number associated with
it. Figure 1 shows a chest CT scan with some of the underlying numbers
superimposed on the scan. Those numbers carry information, but to be
useful in medical care those numbers have to be standardized so that we
know, for example, what tissue quality each number signifies, and what
it means when that number changes over time. Right now, such
standardization does not exist.
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
Figure 1. Pixel numbers superimposed on a chest CT scan.
The first clinical example is chronic obstructive pulmonary
disease, COPD, often called emphysema. Figure 2 shows a patient who has
COPD, and all the black areas are areas of destroyed lung tissue. The
radiologist's interpretation would include a general statement about
the degree of COPD present, but no objective information about, for
example, the actual percentage of lung destroyed, or the thickness of
the walls of the airways. Those objective measures are what the
treating physician wants to know, so that he or she can determine on
the next scan whether the patient is responding to therapy or not. If
the patient is not improving or getting worse, the physician has other
treatment options that he or she could use. The treating physician
needs to have such objective measures of response prior to the time
that the anatomic changes are so obvious that a radiologist can see it
on the film. Right now we radiologists cannot provide that information
because the numbers are not standardized.
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
Figure 2. Chest CT scan of a patient with COPD.
The second clinical example is cancer. PET scans, or positron
emission tomography scans, are now widely available at hospitals in the
US and reimbursed by third-party payers for cancer. These scans show
where glucose is being used in the body. Tumor cells take up much more
glucose than normal cells because they are so rapidly growing. For PET
scanning, patients receive an intravenous dose of glucose that has a
radioactive label. The amount of radioactivity is very small, but the
amount of uptake activity in the tumor tells us how actively the tumor
is growing. If this activity has decreased after therapy has been given
for a couple of weeks, it is a very good sign that the therapy is
working. Oncologists need to know this with accuracy because, if the
therapy is not working for a particular patient, there are often
alternatives that can be given. However there are insufficient
standards for PET scanners to ensure that you would get the same number
for the amount of glucose measured in a tumor on one scanner as on
another scanner, or even on the same scanner after an interval of a few
weeks or more. NIST has already been extremely helpful in this area by
developing a reference object with a source of germanium-68
radioactivity that is traceable back to a source at NIST. This paves
the way for groups such as QIBA to promulgate recommendations for
calibrating scanners that will improve the comparability of
measurements from one scanner to another. However, there is much that
remains to be done, and continued participation by NIST experts is
essential. Figure 3 is a combined PET/CT scan of a patient with
lymphoma, showing a decrease in glucose uptake (yellow) after therapy
has been given.
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
Figure 3. Combined PET/CT scans of lymphoma before and after
The third clinical example is Alzheimer's disease. Many of us
experience lapses of memory such as forgetting where we left our keys
or what we came into the kitchen for, and sorting out whether such
symptoms are due to early dementia or simply the stress of everyday
life is extraordinary difficult. We desperately need objective measures
for Alzheimer's and other dementias. This is true not only for routine
clinical diagnosis in individual patients but also for drug trials to
develop therapies for Alzheimer's. Without objective markers of whether
the disease is responding to a drug or not, it will be impossible to
develop effective therapies. A reliable diagnosis of Alzheimer's will
probably require a combination of objective tests, as is increasingly
true for many diseases, and there are several imaging candidates for
such a multi-factorial approach for Alzheimer's disease. One such
imaging test, for which there is considerable supporting evidence, is
the volume of the hippocampus on MRI scans (Figure 4). However, the
subtle volume differences between normal and abnormal in this small
brain structure, or small changes over the course of several months,
cannot be discerned by radiologists subjectively reading MRI scans. The
scans need to be done on scanners that are calibrated with appropriate
reference objects, and the images need to be acquired with standardized
image acquisition methods, so that computer algorithms would calculate
the same accurate and reproducible hippocampal volume no matter which
scanner was used.
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT]
Figure 4. MRI scan of Alzheimer's Disease.
It has been well-established in many industries and in scientific
research that reference standards play a critical role for all
stakeholders. Reference standards provide a transparent and widely
available toolkit that enables regulators, manufacturers, researchers,
and others to know whether a product is what it purports to be.
Comparable processes do not exist today for many biomedical products
and activities. NIST could apply its in-house expertise to enhance
existing and develop new analytical tools for the biomedical sector,
characterizing relevant reference standards and providing a repository
for such reference standard materials. These improvements are necessary
not only to improve routine clinical care, but also to reduce the size
and time of clinical trials. The ``statistical noise'' due to the
current variability in diagnostic methods forces investigators to
accrue large numbers of subjects to clinical trials to achieve
statistical validity. In addition, the adoption of standardized
analytical methods and consistent reference standards would greatly
enhance the interactions of companies with the FDA. Such improvements
would establish a consistent approach to comparability assessments and
create a level playing field for all companies.
NIST has the potential to develop the measurement tools to support
improved accuracy and reproducibility of current clinical diagnostics,
enable quantitative and comparable medical imaging on current and
future imaging platforms, and develop the methods necessary to enable
and validate the next generation of medical measurement tools.
Improvements to the accuracy and precision of clinical and diagnostic
measurements will have significant short- and long-term economic
impacts in the areas of drug/therapeutic development, and most
importantly, the quality of patient care.
It is clear that the development of standard methods, validation
procedures, and reference materials for a variety of imaging methods
will be of direct benefit to patients as well as to the biotechnology
industry. If researchers working in Federal agencies such as NIST,
government regulators, industry and academic scientists work together
in this effort, it is much more likely that the outcomes will be
successful_for government, for industry, and ultimately for the benefit
of patients. NIST has begun to work with industry, academia, and other
government agencies to identify the measurement tools and standards
required to improve the quality of current biomedical measurements.
NIST has made notable contributions already in the area of reference
standards for x-ray, CT, PET and MRI (http://www.nist.gov/
A list of representative publications is included in the Appendix to
this written testimony. This preliminary work has set the stage (and
raised community expectations) to establish a coordinated program aimed
at providing national standards for all the major imaging diagnostic
methods being used clinically, and supporting industrial and medical
researchers in developing new and better medical imaging instruments
An expanded NIST program in quantitative medical imaging should be
Developing quality assurance processes for CT, PET,
MRI, and Medical Optical clinical imaging.
Identifying, evaluating, and minimizing or
eliminating sources of variability and error in imaging
Developing well-characterized phantoms (reference
objects) to reliably and accurately calibrate a variety of
instruments and systems.
Developing measurement methods traceable to NIST-
Developing standardized image databases for comparing
internal dose models for radiation-based imaging modalities,
and also for evaluating image processing algorithms.
Conducting and evaluating round-robin inter-
comparisons of devices and software.
Working with industry and agencies to optimize image
processing and reconstruction software, and to develop
automated (or semi-automated) image analysis.
Implementing a proficiency testing process to ensure
the inter-comparability of imaging data across different
clinical sites and across different modalities.
Developing standards and methods for inter-
comparability of clinical imaging data to support improved
analysis of change to determine drug efficacy.
This work will improve healthcare quality and lower costs through:
Improved reliability of medical imaging, resulting in:
Increased accuracy of medical imaging
Greater comparability over time and space
Fewer misdiagnoses and unnecessary repeated tests.
More accurate monitoring of disease progression and
Earlier detection of disease facilitating more
effective treatment decisions
Improved reliability and accuracy of clinical trial
Increased quality of the information that goes into electronic
health records, resulting in:
Fewer medical errors
Increased efficiency in healthcare delivery to mobile
Greater confidence for patients and healthcare
providers in the information used to make medical decisions.
NIST scientists have had productive interactions with academic
scientists in the imaging community, and the expanded program described
above would be enhanced by NIST-Academic Centers of Excellence for
Biomedical Research. Industry could contribute to NIST-academic centers
in terms of problem specification.
Another important collaborator would be the American Association of
Physicists in Medicine (AAPM). Currently, the AAPM produces many
detailed scientific, educational and practical reports for technology
and procedures in medical imaging and radiation therapy. These reports
include specific processes for radiation dose measurement and
calibration, quality assurance and peer review. These are presented in
educational forums at national and regional meetings and are also
publicly available. AAPM has recently called attention to the need for
a technology assessment institute to provide industry with independent
pre-market or post-market evaluations. AAPM could provide key
complementary expertise to the scientists at NIST. For example, when
well-defined physical or engineering differences exist between
products, unrelated to different anatomic or physiological phenomenon,
comparative effectiveness can be determined by assessing technology
using quantitative metrics. This would be particularly useful and cost-
effective in situations where simple modifications of an existing
medical technology are introduced or a new technology is available that
is changing rapidly in its potential for proving efficacy. An example
includes the optimization of radiation dose in CT. Image quality can be
assessed quantitatively on different CT scanners at the same radiation
dose levels, providing an objective measure of comparative
effectiveness that may not require a clinical trial. These comparisons
could also include the analysis of safety mechanisms to avoid
accidental over doses as well as a review of quality control
procedures. Another example is the comparative evaluation of
mammography, breast CT, and breast tomosynthesis in detecting and
assessing the extent of breast cancer using various metrics of physical
and psychophysical image quality (e.g., spatial resolution, noise, or
conspicuity) and balancing the results in terms of cost and radiation
dose level. In those cases and at those times, relatively inexpensive
physical measurements or observer-based diagnostic accuracy studies may
be very appropriate. A biomedical research group or institute focusing
on the science behind those topics would be valuable.
In addition to scientists at NIST and at academic centers, the
private sector will continue to develop reference objects, software and
other products that can contribute to the goal of more accurate and
reproducible quantitative measurements in imaging. A valuable activity
for NIST would be to create a user facility where industry and academic
scientists can test, demonstrate and calibrate their products for
optimal use in this arena. For example, different imaging modalities
currently have either none or too many phantoms that are not
standardized, evaluated etc. There are many proprietary solutions that
are difficult to compare and to integrate. The imaging industry would
benefit from a standard for equipment development and sales. The
pharmaceutical industry needs it for clinical testing and having a
comparable quality information source (comparable to clinical lab data
with its existing quality standards).
Very importantly, there is a critical need for a neutral broker,
trusted by the public, to develop an Accreditation of Performance Level
program, with accompanying policies and procedures. NIST is ideally
suited to perform this role. An example of one function of such an
accreditation program would be for NIST to be the secure holder of
image databases. For the independent test of a new algorithm, NIST
could have the system run on randomly selected scans from its database
based on the type of population requested. NIST would give the
sensitivity and specificity of the system, without informing the
company about the specific cases. For each testing event a different
distribution of cases would be selected for the examination. This would
preserve the integrity of the testing cases and also allow testing
across applicable populations.
Clinicians clearly need more objective diagnostic tests, and the
imaging device manufacturers want to provide their customers with such
tools. NIST can be a critical participant in this endeavor because of
its Mission, because of its experience in working with industry on
metrology issues, and because of its expert staff. Though it is
possible for the private sector to pursue many of these ideas without
NIST help, it is easy to believe that they would be strengthened were
NIST to be involved on one or more of these ways. Since the
foundational meeting in 2005, we have made great progress in the
private sector and continue to do so. Now is a very auspicious time to
loop back and again consider the most appropriate role that NIST can
play in what is arguably an inevitable development in the radiology
community for the public good.
Speaking on behalf of the imaging community in
general, we need NIST to expand its involvement in performing
measurement science to develop reference materials, reference
standards, standard processes, and validation procedures in the
biomedical imaging area, especially for CT, PET, MRI, and
medical optical clinical imaging.
To determine current and future metrology needs for
the biomedical imaging community, NIST would be well served by
an advisory board made up of both industry experts and
representatives of imaging device users (patient advocates and
There is precedent for excellent progress being made
from collaborations between scientists at NIST and university
centers. Such collaborations would be enhanced in the future by
establishing one or more NIST-Academic Centers for Biomedical
Research. An example of such a Center would be one to determine
the sources of variability in numbers derived from CT, MRI, PET
and optical scanners, and developing mitigation strategies for
the sources of variance. This is an activity that no single
manufacturer can do alone, and is an activity that academic
physicists or engineers are not funded to do.
The private sector will continue to be a source of
innovative reference objects, algorithms, and other devices to
improve accuracy and reproducibility of imaging devices. A
NIST-managed user facility that could be used by industry and
academic developers to test their devices under standardized,
controlled conditions would be an important asset for this
Finally and very importantly, there is a critical
need for a neutral broker, trusted by the public, to develop an
Accreditation of Performance Level program, with accompanying
policies and procedures. NIST is ideally suited to perform this
Thank you again Mr. Chairman and Members of the Committee. I
appreciate this opportunity to express the imaging community's views on
this important legislation. I welcome your questions.
Representative Medical Imaging Publications from NIST:
1. Coletti JG, Pearson DW, DeWerd LA, O'Brien CM, Lamperti PJ.
Comparison of exposure standards in the mammography x-ray
region. Med Phys 1997;24:1263-7.
2. DeWerd LA, Micka JA, Laird RW, Pearson DW, O'Brien M, Lamperti P.
The effect of spectra on calibration and measurement with
mammographic ionization chambers. Med Phys 2002;29:2649-54.
3. Clarke LP, Sriram RD, Schilling LB. Imaging as a Biomarker:
Standards for Change Measurements in Therapy Workshop Summary
(2006). Acad Radiol 2008;15:501-30
4. Baer TM, Clark CW, Karam L. ``Programs Supporting Quantitative
Imaging in Biomedicine at the National Institute of Standards
and Technology,'' In: Mulshine JL, Baer TM, editors.
Quantitative Imaging Tools for Lung Cancer Drug Assessment. New
York: Wiley; 2008. p. 111-22.
5. Zimmerman BE, Cessna JT, Fitzgerald R. Standardization of 68
Ge/ 68 Ga Using Three Liquid Scintillation Counting
Based Methods. J Res Natl Inst Stand Technol 2008;113:265-80.
6. Levine ZH, Grantham S, Sawyer DS IV, Reeves AP, Yankelevitz DF. A
Low-Cost Fiducial Reference Phantom for Computed Tomography. J
Res Natl Inst Stand Technol 2008;113:335-40.
7. Karam LR, Radiation-based quantitative bioimaging at the National
Institute of Standards and Technology. J Med Phys
8. Zimmerman B, Kinahan P, Galbraith W, Allberg K, Mawlawi O.
Multicenter comparison of dose calibrator accuracy for PET
imaging using a standardized source. J Nucl Med. 2009;50:123.
9. Levine ZH, Li M, Reeves AP, Yankelevitz DF, Chen JJ, Siegel EL,
Peskin A, and Zeiger DN. A Low-Cost Density Reference Phantom
for Computed Tomography. Med. Phys. 36:286:288 (2009)
Biography for Daniel Sullivan
Daniel C. Sullivan, M.D. is Professor and Vice Chair for Research,
Department of Radiology at Duke University Medical Center, coordinator
of imaging activities for the Duke Comprehensive Cancer Center (DCCC),
and Director of the Imaging Core of the Duke CTSA program. He is also
Science Adviser to the Radiological Society of North America (RSNA). He
completed radiology residency and nuclear medicine fellowship in 1977
at Yale-New Haven Hospital, and was in academic radiology for 20 years
before joining the National Cancer Institute at NIH in 1997. From 1977
to 1997 Dr. Sullivan held faculty appointments at Yale University
Medical Center, Duke University Medical Center, and University of
Pennsylvania Medical Center. His areas of clinical and research
expertise are in nuclear medicine and oncologic imaging. From 1997 to
2007 Dr. Sullivan was Associate Director in the Division of Cancer
Treatment and Diagnosis of the National Cancer Institute (NCI), and
Head of the Cancer Imaging Program (CIP) at NCI. Dr. Sullivan's current
responsibilities at Duke include heading the Imaging Core of Duke's
CTSA program, and the Imaging Program in Development for the Duke
Comprehensive Cancer Center. These activities focus on improving the
use of imaging as a biomarker in clinical trials and facilitating
translational research involving new and established imaging methods.
In his role with the RSNA Dr. Sullivan coordinates integration of a
wide range of national and international activities related to
quantitiative imaging, including the evaluation and validation of
imaging methods as biomarkers in clinical research.
Chairman Wu. Thank you very much, Dr. Sullivan.
At this point, it is appropriate to open for questions. I
want to let everyone know that votes will be called fairly soon
on the floor.
Mr. Smith has informed me that he has some scheduling
challenges in coming back after the votes, as do I, and unless
Members object, I will do my level best to get through a first
round of questions for all Members. And I want to thank the
witnesses for making the trip here, but we will also get you
questions in writing through the staff, and look forward to
your responses to all.
So, my five minutes. Dr. Baer, you referred to this, and I
would be interested in hearing from the entire panel about
this. NIST has had some role in biologics, and yet, it has not
played a significant role in standards-setting for the
healthcare industry as a whole.
What do you see as impediments, what has prevented the
healthcare industry from using NIST more broadly, and what do
you think NIST can contribute to some of the current
challenges. I know that much of the testimony went to that, but
I would like to give you all another pass at this, because I
think it is such an important topic.
Dr. Baer, would you like to go first?
Dr. Baer. That would be fine, Chairman Wu.
I think NIST has tremendous capacity to supply the
perspective on standards development and building consensus
within the biomedical, bioscience research area. So, there is
no lack of will or perspective.
I think that at NIST, they do lack some of the expertise
and personnel in the drug development area, and they also lack
the appropriate interfaces to the pharmaceutical and drug
And I think establishing those interfaces through an
advisory panel, as has been suggested, is an excellent first
step. And then, I think we have to do a very serious gap
analysis, in terms of the personnel and expertise at NIST, to
see do they have the appropriate personnel there to address
this rapidly changing industry within the biomedical and
Ms. Terry. I certainly would agree with that, and I think
the industry, while not eager for standards in some ways, is
very eager in other ways. And so, I think in the development of
diagnostics, of imaging, they are looking for ways to make
And what I have seen at NIST, also, in my work with them,
but largely on genetic testing, is excellent individuals who
really want to do the best job, but don't seem to have the
overall structural or architectural support they need there,
Chairman Wu. You mean in the organization?
Ms. Terry. In the organization, and so a division or a
program of biological or biomedical metrology would seem to
make the greatest sense to me.
Dr. Sullivan. I would just add I think it is an
organizational matter of creating a formal program there,
because biology is quite complex. Every patient is unique. It
isn't quite the same as developing other types of devices in
industry, and I think some of the staff there would benefit
from an ongoing interaction with what the real clinical
problems are, and how it relates to the measures.
Chairman Wu. OK, then let me follow that up, and just go
right down to how do you see the organizational structure at
NIST best centered on, say, a joint university/NIST research
center, biomedical research center, or, and something that
includes industry, also? Let us just go across the row again.
Dr. Baer. Well, I think NIST has shown, in many occasions,
the benefits of working closely with academia, and I think
joint institutes, joint research centers, have proven to be one
of the best ways for NIST to advance measurement science.
So, I think that is an excellent approach. However, I do
feel that NIST needs at its Gaithersburg or Boulder facility, a
center of expertise, as Dr. Sullivan was saying, where they can
guide these interactions, and they also need to have that
center properly interfaced to industry.
Chairman Wu. Are they short on personnel, or do they have
the people, but just not properly organized?
Dr. Baer. I think there are some distinct gaps. I feel that
they definitely lack sufficient experts in the drug development
industry and knowledge of the drug development industry in
other areas of bioimaging and molecular analysis. So, there is
definitely a lack of personnel.
I also think that there is a need for a centralized
organization. Many of these individuals are located in
different laboratories. And the VCAT has commented, in several
reports, that though they do expert work on their own, they are
not coherent. They are not organized efficiently, because they
are separated across different locations and different
So it is both a lack of personnel and a lack of real
Chairman Wu. Thank you, Dr. Baer. My time is expiring, but
I want to give Ms. Terry and Dr. Sullivan a cut at this
Ms. Terry. So, I will be quick.
So, I completely agree with that, and in addition, Chairman
Wu, to your question, I would say that the novel partnership
between academia, industry, and government, done well, is the
right thing here. Each of them have very different things to
bring to the equation, and they really could make the right
package for biomedical sciences.
Chairman Wu. Thank you very much. Dr. Sullivan.
Dr. Sullivan. And I would just add, I think there are two
separate things here. One is the partnerships, the
collaborations, that can take place anywhere, sort of
virtually. Second, I think there does need to be a physical
user facility, Boulder might be a place, or Gaithersburg, where
there can be the machines to document compliance with profiles
Chairman Wu. Would the Neutron Facility be one of the
important physical assets?
Dr. Sullivan. Could be. Could be part of that. Yes.
Chairman Wu. OK. Thank you. Mr. Smith's five minutes.
Mr. Smith. Thank you, Mr. Chairman, and I will try to be
Dr. Baer, you mentioned in your testimony interaction with
NIST on development electronic medical standards. Where are we
in the process?
Dr. Baer. Well, I think NIST has been tasked to be a key
player in this whole effort, and the Information Technology
Lab, under the direction of Cita Furlani, is being very
effective in leading the discussion of these standards.
I think this is an enormous challenge, and requires the
coordination of both the private sector and the government
sector to accomplish the task. I think they are making great
progress, and I think it is one of their, if not their highest
priority, it is one of the major priorities in the ITL
[Information Technology Laboratory] Lab, and I greatly admire
the efforts that Cita and her staff have put into this.
I think they are making tremendous progress.
Mr. Smith. So, how far off would you say?
Dr. Baer. I think that is best to ask Cita Furlani. What I
will tell you is it is an enormous challenge, and they have
been making good progress. I think that Cita is the best person
to ask that_answer that question.
Mr. Smith. OK. All right. Thank you.
And Dr. Sullivan, in the medical imaging field, what
percentage of clinics and other organizations use the
suggestions or standards set out by the Radiological Society of
North America, RSNA, and what interaction does RSNA have with
NIST in standards development?
Dr. Sullivan. The programs that I described on the slide
are relatively new, only about a year and a half old, and we do
have representatives from NIST involved in our technical
committees_been very effective working with the physicists who
are at academic sites.
So, the guidelines, we call them profiles from that
program, because we don't want to call them standards or
recommendations, but they are relatively immature at this
point, so we are not yet in a compliance phase, but we do need
a compliance phase, and that is where NIST could be the key
Another organization, the American College of Radiology,
that I did not mention, which is a large organization, does
have what is called appropriateness guidelines for clinical
practice, and virtually all radiologists in all medical centers
follow those. But they don't get to the kinds of standards we
are talking about in the scanners.
Mr. Smith. OK. Anyone else wishing to comment on either of
those questions? If not, that is fine, but I just__
Dr. Sullivan. I just want to add, back to your question
about the electronic health record. I think there are two major
impediments to that, which are not technical. The technology to
do this exists, but the impediments_one is a unique patient
identifier across all of the institutions in the United States,
and second, is the incentives for the organizations and medical
centers to do that, from a business/cultural/social
Mr. Smith. So, when you say unique patient identifier,
would you elaborate?
Dr. Sullivan. When patients go to different medical centers
there, because we don't use Social Security numbers anymore for
privacy reasons, they get some kind of a new number, their name
maybe is spelled differently at different places, include the
middle initial or not, and so, identifying records from one
place that matches up with the same patient in another place is
a huge problem. We don't have a standard way to do that across
the United States.
Mr. Smith. And what are your recommendations in addressing
Dr. Sullivan. I think we need to look at something like the
bioidentifiers, face recognition, iris scans, something like
Mr. Smith. Thank you very much. I yield back.
Chairman Wu. Thank you very much, Mr. Smith.
And now, I recognize the gentlelady from Maryland, Ms.
Edwards. Five minutes.
Ms. Edwards. Thank you, Mr. Chairman. And thank you to the
witnesses. I am in the Fourth Congressional District in
Maryland. It is home to the NIST Gaithersburg facility. I have
had a chance to visit there, and I think that the folks at NIST
actually would agree with some of your comments today about the
need for capacity in some of these areas, and some of the
organizational challenges that they face, so thanks for
pointing those out.
My question actually has to do with this idea of
establishing an advisory board to address the needs of the
biomedical community. Because I want to talk for a minute about
firewalls, and I think we have had other examples, and we don't
have to name agencies, where we have had these kind of advisory
boards where you incorporate the private sector, academia,
government, and you have to deal with issues around conflicts
of interest, around sort of how you are perceived, whether it
is perceived or real, in the public, to make sure that there is
real accountability and transparency in process.
And so, I wonder if you could give us some suggestions or
recommendations about how to avoid some of the mistakes that we
have seen in similarly situated advisory boards, and how that
could operate differently in the context of the work at NIST.
Ms. Terry. So, I would like to take a stab at that,
So, I think there is the saying that without a conflict,
there is no interest, and I usually begin things that I speak
about saying I have the greatest conflict, because I have the
greatest interest, and children with a disease certainly make
one, sometimes, crazy.
I think the way that we avoid this, and in fact, the health
information standards committee that I am sitting on right now
is a mixture of the industry, the vendors, the universities,
and the people who need this information for the electronic
health record, is by mixing those people together, and by
having strong leadership for the committee.
And in many cases, a kind of chairpersonship by industry
and government, or industry and the nonprofit world, seems to
be able to balance interests, and also, to lay down the right
rules. And again, I will use this committee as an example. It
has been remarkable to see the hard work that everyone is
doing, the turf battles that happen in public instead of in
private, and in the resolutions that seem to be able to take
into consideration those conflicts, because they are named.
So, I think as long as they are transparent, obvious,
available to everyone, sunshine on the data, I have seen real
wonderful advances in groups like these.
Dr. Baer. I would agree completely with Sharon's comment,
and stress the importance of having patient advocacy groups,
which can be somewhat more neutral brokers and watchdogs. I
think that transparency is the issue, and her statement without
conflict, there is no interest is absolutely right on.
The other comment I would make is NIST is used to acting
like a neutral broker in many, many areas of the industry
within the United States. So this is not a unique problem, and
I think NIST has established a tradition of being able to
function very adequately in this role as a neutral broker.
Dr. Sullivan. I don't have anything to add. I agree.
Ms. Edwards. Thank you. Thank you, Mr. Chairman.
Chairman Wu. Thank you very much, and now, the gentlelady
from Illinois, Ms. Biggert, five minutes.
Ms. Biggert. Thank you, Chairman.
One of the first years that I was here, we had the report
on the Human Genome Project, which Dr. Francis Collins, of
course, worked on, so and now, he has moved to chair NIH, which
I think is fabulous, because he worked so much with us, and did
so much, obviously, on that project.
But what is the current interaction between NIH and NIST to
assist in demand for stricter medical standards? Dr. Sullivan?
Dr. Sullivan. In the imaging area, I know there have been
connections between, particularly, the National Cancer
Institute [NCI] and NIST, going back over about a decade. There
was a major workshop in 2006, organized by NIST, with
cooperation from NCI and FDA kind of laying out a path forward
for some of these issues related to medical scanners.
And there have been some continued interactions. I
mentioned that some of the folks involved in that workshop are
now in the committees we are working with the QIBA
[Quantitative Imaging Biomarker Alliance] activity, the NCI
people as well.
So there some precedent for those kind of interactions. I
think they could be strengthened by making this more a priority
from the management perspective within NIST.
Ms. Biggert. OK, then. And looking at all of your
backgrounds, and you have all done so much and so many
different things, but when I look at Sharon Terry, and how she
got into this because of a family situation, and yet, she has
got a patent on this genetic disease, finding the gene
diagnostic and then, the research and having a patent for the
invention associated with the gene, how do you all get together
and work on this?
It seems like you have got the framework with NIST, and you
have got your offering, but how do you get to this way where
you are talking about standards, and how the whole group comes
Ms. Terry. So, I will take a crack at that.
I think that is an excellent question, because I think what
happens is, as I said, you know, in our case, we are sort of
slammed up against walls. So, essentially, what we do is we
consult with people like Dr. Sullivan or Dr. Baer and say, ``we
can't find a way to measure this or measure that, how do we
make a''_for example, for all of us, a clinical trial is
important. So, I have colleagues who are trying to do trials
where imaging is going to be the biomarker, the end mark,
endpoint, and they can't do the right trial, because they can't
measure what they need.
And so, our collaborations, I think, are as good as they
can be without the standards, but with the standards, I think
it would be much clearer what is my job, what is their jobs,
and how we can work with one another toward real endpoints in
clinical medicine that will produce drugs and therapies and
treatments that we need.
Ms. Biggert. Go ahead.
Dr. Baer. Just to build on Sharon's comment, you know,
there is a natural tendency within all of these communities to
want standards. Again, this is not regulation. This is
consensus building standards, and in the discussions we have
had at all levels, with NIH, the FDA, and the CDC [Centers for
Disease Control], they really want NIST's efforts in this area,
because they do not focus on building these consensus
standards. It is not their role.
The same thing is true in the private sector and academic
research. These standards just accelerate progress, so there is
a natural tendency for people to want this to happen, and the
resources provided by the U.S. Government are absolutely
critical to support these efforts.
Ms. Biggert. But with the medical costs rising, obviously,
this is something that we are facing, in the country, and what
is going on as far as healthcare. And at this rapid pace, is
there a concern that having NIST decided what methods or
standards may increase the costs of providing medical care?
Dr. Baer. I think, again, NIST won't make the decision.
NIST will lead a discussion which will result in a consensus.
And quite the contrary. The lead toward personalized medicine,
and quantitative tests that will enable that, will reduce the
number of tests that are done. As it was mentioned, tests for
PSA and TSH, thyroid stimulating hormone, which are done tens
of millions of times a year, and they are repetitive tests that
need to be done, because of the lack of reproducibility and
Personalized medicine will allow the most effective
therapies to be prescribed to patients, based on their personal
molecular diagnosis. I firmly believe that this will
substantially reduce the cost of medical, and it is a critical
part of the overall program to do so.
Ms. Biggert. Well, that is good, because obviously, if we
eliminate competition or disallow some forms of testing, then
this would be in the opposite direction. Or, if there is
picking winners or losers. We have had that in the banking, we
don't want to get this into the scientific__
Ms. Terry. I think, in fact, we will have better, cleaner,
clearer competition in the sense of innovation and competition
if we have standards. Because innovation will build on
standards very, very rapidly. We are starting to see that in
the health information technology field, and I think we would
see it in other fields as well.
Dr. Sullivan. Yes, I would endorse that. Two points.
One is I also agree it would help to reduce duplication in
the medical imaging area. We don't have good data on this, but
it is estimated maybe 20 or 25 percent of scans are just
duplicate scans, because they can't compare them. And they are
very expensive, so that would be a huge cost.
In terms of competition, in our work with the medical
device manufacturers, and these are all of the large companies,
GE, Phillips, Siemens, Toshiba, they view standards as an
opportunity for competitiveness. That is, they can work to
claim that their device is more compliant than their
competitors with these standards.
Ms. Biggert. Thank you very much. I yield back.
Chairman Wu. Thank you very much, Ms. Biggert. Thank you
all very, very much for this very helpful testimony. We do have
additional questions, which will be submitted in writing. I
appreciate the distance that you all have come. I appreciate
the work that you have done in your respective fields, and look
forward to hearing more about that work as well.
Unless there are any other additional questions from the
panel. Thank you all very, very much for appearing this
afternoon. The record will remain open for two weeks for
additional statements from the Members, and for answers to any
follow-up questions the Committee may ask of the witnesses.
The witnesses are excused with the panel's great gratitude,
and the hearing is now adjourned.
[Whereupon, at 2:45 p.m., the Subcommittee was adjourned.]
Additional Material for the Record
Testimony of Dr. Karen Mann, PhD, President of the Association for
Chairman Wu and Members of the Subcommittee_thank you for the
opportunity to provide written testimony on How Can NIST Better Serve
the Needs of the Biomedical Research Community in the 21st Century.
My name is Karen Mann and I am the current President of the
Association for Molecular Pathology (AMP), an international medical and
professional association representing approximately 1,800 physicians,
doctoral scientists, and medical technologists who perform laboratory
testing based on knowledge derived from molecular biology, genetics and
The modern healthcare system offers great potential for
personalized and effective medical care. However, the recognition and
implementation of advances in medical research will be hindered by a
lack of certified reference materials. Molecular assays provide the
cutting edge diagnostics for many individualized therapies in oncology,
transplantation, infectious disease and genetics, but the production of
certified reference materials has fallen far behind the technical
capabilities of these assays. Reference materials are important to
ensure the necessary sensitivity, specificity and level of
reproducibility of intra- and inter-laboratory test results. The best
approach to achieve consistent and comparable quantitative data amongst
laboratories is by the use of internationally established reference
\1\ Robertson JS. ``International standardization of gene
amplification technology.'' Biologicals 26:111-3, 1998.
To illustrate the challenges of the dearth of reference materials,
I will provide you with examples from four areas of active innovation
in molecular diagnostics.
Example 1: Targeted therapeutics and tumor markers
Targeted therapeutics are drugs that directly target genes or
genetic pathways involved in disease. Molecular testing is used to
identify patients with these mutations in order to direct therapy to
the appropriate patients, and, in some cases, to monitor response to
therapy. Reference materials are necessary to ensure that these tests
have appropriate sensitivity, specificity, and reproducibility. Chronic
myeloid leukemia (CML) is a paradigm for molecular diagnosis and
targeted therapy. Historically, the only definitive treatment was bone
marrow transplant, a treatment with high morbidity and mortality and
limited utility. A recently developed novel class of medicines,
tyrosine kinase inhibitors (TKIs), has revolutionized the treatment of
TKIs specifically target the oncogenic BCR-ABL fusion protein seen
in CML, resulting in effective control of the tumor cells with
relatively few side effects. The standard of care for monitoring the
effectiveness of CML therapy is the quantitative molecular assessment
of the level of the BCR-ABL fusion transcript in the patient's blood.
Response to therapy is measured
by transcript level and rising levels of the fusion transcript
indicate early relapse, development of resistance mutations, and the
need to alter therapy. Accurate assessment of the level of BCR-ABL is,
therefore, essential for both the individual patient and to accurately
compare results between centers in clinical trials for improvement of
These advances have obviated the need for transplant in most CML
patients, but the lack of standardized reagents has limited the
reproducibility of these assays within and between laboratories.
Therefore, if a patient has samples sent to different laboratories, as
happens if they switch healthcare providers, it is impossible to
accurately monitor the response to therapy. Therefore, quantitative
standards for monitoring BCR-ABL are urgently needed. Furthermore, the
model provided by CML may become the standard for other genes with
molecularly targetable mutations or mutations suitable for minimal
residual disease monitoring; e.g. PML-RARA and variants, FLT3, cKIT,
PDGFRA, PDGFRB, NPM1, ETO-AML1, JAK2, MLL-mutation variants, etc.
Example 2: Companion diagnostic tests
Molecularly targeted therapies are frequently expensive and
sometimes have significant side effects. Molecular pharmacogenomic
assays (also called companion diagnostics) are used to identify
patients likely or unlikely to benefit from these therapies, providing
a method for optimizing the cost-effective delivery of healthcare. This
is exemplified by the recent recognition of the role of KRAS mutations
in colorectal cancer to identify patients unlikely to benefit from
monoclonal antibody therapy (Cetuximab/Erbitux) that inhibit the
epidermal growth factor receptor (EGFR). Mutations in KRAS preclude
response to this therapy. However, the sensitivity and specificity of
different molecular assays for identification of KRAS mutations varies
with technique. Additional activating mutations of KRAS have been
identified which need further study in order to understand whether they
also cause resistance to anti-EFGR therapy. Standardized reagents are
urgently needed to allow comparative analysis between clinical
protocols. Mutations in the EGFR gene itself also appear to predict
responsiveness to EGFR small molecule tyrosine kinase inhibitors (TKIs)
in non-small cell lung cancer (NSCLC). However, EGFR mutations are
considerably more varied than KRAS mutations, demonstrating the need
not only for standardized reagents but also for an up-to-date EGFR
somatic mutation database that can predict TKI response in NSCLC for
Example 3: Transplant follow-up care and quantitative standards
Standardized molecular reagents are also urgently needed in the
transplant setting. At the end of 2006, over 170,000 people in the U.S.
were living with a functioning solid organ transplant; 27,578 solid
organ transplants were performed in 2007.\2\ From its founding in 1986
through 2004, the National Marrow Donor Program coordinated more than
20,000 bone marrow and peripheral blood stem cell transplants.\3\ All
patients who have undergone transplants are given immune-suppressive
drug therapy and are as a result more susceptible to viral and fungal
diseases. Viral diseases can result via transmission from the donor
tissue, exposure to the environment or more typically, reactivation of
the patient's own latent viruses, held for years within their own body.
\2\ Wolfe RA, et al. ``Trends in organ donation and transplantation
in the United States, 1998-2007.'' American Journal of Transplantation
\3\ U.S. Department of Health & Human Services Health Resources and
Services Administration (HRSA). 2004 Biennial Report of the National
Bone Marrow Donor Registry. Available online at http://
Several common viruses represent recognized and severe
complications of organ and bone marrow transplantation, which adds
excessive costs to US healthcare systems. Quantitative testing for
viruses (viral load testing, e.g. for CMV, EBV, and BK viruses) is
considered standard of care for perpetual monitoring of transplant
patients. Current laboratory tests, however, show marked variability
among commonly used methods because there are no established
quantitative virus standards. Because of the variability among
laboratory tests, repeat testing is often required when a patient
switches health insurance or travels to a different hospital or city.
Therefore, quantitative virus standards are urgently needed by the
clinical laboratory community in order to provide accurate,
reproducible, and comparable results and to reduce errors and repeat
testing, all of which add to overall healthcare costs for this already
costly group of patients.
Example 4: Reference gene sequence database
Currently, clinical sequencing methods rely either on the use of
public sequence databases for sequence comparisons or on the use of
annotated databases owned by commercial companies, which require high
proprietary fees. Genetic sequence banks such as GenBank are
unacceptable for use in clinical laboratories because of the open
platform for those who enter sequences and the limited sequence
verification for GenBank submission. Clinical laboratories performing
gene analyses need a ``certified'' reference sequence that is locked
Clinical laboratories rely on accurate genotypic bacterial
identification based on the 16S rRNA gene for many fastidious microbes
and fungi. The use of the 16S rRNA gene for identification of bacteria
and fungi provides a faster method to identify slow growing organisms.
Traditional methods may take up to 3 weeks to identify the microbe and
delays in adequate treatment can occur, causing mortality and
increasing hospital costs and in some cases, like tuberculosis, a risk
to the public health. Two databases services, freely available on the
Internet, offer an improved scenario, with some level of verification:
1) The Ribosomal Differentiation of Medical Microorganisms (RIDOM), and
2) the Ribosomal Database project (RDP) from the University of
Michigan. These databases offer improvements in secondary-structure
based alignment that provides better support for short partial
sequences and improves handling of certain sequencing artifacts.
However, limitations exist with these databases including, but not
limited to, limited species representation and research use only
While improved over GenBank, experience in the clinical laboratory
with analysis of the 16S rRNA gene of patient strains has shown that
clear-cut results are not the rule as the existing databases are not
always well annotated and taxonomic changes are not regularly and
rapidly updated. Commercial databases, such as MicroSeq (Applied
Biosciences), and databases from reference laboratories such as Mayo
Clinic and ARUP Laboratories offer better coordination with clinical
laboratories, yet still rely on the subset of microbes submitted to
them for identification to populate their databases.
As many clinical, research, and environmental laboratories
currently use 16S-based identification of bacteria, including
mycobacteria, a widely available quality-controlled database that
interfaces freely and seeks to populate it with medically identified
microbes from across the globe is long overdue. It is essential to
accurately identify species or detect true sequence variations leading
to the discovery of new species, with data validation protocols akin to
that of 21 CFR Part 11 compliance. Ideally, such a database would
provide ribosome related data and services to the clinical community,
including online data analysis and aligned and annotated Bacterial and
Archaeal small-subunit 16S rRNA sequences, as well as fungal rRNA
sequences, and genetic sequences related to antimicrobial resistance.
In terms of ``personalized medicine'' this resource would be valuable
as sequence analysis of resistance mutations will be integral to
initiatives such as personalized anti-tuberculosis (TB) therapy so that
clinical laboratories could quickly identify drug resistant TB (MDR and
XDR TB), a priority identified by the NIH.
The need for certified reference sequences extends to human genes,
for both inherited diseases and acquired disorders (cancers). For
example, the RET proto-oncogene is associated with Multiple Endocrine
Neoplasia Type 2 (MEN2). From GenBank, two isoforms are given as well
as alternative assemblies. One reference sequence lists a known minor
allele as the wildtype allele. Reference sequences differ as some only
include the coding region, whereas others include the entire genomic
sequence. In addition, sequences may include the 5' untranslated region
or begin with the first base of the transcribed mRNA. All these
differences can cause confusion between reports from different
laboratories testing for the same disease, based on which reference
sequence is used. A clinically certified reference sequence would be
checked to determine that the most common sequence is listed as the
reference, and document known benign SNPs. The reference sequence would
ideally have the chromosome, locus and sequence numbering so that
results from different laboratories will be consistent. Annotating
positions of the SNPs could help in designing assays thereby reducing
the potential of false negative or positive results. A list of known
benign SNPs can also help in interpretation when these variants are
PRIORITIES: STANDARDS ARE URGENTLY NEEDED
While in the end, we hope to have standardized reference materials
for all diagnostics targets and certified reference databases for all
clinically relevant gene sequences, some are more urgently needed than
a. Cytomegalovirus (CMV), quantitative assay standard,
a recognized complication of organ transplantation
b. BCR/ABL Adelaide standard; BCR/ABL tests are used
to diagnose patients with a specific leukemia and to
monitor their response to treatment
c. KRAS mutation standards; KRAS mutation analysis
testing is used to select patients for a specific
d. EGFR mutation standards; EGFR mutation analysis
testing is used to select patients for a specific
2. Short term (one year)_all quantitative assay standards.
a. BK virus (BKV), a recognized complication of kidney
b. Epstein Barr Virus (EBV), a recognized complication
of organ transplantation
3. Medium term (1-3 years)
Below is a list of infectious agents, the diagnostic tests for
which require standardized reference materials as well as note of the
Certified Gene Sequence Databases (CGSDs). In addition, there is a
significant need for reference standards for a number of oncology
tests. AMP recommends that an ongoing program be established at NIST to
create certified reference standards for molecular diagnostic tests and
that NIST consult with molecular pathology experts to identify and
prioritize standardized reference material development.
a. Adenovirus, quantitative assay standard; important
for directing antiviral treatment in immunosuppressed
b. Enterovirus, qualitative assay standard
c. Hepatitis B virus (important for liver transplants
and also in the general population), quantitative assay
d. Herpes simplex (HSV), types 1 and 2, qualitative
assay standard, recognized complications of organ
e. HHV-6, HHV-7, and HHV-8, increasingly common
complications of organ transplantation, which may add
severity to the more common CMV infections
f. HTLV 1 and 2, qualitative assay standard, important
for transfusion services
g. Human metapneumovirus (HMPV), qualitative assay
h. Influenza virus, qualitative assay standard
i. JC virus, quantitative assay standard, closely
related to BKV
j. Parainfluenza virus, qualitative assay standard
k. Parvovirus B19, quantitative assay standard
l. Respiratory syncytial virus (RSV), both qualitative
and quantitative assay standards; quantitative assays
are used as prognostic markers for patient care
m. Varicella zoster virus (VZV), recognized
complication of organ transplantation
n. Certified Gene Sequence Databases (CGSDs)
(1) Gene mutation sequence database, suitable
for clinical test reference
(2) Infectious agent (bacteria, viruses)
sequence database, suitable for clinical test
o. Scientific advisory committee to identify and
prioritize areas of needed references materials and to
direct resources and the work of the CGSDs
AMP's Ongoing Efforts
AMP professional committees have collaborated with NIST and the CDC
previously to identify, characterize and make available reference
material. For example, characterized cell lines and a NIST standard are
now available for Fragile X pre-mutation sizing. These can be used for
test validation, proficiency testing, and controls or calibrators.\4\
In addition, AMP provided a detailed list of critical needs gathered
from the experience of AMP members to NIST in June 2009.
\4\ Amos Wilson J, et al. J Mol Diagn. 2008 Jan;10(1):2-12
Consensus characterization of 16 FMR1 reference materials: a consortium
A focus of AMP's Clinical Practice Committee is on increasing the
speed with which the National Institute for Standards and Technology
(NIST) can prepare quantitative standards, which is critical to the
national and international laboratory community and their ability to
deliver accurate test results. The deliverable would be purchasable
standardized reference materials that would ideally be available for
inter-laboratory comparison studies and purchase by commercial and
clinical laboratory communities. AMP estimates that it will cost
approximately $500,000 to develop each set of reference materials and
encourages Congress to consider funding this much needed initiative at
NIST. With some of the costs being offset by the purchasing of
materials, this is an innovative way for government to not only advance
biomedical science but generate funds.
AMP stands ready to collaborate with NIST and work with Congress to
do its part to hasten the process to achieve available certified
reference materials for all clinical tests. Thank you very much for
your attention and continued efforts to advance biomedical research
through programs at NIST.