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Library of Congress Cataloging‑in‑Publication Data

Lundblad, Roger L.
Development and application of biomarkers / Roger L. Lundblad.
p. ; cm. -- (Protein science)
Includes bibliographical references and index.
Summary: “A comprehensive assessment of biomarkers, this book covers the history and
current status of the application of biomarkers in diagnostics and prognostics. It explores the
technology used for the study of biomarkers, and the validation of biomarkers including a
comparison of the various technologies used to identify and measure biomarkers. The editors
emphasize the technology underlying biomarkers and the translation of basic science to
clinical laboratory technology, including the commercial development of biomarkers. The book
also covers proteomics and proteomic technologies and their applications in the identification
of biomarkers”--Provided by publisher.
ISBN 978-1-4398-1979-1 (hardback : alk. paper)
1. Biochemical markers. I. Title. II. Series: Protein science series.
[DNLM: 1. Biological Markers. 2. Proteomics--methods. QW 541]

R853.B54L86 2011
610.28--dc22 2010032787

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Contents
Preface......................................................................................................................vii
Acknowledgments......................................................................................................ix
Author........................................................................................................................xi

Chapter 1 Introduction to Biomarkers...................................................................1

References.............................................................................................5

Chapter 2 Application of Biomarkers in Diagnostics, Prognostics,

Theranostics, and Personalized Medicine........................................... 13
Introduction......................................................................................... 13
Nomenclature/Definitions................................................................... 13
Biomarkers and Diagnostics................................................................ 15
Biomarkers and Screening.................................................................. 16
Biomarkers and Prognosis................................................................... 17
Biomarkers and Theranostics and Personalized Medicine................. 17
Biomarkers and Specific Pathologies.................................................. 21
Rheumatoid Arthritis..................................................................... 23
Inflammation Biomarkers in Different Pathologies.......................28
Biomarkers in Ophthalmology....................................................... 39
Biomarkers in Neurology............................................................... 43
Cardiac Biomarkers........................................................................ 43
Biomarkers in Renal Disease.........................................................46
Biomarkers for Bone....................................................................... 51
Biomarkers for Exposure to Environmental Toxins....................... 51
Biomarkers and the Development of Biopharmaceuticals.................. 53
References........................................................................................... 55

Chapter 3 Development of Biomarkers for Oncology..........................................97

Intermediate Biomarkers and the Precancerous Condition................ 98
Cancer and Inflammation....................................................................99
Head and Neck Cancer...................................................................... 102
Ovarian Cancer................................................................................. 104
Pancreatic Cancer.............................................................................. 109
Prostate Cancer................................................................................. 109
Breast Cancer.................................................................................... 112
References......................................................................................... 125

v
vi Contents

Chapter 4 The Use of Proteomics to Discover Biomarkers............................... 151

Blood������������������������������������������������������������������������������������������������ 152
Urine������������������������������������������������������������������������������������������������� 155
Saliva������������������������������������������������������������������������������������������������ 158
Miscellaneous Biological Fluids/Excretory Products as Sources
of Biomarkers.................................................................................... 160
Biomarkers in Tissue Samples.......................................................... 160
References......................................................................................... 169

Chapter 5 Modified Proteins, Oligosaccharides, and Oligonucleotides

as Biomarkers.................................................................................... 191
References......................................................................................... 198

Chapter 6 Complex Biomarkers: Cells, Cell Membrane Proteins, and Cell

Fragments as Biomarkers..................................................................207
References......................................................................................... 214

Chapter 7 Use of Microarray Technology in Biomarker Discovery

and Development............................................................................... 223
References......................................................................................... 241

Chapter 8 Development of Assays for Biomarkers............................................ 257

Appendix 8.1: Model Standard Operating Procedure
for an Assay.....................................................................................268
References......................................................................................... 268
Index....................................................................................................................... 281
Preface
The term “biomarker” has assumed an identity of its own in the last decade. While
it has been in use for a number of years, it has been most extensively used in geol-
ogy. The term was first introduced in biomedical research in 1980 and has since
found wide acceptance. While a more cynical approach could have been taken,
I have tried to rationalize the current enthusiasm for biomarkers with the use of
well-established clinical laboratory analytes in clinical medicine. As an example,
O. Collinson (Cardiac markers, Br. J. Hosp. Med. (Lond) 70, M84–M87, 2009)
notes that while scarcely a week passes by without the report of a new cardiac
marker (biomarker), only two older analytes, troponins and B-type natriuretic pep-
tide, are in routine use. This book tries to catalog the various existing biomarkers
in clinical medicine and tries to match the expectations for advances in screening
technologies with the realities of statistical analysis. Finally, it is hoped that this
book will encourage consideration of biomarkers more as a concept than tangible
analytes, and that biomarker research will equally enhance the understanding of
disease and the development of a diagnostic.

vii
Acknowledgments
First I thank Barbara Norwitz and Jill Jurgensen for their patience and encouragement
during the preparation of the manuscript. Professor Keith Baggerly at University of
Texas M.D. Anderson Cancer Center provided some useful insight into the issue of
screening and biomarkers. Professor Ralph Bradshaw at the University of California
at San Francisco brought about a sense of reality to both biomarkers and UNC
basketball in 2010. Dr. Chris Burgess provided insight into pre-analytical issues
from his castle in the U.K. Finally, Trish Maloney and other research librarians at
University of North Carolina at Chapel Hill provided invaluable support.

ix
Author
Roger L. Lundblad is a native of San Francisco, California. He received his under-
graduate education at Pacific Lutheran University and his PhD in biochemistry at the
University of Washington. After postdoctoral work in the laboratories of Stanford
Moore and William Stein at The Rockefeller University, he joined the faculty of the
University of North Carolina at Chapel Hill. He joined the Hyland Division of Baxter
Healthcare in 1990. Currently, Dr. Lundblad works as an independent consultant at
Chapel Hill, North Carolina, and writes on biotechnological issues. He is an adjunct
professor of pathology at the University of North Carolina and the editor-in-chief of
the Internet Journal of Genomics and Proteomics.

xi
 1 Introduction
to Biomarkers
Biomarker research is an important category in current biomedical research. The
number of journal citations (from SciFinder©) has increased from approximately
1000 in 2000 to more than 7000 (32,000 from PubMed) in 2008; the total number
of citations from PubMed using biomarker was greater than 450,000. While the use
of the term “biomarker” is highest in biomedical research, there is substantial use of
this term in geology*; indeed the origin of the term appears to be in geology and it
is not clear as to the first use in biomedical research. The first use in a journal article
title (based on a PubMed search) was in 1980.1,2 The term biomarker is formed from
biological and marker, and while this seems straightforward enough, it has evolved
to describe a broad range of chemicals and physiological phenomena. A definition
for the term biomarker was proposed by a working group convened under the aus-
pices of the National Institutes of Health (United States) in 2001.3 A biomarker is
defined as “a characteristic that is objectively measured and evaluated as an indi-
cator of normal biological processes, pathogenic processes, or pharmacological
responses to a therapeutic intervention.” Thus, in the broad sense, a biomarker may
be diagnostic and/or prognostic, and may or may not be useful as a screening tool
for population studies. For example, prostate-specific antigen (PSA) was earlier
used as a biomarker for prostate cancer and while more recently there has been
some concern about diagnostic value,4–6 it does retain great value as a prognostic
biomarker.7–10 Likewise, CA-125 is considered not useful as a screening tool but is
useful for guiding treatment options in diagnosed patients and is a strong prognos-
tic indicator.11–18 Referring back to the above definition for biomarker, it might be
useful to define “characteristic.” The Oxford Dictionary of the English Language
defines “characteristic” in a number of different ways; the one that appears to be
most applicable for biomarker is “A distinctive mark, trait, or feature; a distinguish-
ing or essential peculiarity or quality.” Thus, a biomarker may be a molecule such
as a protein or a peptide,19–21 a modified protein such as through a process of oxida-
tion,21–23 a nucleic acid24–26 or modified nucleic acid,27–29 lipids,30–34 and carbohy-
drates.35–37 Biomarkers might reflect larger biological characteristics such as those

* There are hundreds of citations for the use of the term biomarker in the geochemical literature where
it is used to describe organic material (“molecular fossils”) in crude oil, which can be used to assign
source. See Jacquot, F., Doumenq, P., Guiliano, M. et al., Biodegradation of the (aliphate + aromatic)
fraction of Oural crude oil. Biomarker identification using GC/MS SIM and GC/MS/MS, Talanta 43,
319–330, 1996. See also Bauersachs, T., Kremer, B., Shouten, S. et al., A biomarker and delta N-15
study of thermally Silurian cyanobacterial mats, Organic Geochem. 40, 149–157, 2009; Ozcelik, O.,
Altunsoy, M., Acar, F., and Erik, N.Y., Organic-geochemical characteristics of the Milocene Lycian
basin, western Taurides, Turkey, Int. Geol. Rev. 51, 77–93, 2009; Samuel, O.J., Cornford, C., Jones, M.
et al., Org. Geochem. 40, 461–483, 2009.

1
2 Development and Application of Biomarkers

detected at the cellular level by imaging such as positron emission tomography;38–41

diffusion magnetic resonance;42–44 ­metabolomics, which uses gas chromatography
coupled with mass spectrometry for the identification of biomarkers;45–49 and vari-
ous other imaging technologies for the study of biomarkers at the cellular level.50–52
There are some studies that describe blood pressure53–56 and other fluid pressures57
as biomarkers as well as arterial stiffness measured with pulse wave velocity.58 One
group has used inflammation as a biomarker for the prognosis of ischemic stroke.59
There is interest in system biology, which identifies a biomarker as a pattern rather
than a single characteristic.60–64 It would appear that a biomarker is a characteristic
that can be used either as a diagnostic or a prognostic while the ultimate goal is a
characteristic, which could be used as a screening tool65–68 for pathologies that tend
to be somewhat “silent” prior to overt clinical display. The current work will focus
on approaches to the identification, validation, and implementation of biopolymers,
which can be used as biomarkers both for population screening and as surrogate
endpoints for therapies.
As a start, I will try to trace the path to biomarkers. I have alluded to the evolution
of the term from geological sources and will pursue that no farther. So, how have
we moved from classical clinical and laboratory markers such as HbAlc, glucose,
lipids, blood pressure, body mass index for type 2 diabetes to more sophisticated
biomarkers?69 My bias is that the development of analytical technologies such as
mass spectrometry and ultra-high performance liquid chromatography together with
computational ability to process large amounts of data have driven the search for bio-
markers; thus, proteomics (see Chapter 4) has been the enabling technology under-
lying most of the searches for biomarkers. In that sense, the search for biomarkers
has not been hypothesis-driven although there is progress in a hypothesis-driven
approach.70–73 It is also noted that biomarker research is also driven by the devel-
opment of therapeutic approaches, which require diagnosis for application such as
seen in breast cancer74–77; biomarkers that are developed in parallel with therapeutic
products are referred to as companion diagnostics,77–82 which seem to be related to
theranostics.83 As will be noted at several points in this book, the issue of nomen-
clature that has gotten somewhat out of control appears to be related more toward
marketing than scientific content.
Biomarkers may be classified as to disease application such as cancer biomark-
ers, clinical application such as a screening biomarker, and system/organ biomarkers
such as renal biomarkers. DeCaprio has discussed the classification of biomarkers in
some detail,84 and the reader is directed to this source for a larger discussion of this
subject. DeCaprio suggests that the term biomarker has been diluted by overuse and
I am of the same opinion. Referring to a laboratory analyte as a biomarker does not
enhance value of the analyte and discovery of a biomarker by a sophisticated labora-
tory technique such as mass spectrometry does not endow the analyte with magical
properties. The use of the term biomarker as a response to an environment stress or
in response to a therapeutic intervention seems quite reasonable. The term biomarker
then is more of a concept than a laboratory analyte, where the discovery of the bio-
marker is closely related to the biology underlying the production of the biomarker.
I cannot emphasize this point too strongly as an understanding of the biology will
increase the chances of developing an assay, which is robust and reproducible.
Introduction to Biomarkers 3

Dr. Keith Baggerly at M.D. Anderson notes that “Only if the data are reproducible can
you talk about whether they are right.”85 The issue of reproducibility in the complex
area of biomarker discovery and development has resulted in the emerging disci-
pline of forensic bioinformatics86 to evaluate high-throughput studies such as those
involving microarray technology.
Various investigators have referred to the search for biomarker as “searching for
a needle in a haystack.”87–93 Peck has recently suggested burning the haystack to find
the needle within the context of eliminating unsuccessful drug candidates earlier
in the development process.94 More germane to the current discussion is a paper by
James Bearden that appeared in 1972,95 which I recommend for serious consider-
ation within the context of current biomarker research; I also direct the reader to
a recent Web site for a discussion of the expression “needle in a haystack.”96 The
analogy here is how to find something that is significantly different from similar but
not identical materials; in the case of biomarkers, how does one identify something
abnormal when such material is only slightly abnormal when compared to normal.
The understanding of “normal” presents its own problems. Murphy97 lists seven
d­ efinitions/meanings for the word “normal” including having probability density
function, most representative of its class, most commonly encountered in its class,
and commonly aspired to.
Much of the work on the development of biomarkers centers on the use of blood
as a source (see Chapter 4), and there is much data on “normal” composition since
blood is used so frequently for traditional diagnostic purposes.98–101 Palkuti99 presents
a good summary of the establishment of normal. A normal range (reference interval)
must be established for each analyte (biomarker); this is value expected for 95% of
the population.101 The term “reference interval” has replaced the term “normal”; this
is also referred to as reference range or reference values. At one time, a reference
interval could be obtained from a pool of 30 individuals. The current approach to the
determination of a reference interval uses a population of at least 120 individuals102
although arguments are made for smaller sizes in unusual circumstances.103 Ceriotti
and colleagues104 have recently discussed current concepts in the development of ref-
erence intervals. Reviews of importance for the consideration of reference intervals
include that of Friedberg and colleagues,105 Ricós and coworkers,106 and the excellent
chapter by Solberg in Tietz.107
The establishment of a reference standard and a reference interval is usually not
considered until the process of transition from biomarker discovery to validated
assay (see Chapter 9); however, the concept of reference intervals/normal should
be considered in the discovery of biomarkers. It is worth noting that 198 (200) sub-
jects are required to obtain a reference range with 99% confidence level.108–110 The
issue is further complicated by the suggestion that each significant subgroup (gender,
age, etc.) contains 200 subjects.111 This is likely necessary for the development of
a screening assay but it is likely that less onerous requirements can be developed
for developmental use. Research on biomarkers can be limited by smaller numbers
of subjects and the cost of the experimental analyses. Some studies are relatively
large112 while others are embarrassingly small.113
The concept of normal is confounded by the related issues of biological variation
and the “index of individuality.” Biological variation includes issues such as gender,
4 Development and Application of Biomarkers

age, and ethnicity, which can be addressed by the identification of the subject and
diurnal variation,114 which can be addressed by sample collection time. Somewhat
more difficult to assess are the effect of drugs such as that of oral contraceptives on
C-reactive protein levels in women.115 More complicated are effects of season116–118
and occupation116,117,119 (excluding exposure to environmental agents). There are
several substantial works on biological variation.120,121
The index of individuality122,123 is an approach to assessing the effect of intra-
individual variation on the measurement of clinical analytes and is closely related to
biological variability. This has been the subject of considerable discussion124,125 over
the years and continues to be of importance but does depend on the analyte.126–129
The index of individuality is of importance more for the application of biomarker
research (development of assays as in Chapter 8) than the actual discovery process as
it is argued that a “one-hit” wonder should be seriously considered.130 Jensen and col-
leagues131 observed that there was extensive biological variability in bone biomarkers
and a single measurement was of little value. There was a great difference in indi-
vidual biomarkers; urinary hydroxyproline has a high index of individuality (1.23)
such that 255 samples would be required to determine the true mean while osteo-
calcin in serum had a low index of individuality of 0.23 with six samples required
for the determination of true mean. In general, individual (single subject) variation
is suggested to be minor compared to intra-individual variation.132,133 There are sev-
eral studies that have attempted to “isolate” the variance in sample preparation from
“downstream” variance in the analytical instrumentation and data analysis. Anderle
and coworkers134 have presented an analysis of proteomic expression profiling by
HPLC-MS. The model sample was human serum. Sample preparation involved
several steps: removal of albumin and IgG, reduction/alkylation, and tryptic diges-
tion in a process known as shotgun proteomics.135 Choe and Lee136 observed a high
CV in their studies on the reproducibility of two-dimensional gel electrophoresis
and reported a method for assessing variability. Knudsen and colleagues evaluated
pre-analytical variability and biological variability on IL-6 concentration in healthy
subjects and patients with rheumatoid arthritis.137 It was concluded that a change of
greater than 60% is likely to indicate changes in disease activity.
The previous material is not meant to discourage investigators but is intended to
emphasize that despite the large amount of published work, the search for biomarkers
is not a trivial endeavor and considerable effort should be taken to carefully plan the
work. The availability of user-friendly instrumentation has been both a blessing and a
curse. The availability of instrumentation for surface plasmon resonance has enabled
the rapid acquisition of data on molecular interactions and the study of ­biomarkers.138,139
In the hand of skilled investigators,140 good, reproducible data can be obtained. However,
a critical evaluation of the literature141 would suggest that there is a lack of careful inves-
tigators. The record of transition from discovered biomarker to clinical assay (approved
FDA assay) is suggested to be one per year since 1998.20,142 While some of the fault
can be ascribed to the cost of obtaining data sufficient for approval,143 there are likely
other issues such as poor understanding and appreciation of pre-analytical issues, lack
of understanding of the biology of the system in question, difficulty in migration from
discovery platforms to commercial analytical platforms, and failure to understand that
a new assay must add true value to the overall therapeutic process.
Introduction to Biomarkers 5

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Introduction to Biomarkers 7

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