18
Bioinformatics
ROBERT E. HOYT • WILLIAM R. HERSH • INDRA NEIL SARKAR
LEARNING OBJECTIVES
After reading this chapter the reader should be able to:
• Define bioinformatics, translational bioinformatics,
and other bioinformatics-related terms
• State the importance of bioinformatics in future
medical treatments and prevention
• Describe genomics and its important implications for
health care
INTRODUCTION
This chapter is focused on “bioinformatics,” the study
of data and information as it relates to knowledge within
the context of the life sciences. Bioinformatics traces
its formal beginning to 1970, when the term was first
introduced in scientific literature.1 In many ways, bioin-
formatics has evolved in parallel with health informatics.
Significant advances in bioinformatics have given rise
to contemplation of its applications within the context of
biomedicine and health (the sub-discipline of biomedical
informatics referred to as “translational bioinformatics.”)
Definitions
The chapter begins with common definitions and the
next section provides a short primer on genomics, which
underpins many of the concepts used for bioinformatics
within the context of health.
Bioinformatics has been defined as, “the field of
science in which biology, computer science and infor-
mation technology merge to form a single discipline.”2
Bioinformatics makes use of fundamental aspects
of computer science (such as databases and artificial
intelligence) to develop algorithms for facilitating the
development and testing of biological hypotheses, such
as: finding the genes of various organisms, predicting
the structure or function of newly developed proteins,
developing protein models and examining evolutionary
• List major private and governmental bioinformatics
databases and projects
• Enumerate several bioinformatics projects that involve
electronic health records
• Describe the application of bioinformatics in genetic
profiling of individuals and large populations
relationships.3-4 A related term is computational biology,
which refers to the computational aspects of molec-
ular biology. Translational bioinformatics focuses on
the “development of storage, analytic and interpretive
methods to optimize the transformation of increasingly
voluminous biomedical data into proactive, predic-
tive, preventive and participatory health.”5 Simply put,
translational bioinformatics is the specialization of bioin-
formatics for human health.
Bioinformatics is sometimes said to work with the
various “omes” and “omics.” They include:
• Genomics - the study of genetic material in an
organism (e.g., the genes that may be associated
with a disease).
• Proteomics - the study at the level of proteins (e.g.,
through the components, structure, and functions).
• Pharmacogenomics - the study of genetic material
in relationship to drug targets.
• Metabolomics - the study of genes, proteins or metab-
olites.
• Interactome - biomolecular pathways and interac-
tions of proteins
• Microbiome - microorganisms inhabiting an indi-
vidual
• Exposome – environmental factors to which an
organism is exposed
• Bibliome – the literature of science
357
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• Metagenomics - the analysis of genetic material polymorphisms (SNPs) (pronounced “snips”). There
derived from complete microbial communities har- are three general types of alterations: single base-pair
vested from natural environments.6 changes, insertions or deletions of nucleotides, and
In addition, bioinformatics studies the relationship reshuffled DNA sequences. As an example, one indi-
between the genotype, which is the genetic information vidual might have a chromosome with the sequence
that is associated with biological function7 and the pheno- TGGC, while another might have the sequence TAGC.
type, which is the observable characteristic, structure, Each of these is referred to as an allele. Although SNPs
function and behavior of a living organism. Examples of are common, their significance is complex and difficult
phenotypes include hair color, height, and development to decipher.8-10
of diseases. The phenome refers to the total phenotypic Another type of genetic variation is copy number
traits. variations (CNVs). These are repeats of DNA sequences
of 50 nucleotides or longer. There may be many CNVs in
an individual’s genome. Anywhere from 4.8% to 9.5%
GENOMIC PRIMER of the human genome is CNVs. Some of these copies of
genomes are deleterious, others are not. When they are
The human body has about 100 trillion cells and each
deleterious, they are so-called unbalanced rearrange-
one contains a complete set of genetic information (chro-
ments, involving either loss or gain of segments of the
mosomes) in the nucleus; exceptions are eggs, sperm, and
genome.11
red blood cells. Humans have a pair of 23 chromosomes
An additional cause of genetic variation is epigenetics,
in each cell that includes an X and Y chromosome for
which is the variation in the phenotype or gene expression
males and two Xs for females. Offspring inherit one
that is caused by mechanisms other than DNA sequence
pair from each parent. Chromosomes are listed approxi-
differences.12 The molecular mechanisms for epigenetics
mately by size with chromosome 1 being the largest and
are beginning to be unraveled, such as DNA methyla-
chromosome 22 the smallest. Organisms have differing
tion.13 Epigenetics shows that there is influence of the
numbers of chromosomes (e.g., our closest extant primate
environment on the expression of genes, and therefore
relatives, chimpanzees, have 24 pairs). Chromosomes
leading to genetic variation.
consist of double twisted helices of deoxyribonucleic
A great deal of progress has been made with genetic
acid (DNA). DNA is composed of four sugar-based
testing and our understanding of the human genome and
building blocks (“nucleotides”: adenine [A], thymine [T],
genetic variations. Genome-wide associations studies
cytosine [C], and guanine [G]) that are generally found
(GWAS) look at associations between genomic variants
in pairs (following “Watson-Crick” pairing templates:
and traits of the phenotype.14 The variations or SNPs
A-T, C-G). DNA is often referred to as the “blueprint for
discovered are said to be associated with the disease, but
life.” As such, a given organism’s DNA encodes its full
true cause and effect cannot be ascertained.15 Similarly,
complement of proteins essential for cellular function.
phenome-wide association studies (PheWAS) are being
Some of the encoding of DNA also enables it to control
carried out comparing genes to disease associations, most
the expression of proteins or affect how other portions
recently using the electronic health record for phenotyp-
of DNA may be decoded based on a biological context
ical information.16
(e.g., to accommodate for faulty DNA decoding or DNA
Genetic material can be obtained from blood, saliva,
damage that may be encountered due to environmental
skin and hair samples. Full genome sequencing has
phenomena). Genes are regions on chromosomes that
historically been an expensive, time-consuming, and
encode instructions, which may result in proteins that
complicated process, although the cost of full genome
then in turn enable biological functions. The process
sequencing has dropped to approximately $1000 (US).
of decoding genes involves transcribing the DNA into
SNP-based genomic profiling is available now for less
ribonucleic acid (RNA) and then translation into amino
than $200 US (e.g., 23andMe). This cost differential is
acids that form the building blocks for proteins (Figure
largely because SNP genotyping analyzes about 0.1 –
18.1). Collectively, the complete set of genes is referred
0.2% of the genome in contrast to every single nucleotide.
to as the “genome” (based on the combination of the
Even more cost effective is ultra-low-coverage (ULC)
terms “gene” and “chromosome”).
sequencing techniques that analyze the same 10-20% of
It is estimated that humans have between 20,000
the genome and cost $60 US. SNP-based genotyping has
and 30,000 genes and that genomes are about 99.9%
more specificity since it uses a technique the seeks to
similar between individuals. Variations in genomes
identify SNPs from a library of a priori selected SNPs
between individuals are known as single nucleotide
of interest (using a technology called “microarrays”);

by contrast ULC techniques may be more sensitive but
may be difficult to ensure reproducibility. Therefore,
ULC techniques may serve the role of SNP discovery,
whereas SNP-based genotyping can serve the role of
SNP identification.
Figure 18.1: Genes (Courtesy of National Institute of
General Medical Sciences, National Institutes of Health)
Often, we do not want to know just the genome
sequence but the amount that the genes are actually
expressed.17 Some call the genome itself a “parts list,”
whereas what we want to know is how much those parts
are used. One of the early techniques for measuring gene
expression was the gene microarray. These are chips
that allow measurement of many different biological
substances, not only DNA and RNA, but also protein.
When nucleotides are measured there are 25-base strands.
Since most genes are longer than 25 bases, there are more
than one spot per gene. And in fact, a typical microarray
chip has up to 1 to 2 million of these spots, so many
different genes or transcriptions of RNA of those genes
can be measured on microarrays. The technology has
now become very easy to mass produce. The initial
application of microarrays was to measure gene expres-
sion, i.e., the mRNA that had been transcribed. But other
applications of microarrays have emerged, including the
sequencing of unknown DNA. Microarrays are being
supplanted by a newer technology called RNA-seq, which
measures mRNA more accurately.
Chapter 18: Bioinformatics 359
IMPORTANCE OF TRANSLATIONAL
BIOINFORMATICS
Besides diagnosing the 3,000 to 4,000 hereditary
diseases that are currently known, bioinformatics tech-
niques may be helpful to discover future drugs targets,
develop personalized drugs based on genetic profiles and
develop gene therapies to treat diseases with a strong
genomic component, such as cancer. One approach that
has been explored to enable gene therapies involves the
use of genetically altered viruses that carry human DNA.
This approach, however, has not been definitely shown
to work and has not been for general use by the FDA.
Recent years has seen significant advances in genome
editing using a technology called CRISPR/Cas9 gene
editing. However, while manipulation of genomes in
other organisms, such as microbes, has shown promise
for energy production (“bio-fuels”), environmental
cleanup, industrial processing, and waste reduction,
clinical applications are still nascent in their design
and approval. Nonetheless, the advent of technologies,
such as CRISPR/Cas9, suggest that genome editing will
become a viable path for treatment of genetically based
conditions within the next decade.18
This chapter will deal primarily with translational
bioinformatics (TBI), the identified area of focus in
bioinformatics that is focused primarily on the use of
bioinformatics approaches to address challenges in
biomedicine and health. A significant goal of TBI is to
enable bi-directional crossing of the translational barrier
between the research bench and the bed in the medical
clinic. With growing genome-wide and population-based
research data sets, more genotype-phenotype associ-
ations are being uncovered that potentially can detect
and treat diseases with a genetic component earlier.
Such associations may also help create tailor made drugs
for higher efficacy. Figure 18.2 demonstrates the bidi-
rectional nature of data and information flow between
bioinformatics and health informatics. The emergence
Figure 18.2: Translational bioinformatics (Adapted
from Sarkar et al)19
360 Chapter 18: Bioinformatics
of translational bioinformatics is primarily due to the
rapid advances in both sub-disciplines, and the realiza-
tion of the potential to leverage biological data within
the context of clinical care. In other words, a variety of
advances in bioinformatics, such as faster and cheaper
DNA sequencing, and more widespread adoption of
electronic health records have made this possible.
Pharmacogenomics is an illustrative example of how
translational bioinformatics can be used within the
context of pharmaceutical development to make use of
genomic information for better drug discovery and utili-
zation. Drug companies are faced with the huge expense
of drug development, the long road to producing a new
drug and expiring patents. Drug failures are common
and can be due to complex combination of a lack of
clinical efficacy, side effects and commercial issues.
Unfortunately, animal models are often inadequate for
the development and evaluation of drugs for treating
human conditions. It is thus the goal to use genetic infor-
mation for:
• New indications for an old drug (repurposing)
• New targets for existing drugs (e.g., treatment of
tongue cancer using RET inhibitors)
• Drugs to work better in certain patient groups
(gender, age, race, ethnicity, etc.) with possible
genetic variants
• Knowing ahead of time what drugs to avoid due to
higher incidence of side effects that are genetically
modulated
• Develop clinical decision support in electronic health
records based on pharmacogenomics 20-21
Multiple projects are underway to integrate genetic
and clinical data that will be discussed later in the
chapter. Electronic health records (EHRs) and health
information exchange (HIE) efforts, which are rapidly
becoming ubiquitous, thanks in large part to federal
incentives, are poised to contribute massive amounts of
patient information (including demographic, laboratory,
and clinical data). It is important to also note that in
addition to genomic and clinical data, environmental
data may offer valuable insights into the understanding
and eventual treatment of disease.
Another important application of translational bioin-
formatics is in cancer genomics. There have been
so-called hallmarks papers that describe the state of the
knowledge on how cancer cells proliferate and evade
death by a number of mechanisms within living organ-
isms.22 When whole genome sequencing is applied to
tumor cells, it shows that they undergo genomic changes
that give them the ability to proliferate and metastasize
within living organisms.23 It has also been discovered that
cancer gene mutations, within tumors, are heterogeneous,
so cancer cells evolve and attain this ability to proliferate
outside the normal defense mechanisms of organisms.24
Another important discovery is that some genomic
changes representing common tumor types occur in
different cancer locations, so that the same mechanism
may occur in more than one type of cancer.25-26 There
has also been improved understanding of gene function,
and of course this may aid in the development of better
treatments.27
BIOINFORMATICS PROJECTS AND CENTERS
The Human Genome Project
One of the greatest accomplishments in biomedicine
was the completion of the Human Genome Project (HGP).
This international collaborative project, sponsored by the
US Department of Energy and the National Institutes
of Health, was started in 1990 and finished in 2003.
In the process of acquiring the human genome (as a
complete set of DNA sequences, encompassing all 23
chromosomes), genome sequences for several other key
organisms (“model” organisms) were also acquired.
These included the Escherichia coli bacterium, fruit
fly (Drosophila melanogaster), and house mouse (Mus
musculus). By mid-2007 about three million differ-
ences (SNPs) had been identified in human genomes.
Appreciating the potential significant societal impact, the
HGP also addressed the ethical, legal and social issues
associated with the project. Since the completion of the
HGP, attention is now more focused on the development
of approaches to analyze and learn from volumes of data
representing increasing numbers of individuals.11,28-29
These analyses include the annotation of information
associated with disease onto chromosomes. Figure
18.3 displays the DNA sequencing of just chromosome
number 12. Huge relational databases are necessary to
store and retrieve this information. New technologies
continue to emerge that reduce the necessity to sequence
an entire human genome, such as DNA arrays (gene
chips) that help speed the analysis and comparison of
DNA fragments.30 The cost of the HGP was close to $3
billion; but over time, costs have dramatically dropped
for genetic analysis.7
National Human Genome Research Institute (NHGRI)
NHGRI is an NIH institute that provides many
educational resources on their web site. Like other
NIH institutes, they conduct and fund research within
their intramural division, as well as support extramural
research with external partners. Their health section has

Figure 18.3: Chromosome 12 (Courtesy of the National Library of Medicine)
multiple resources for patients and healthcare profes-
sionals with emphasis on the Human Genome Project.
The “Issues in Genetics” section covers important
controversies in policy, legal and ethical issues in genetic
research. They include a large glossary (200+) of genet-
ics-related definitions, also available as a software app
for the iPhone and iPad.
In 2003, NHGRI launched the Encyclopedia of DNA
Elements (ENCODE) Project. ENCODE is comprised
of a consortium of laboratories with the goal to study
and characterize the functional elements of the human
genome. All ENCODE data are free for research
purposes. In 2012, 1640 data sets were published, which
continue to produce controversy. For example, ENCODE
researchers posited that 80% of the human genome is
active and performing a role (and thus not “junk” DNA
as has been previously thought).31
Human Microbiome Project (HMP)
It is estimated that less than 0.01% of microbes on Earth
have been cultured, characterized, and sequenced. As an
exception, the complete genome for the common human
parasite Trichomonas vaginalis was reported in 2007 in
the journal Science.32 The HMP is an NIH-sponsored
Chapter 18: Bioinformatics 361
initiative that catalogued the myriad of organisms
that co-exist with humans and heretofore have been
rarely studied (e.g., flora from oral, nasal, skin, and
the gastrointestinal tract). It is important to note that
microbial cells on the human body outnumber human
cells by a factor of 10 to 1. Initial efforts were aimed
at identifying the microbiome in health patients. More
recently, extensive work has been done to identify the
microbiome in multiple disease states with results too
comprehensive to cite in this chapter. Three areas the
HMP is currently focusing on include pregnancy and
pre-term birth, onset of inflammatory bowel disease and
onset of type 2 diabetes.
The HMP used metagenomics, as explained in the
definitions section. As detailed on the HMP web site
their goals were as follows:
• Determine whether individuals share a core human
microbiome
• Understand whether changes in the human micro-
biome can be correlated with changes in human
health
• Develop new technological and bioinformatics tools
needed to support these goals
• Address the ethical, legal and social implications
raised by human microbiome research6
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Human Variome Project
This is an international non-governmental organiza-
tion that began in 2006 with the goal to create systems
and standards for storage, transmission and use of genetic
variations to improve health. Rather than catalogue
“normal” genomes they focus on the abnormalities that
cause disease. Another aspect of their vision is to provide
free public access to their databases.33
The PhenX Project
The goal of this project is to identify 15 high-quality,
well established measures and standards for each of
21 research domains. Standardization is important so
that phenotypical, risk factors and environmental expo-
sures can be compared. For example, if everyone used
a common set of standards data could be more readily
compared or combined to gain more statistical power.34-35
1000 Genomes Project
This is an international initiative with the goal to
catalogue and study the genomes of 2500 individuals
from 26 populations, looking for genetic variations that
occur at a frequency of about 1%. The data will be free
for researchers and hosted on Amazon’s Web Services.
The project produced 200 terabytes of data during its
active phase from 2008 to 2015.36
Pediatric Cancer Genome Project
St. Judes Children’s Hospital-Washington University
created this initiative to combat childhood cancer. Data
generated from 800 subjects will be offered free to
researchers. As an example of a positive result from
this project, two gene variations associated with 50%
of low grade gliomas (brain tumors) were identified.37
Global Alliance for Genomics and Health
In June 2013, a Global Alliance was formed to share
genetic and clinical information. The Alliance was
formed by 500 international medical and research orga-
nizations. They develop standards for sharing genetic
information, information technology platforms with open
standards and patient consent policies.38
Pharmacogenomics Knowledge Base (PharmGKB)
This Stanford University based resource catalogues
the relationships between genes, diseases and drugs.
There are sections on drugs, pathways, dosing guidelines
and drug labels. Information is downloadable.39
Framingham Heart Study SHARe Genome-Wide
Association Study
In 2007, the Framingham Heart Study began a new
phase by genotyping 17,000+ subjects as part of the FHS
SHARe (SNP Health Association Resource) project. The
SHARe database is located at NCBI’s dbGaP and will
contain 550,000 SNPs and a vast array of phenotypical
(combined characteristics of the genome and environ-
ment) information available in all three generations of
FHS subjects. These will include measures of the major
risk factors such as systolic blood pressure, total, LDL
and HDL cholesterol, fasting glucose, and cigarette use,
as well as anthropomorphic measures such as body mass
index, biomarkers such as fibrinogen and C-reactive
protein (CRP) and electrocardiography (EKG) measures
such as the QT interval. Because of this initiative, they
have been able to publish multiple articles on genetic
associations and heart disease.40
The Mayo Clinic Bipolar Disorder Biobank
Researchers at the Mayo clinic and other institutions
are analyzing the genetic and clinical information on
2000 patients in their biobank to determine genetic
aspects of bipolar disorder. It is hoped that data generated
from this project will lead to earlier and better treatment
of this mental health disorder.41
Informatics for Integrating Biology
and the Bedside (i2b2)
i2b2 is a National Institutes of Health National Center
for Biomedical Computing initiative located at Harvard
Medical School. The Center has developed open source
software that will enable investigators to mine existing
clinical data for research. Specifically, they will develop a
scalable computational framework to speed up translation
of genetic findings into healthcare. There are multiple
member institutions, including international ones. The
project was designed to allow users to query a system-
wide de-identified repository for a set of patients meeting
certain inclusion or exclusion criteria. On the web site,
users can download client-software, client-server soft-
ware and the source code.42 The i2b2 infrastructure has
been shown to be generalizable to multiple sites for a
range of clinical conditions.43
The Observational Health Data Sciences and Informatics
(OHDSI)
OHDSI is a multi-stakeholder, international collabo-
ration that aims to make the best use of available large

health data sets. Health data exist in a variety of file
formats and often require standardization for both use
and supporting data integration tasks. From the perspec-
tive of translational bioinformatics, OHDSI represents a
major initiative that provides datasets that can be inte-
grated with biological data. For example, within the
context of studying drugs, it is useful to know reported
adverse events. While the US FDA does make available
data collected from its adverse event reporting system
(FAERS), these data are challenging to use for large scale
analyses. AEOLUS is an artifact of an OHDSI initiative
(LAERTES) that standardizes FAERS data such that it
can be used within a range of studies, including those
involving translational bioinformatics.44
All of Us
Conceptualized at the end of the Obama administra-
tion, the All of Us program (which is a key element of the
Precision Medicine Initiative) is a White House initiative
to develop a US cohort of individuals that will support the
development and evaluation of next-generation, person-
alized treatments. The All of Us program is built around
the fundamental tenets of precision medicine, i.e., the
right treatment for the right patient at the right time.
In this way, the success of this endeavor, which is just
formally launching at the writing of this text, will result
in a paradigm shift in how biological data can be used to
inform health care in a meaningful and efficient manner.45
The Cancer Genome Atlas (TCGA)
The suite of conditions that comprise cancer have a
strong genomic component. The TCGA project is a joint
initiative between the National Human Genome Research
Institute and the National Cancer Institute, both of the
National Institutes of Health, that aims to provide one
of the largest collections of cancer-related genomic data.
Currently, the initiative focuses on 33 cancers and the
TCGA provides access to genomic data associated with
tumor samples gathered from more than 11,000 patients.46
Bioinformatics Data and Information Resources
The bioinformatics community has produced a wide
variety of knowledge-based information resources that
not only provide access to research results but also facil-
itate scientific discovery information from genomics.
Much of this activity is led by the National Center for
Biotechnology Information (NCBI), which is part of the
National Library of Medicine. A catalog of NCBI and
other resources is provided annually in the open-ac-
cess journal Nucleic Acids Research. In fact, there is an
Chapter 18: Bioinformatics 363
annual database issue that covers the myriad of data-
bases available. And there’s also a web server issue that
covers accessible resources that can be accessed over the
Internet. NCBI was created in 1988 and hosts dozens of
databases associated with biomedicine, including the
popular MEDLINE and GenBank databases. NCBI
provides access to sequences from over 500,000 organ-
isms (via GenBank), including the complete genomes of
thousands of organisms (via NCBI Genome). Genomes
represent both completely sequenced organisms and
those for which sequencing is still in progress. Popular
NCBI databases, which are linked by a common interface
(Entrez), are listed in Figure 18.4. On the Genome project
web site one can search for specific genes or proteins
from different species. Figure 18.5 shows the result of a
search for the tumor protein TP53.
The NCBI site also provides access to BLAST+
(new Basic Local Alignment Search Tool) that enables
the identification of significantly related (based on a
“expectation” value or “e-value”) nucleotide or protein
sequences from within the protein and nucleotide data-
bases.47 Magic BLAST is a recently developed tool that
enables rapid searching for related sequences (e.g., as
might arise from a full sequence of a human being) to a
reference genome.48 Also available on the NCBI site are
databases where one can find data about a gene (Gene),
its location on the chromosome (MapViewer), its variants
(dbVar), and data about patients who have the gene or its
variants (dbGaP).
GenBank
This database was established in 1982 and is the NIH
sequence database that is a collection of all publicly avail-
able DNA sequences. Along with EMBL (Europe) and
DDBJ (Asia), GenBank is a member of the International
Nucleotide Sequence Database Consortium (INSDC),
which provides free access to sequence data from nearly
anywhere with an Internet connection. Interestingly,
many biological and medical journals now require
submission of sequences to a database prior to publica-
tion, which can be done with NCBI tools such as BankIt.49
The Online Mendelian Inheritance in Man (OMIM)
Originally an NCBI database but now a standalone
resource, Online Mendelian Inheritance in Man (OMIM)
is a database of genetic data and human genetic disorders.
It was originally developed by Johns Hopkins University
and Dr. Victor McKusick, a pioneer in genetic metabolic
abnormalities. It includes an extensive reference section
linked to PubMed that is continuously updated.50
364 Chapter 18: Bioinformatics

Figure 18.4: NCBI Databases (Courtesy National Library of Medicine)

Figure 18.5: Entrez search for tumor protein (Courtesy National Library of Medicine)

World Community Grid
This project was launched by IBM in 2004 and simply
asked people to donate idle computer time. By 2007
over 500,000 computers were involved in creating a
super-computer used in bioinformatics. Projects include
Help defeat Cancer, Fight AIDS@Home, Genome
Comparison and Human Proteome Folding projects. This
grid promises to greatly expedite biomedical research
by analyzing complex databases more rapidly because
of this grid.51
PERSONAL GENOMICS
The availability of population-based genetic data, the
decreasing cost for human genome determination and
the availability of commercial personal genetic testing
companies provide greater personal uses of genomic data.
Population Studies: There are several ongoing initia-
tives that will leverage genomic data in the context of
population studies. For instance, Oracle Corporation has
partnered with the government of Thailand to develop a
database to store medical and genetic records. This initia-
tive was undertaken to offer individualized “tailor made”
medications and to offer bio-surveillance for future
Figure 18.6: Cost per Genome over time (Courtesy National Human Genome Research Institute, National
Institutes of Health)11
Chapter 18: Bioinformatics 365
outbreaks of infectious diseases such as avian influenza.52
Not all such initiatives have been successful. Perhaps the
best known is DeCODE Genetics Corporation, which
aimed to collect disease, genetic and genealogical data
for the entire population of Iceland; however, it filed for
chapter 11 bankruptcy in 2009.53 Nonetheless, DeCODE
continues the development of personal genomics based
solutions, largely in partnership with organizations such
as Pfizer.
Decreasing Cost of Human Genome Determination:
Coinciding with the completion of the HGP, the NHGRI
has kept track of the cost to perform DNA sequencing of
an entire human genome over the past decade. As Figure
18.6 indicates the cost has dropped from an initial cost
of $100,000,000 to a current cost of less than $1,000 per
genome in 2017. Notably, the decrease in cost of genome
sequence is exceeding Moore’s Law (attributed to Intel
co-founder Gordon Moore, and states that the cost of
computing power will be halved every 18 months based
on advances in technology).11
Personal Genetics Testing. Many patients may want to
know their own genetic profile, even if the consequences
are uncertain. The following are examples of personal
genetics companies (“direct to consumer genomics”):
366 Chapter 18: Bioinformatics
• AncestryDNA is a separate service offered by
Ancestry.com. Their analysis will determine eth-
nicity estimates and will identify remote relatives.
Saliva samples are needed, the cost is $79 and the
turnaround time is six to eight weeks.54
• 23andMe is a direct to consumer online genetic
testing company. For $199 they send a testing kit
to homes based on analyzing saliva with a turn-
around time of four to six weeks. Currently, they
look for 240 diseases, multiple carrier states and drug
response conditions (a substantial increase in the last
two years). They also offer an analysis of ancestry
based on the genetic profile.55 In 2010 a genome wide
association study (GWAS) was published that used
this technology and showed that patient question-
naire results correlated well with genetic results.
Additionally, they were able to describe five new
genotype-phenotype associations: freckling, photic
sneeze reflex, hair curl and failure to smell aspar-
agus.56 Google’s co-founder Sergey Brin was one
of the early funders of 23andMe, focusing on a
project through this company to study the genetic
inheritance of Parkinson’s disease. They hope to
recruit 10,000 subjects from various organizations
and offer a discount price for complete analysis. In
late 2013 the FDA instructed the company to stop
performing genetic analyses for medical conditions
until they receive 510(k) (pre-market) clearance,
which they subsequently received.57 In 2017, they
offered a Health and Ancestry analysis for $199
and an Ancestry analysis for $99. The Health
analysis includes genetic risk (e.g. celiac disease,
macular degeneration, etc.), wellness reports, trait
reports (e.g. eye color, skin pigment) and carrier
status reports (e.g. polycystic kidney disease, cystic
fibrosis, etc.).
• Myriad™ specializes in genetic testing for cancers
with a hereditary component, such as breast, endo-
metrial, melanoma, ovarian, colon, prostate, gastric
and pancreatic cancer.58 A sentinel Supreme Court
decision took place in 2013 that determined that
Myriad could not patent BRCA gene testing.59
As pointed out by Harold Varmus (American Nobel-
prize winner, who was a former director of the NIH, and
the current director of the NCI), personal genetics “is not
regulated, lacks external standards for accuracy, has not
demonstrated economic viability or clinical benefit and
has the potential to mislead customers.”60 For genetics to
enter the mainstream, new technologies and specialties
will need to be developed and numerous ethical ques-
tions will arise. Just finding the abnormal gene or SNP
is the starting point. Understanding the sensitivity and
specificity of genetic tests within clinical contexts will
be essential for them to be accepted. In general, patients
may not be willing to undergo major procedures (e.g.,
a prophylactic mastectomy or prostatectomy to prevent
cancer) unless the genetic testing is nearly perfect. It is
also important that genetic counseling be available to help
patients understand the implication of genetic suscep-
tibility tests (versus genetic guarantee of disease, such
as the mutations associated with Huntington’s disease).
Additionally, the Genetic Information Nondiscrim-
ination Act of 2008 was passed to protect patients
against discrimination by employers and healthcare
insurers based on genetic information. Specifically, the
Act prohibits health insurers from denying coverage
to a healthy individual or charging that person higher
premiums based solely on genetic information and bars
employers from using individuals’ genetic information
when making decisions related to hiring, firing, job
placement, or promotion.61
Many obstacles face the routine ordering of genetic
tests by the average patient. Ioannidis et al. pointed out
that for genetic testing to be reasonable several facts must
be true. The disease of interest must be common. Even
with breast cancer, when seven established genetic vari-
ants are evaluated, they only explain about 5% of the risk
for the cancer. If the disease (e.g., Crohn’s disease) is rare,
then the test must be highly predictive. For genetic testing
to be relevant one should have an effective treatment to
offer, otherwise there is little benefit. The test must be
cost effective, as many currently are too expensive. As
an example, screening for sensitivity to the blood thinner
warfarin (Coumadin) makes little sense now due to cost.62
A 2010 Lancet journal commentary warned of addi-
tional concerns. Whole-genome sequencing will generate
a tremendous amount of information that the average
physician and patient will not understand without exten-
sive training. At this point, health care lacks adequate
numbers of geneticists and genetic counselors that under-
stand the implications of data being made available
thanks to continued advances in biotechnology. Patients
will need to sign an informed consent to confirm that
many of the findings will have unclear meaning. They
will have to deal with the fact that they may be found to
be carriers of certain diseases that may have impact on
childbearing, etc. Genetic testing may cause many further
tests to be ordered, thus leading to increased healthcare
expenditures. As more information about whole-genome
sequencing is gained, more patients will desire it but who
will pay for it? And, can the costs be justified?63
Two other articles drive home additional practical
points. When the risk of cardiovascular disease based
on the chromosome 9p21.3 abnormality was evaluated