Biosurveillance and Bioinformatics: A Comprehensive Overview

INFO-I530 (Foundation of Health Informatics) Biosurveillance and Bioinformatics Lecture #12

Lecture in a Nutshell • Biosurveillance • Introduction • Error Reporting • Infectious Disease Surveillance • Web and Biosurveillance • Bioinformatics • Introduction • Gene Biology • Knowledge Extraction • Sample Knowledge Discoveries

Biosurveillance

Introduction • Bioterrorism is the malicious introduction of biological agents such as viruses, bacteria toxins into a civilian population  civilian system, and in particular local hospitals, community physicians and the public health system that are the first detector and first responder. • Short window of opportunity exists between the first cases being identified and a second wave of the population becoming ill through person-to-person transmission  public authorities will need to determine that an attack has occurred, identify the organism or agent, and commence prevention strategies such as mass vaccination or administration of prophylaxis. • Computer based disease surveillance systems have been in place since at least the mid-1980s. However, it is only recently that the focus has shifted from improving internal reporting processes for public health authorities, to extending electronic reporting to the clinical workplace.

Error Reporting • For a bioterrorist event to be identified rapidly and accurately, several critical events must occur:The event needs to be detected: non-specific symptoms like fever, chills, malaise and fatigue are unlikely to raise clinical suspicion. If an event is indistinguishable from the 'background noise' of other normal clinical presentations, then it will not be recognized. In contrast with natural epidemics, a bioagent attack exposes a large number of people at the same time, producing a compressed epidemic curve with a peak in a matter of hours or days.The event needs to be recognizable: then clinicians must have access to diagnostic knowledge to identify bioagent events and an awareness that they need actually to consult that knowledge.The existence of the event needs to be communicated rapidly: Clinicians need to communicate to public health organizations capable of initiating a population response.

Error Reporting cont. • Biosurveilance communication flow • Sentinel presentation of patient to clinician in absence of prior evidence of a bioterrorist event. • Clinician consults colleagues or evidence-resources such as online system of journals, texts and paper guidelines. • Clinician sends patient specimens to laboratory for testing. • Clinician (possibly) sends report to public health authority, before laboratory result. • Laboratory identifies bioagentin patient specimen. • Laboratory notifies referring clinician. • Laboratory notifies public health authority. • Public health authority sends out a communication to laboratories and clinicians in geographic region considered under threat. • Patients present to clinician after public health authority warning.

Error Reporting cont. A biosurveillance system in the broadest sense is not just a piece of technology but a complex socio-technical system of people, processes, channels and tools. CDSS technology will probably be an indispensable tool in assisting clinicians make critical diagnoses, and that effective use of communication channels like the Internet may make the difference between local containment and wide spread of a bioagent amongst the population. Biosurveillance communication flows

Infectious Disease Surveillance • There is a substantial underreporting of notifiable infectious diseases by medical practitioners. There is also a substantial time gap between the clinician and laboratory reports. • In general, failure to comply with reporting by clinicians seems to be related to failures in communication between the managers of the surveillance system and the medical practitioners  simplification of the notification process and timely feedback of surveillance information. • Laboratory reporting of notifiable diseases can be speeded up by the introduction of automated data extraction and electronic communication to public health departments. • CDC's National Electronic Disease Surveillance System (NEDSS) is a contributing infrastructure to bioagent detection systems. • The advantage of expert systems is that they can look for patterns in data, and then correlate them with patient-specific data.

Infectious Disease Surveillance cont. Comparison of existing biosurveilance systems

Infectious Disease Surveillance cont. • General traditional didactic measures such as lectures or formal examinations do not change clinical performance or improve clinical care. Interactive educational activities, structured around actual problems in the clinical workplace, are much more successful. • For clinicians to be able to devote their scarce attention to bioagent risks, either it must become a routine part of their daily practice, or other means must be devised which reduce the costs of accessing such information. • The just-in-time model has echoes of earlier attempts to support clinical decision-making through the use of intelligent or expert computer systems  it attempts to integrate the decision support system into the routine activities of clinicians. • The preferred mode of information access and decision support for clinicians is face-to-face conversation with colleagues  online systems will only be used for a small portion of clinician decision problems  any just-in-time decisions support for bioterrorist surveillance must recognize the importance of interpersonal communication, and provide assistance to clinicians in locating appropriate colleagues to discuss potential bioagent incidents

Web and Biosurveillance • Clinical Push Narrowcast  a clinician reports an event to a public health authority. Threshold of suspicion can be raised by: • multiple presentation of patients with similar symptoms • symptoms that are unusual • notification of a likely bioterrorist event by a public health authority Web can used as a communication tool. Clinicians working in the community may not have ready access to Web. Any Web-based notification mechanism needs to be part of a larger reporting system. • Clinical Pull Narrowcast  a clinician can request information to assist in deciding whether a patient has been exposed to bioagent. The web may be an appropriate delivery vehicle for decision support information, including both active and passive information services. The CDSS should be localized, just-in-time, integrated in a clinical setting, embedded by voice and video for face-to-face consultation, desgined to be compatible with small screen devices, and implemented as a non-impeding workflow process.

Web and Biosurveillance cont. • Authority Push Synchronized Narrowcast  public health authorities can contact a specific clinician in regard to a given patient:This form of communication task requires a point-to-point synchronous channel – from phone, pager and fax to face-to-face conversation; and should include video (image,…). Web will act as a redundancy (backup) measure as well, in case of a disruption in other communication channels. • Authority Push Asynchronized Broadcast  public health authorities can broadcast information to clinicians to raise their level of awareness and suspension during a suspected bioagent exposure:It is the role of public health authorities to 'calibrate' physicians to a higher degree of suspicion during periods of suspected or confirmed bioterrorist attack, rather than to routinely remind clinicians to be alert in the absence of a genuine threat.The UK has an emergency 'cascade' system called Public Health Link, which is an electronic urgent communication system to health professionals that is initiated in the office of the Chief Medical Officer.

Bioinformatics

Introduction • In the early 1980s, methods for DNA sequencing became widely available, and produced an exponential growth in molecular sequence data. • From the mid-1990s onwards, genetic sequence data for the whole genome of organisms were amassed. Completely sequenced genomes were available by 2003 for more than 100 organisms (e.g. Human Genome Project). • Databases such as GenBank and EMBL (the European Molecular Biology Laboratory nucleotide sequence database) were developed to accommodate this growth in sequence data, and were made available to the research community through the Internet. • Bioinformatics (or computational biology) is the name given to these computationally intense activities associated with the genome sciences. • Bioinformatics is also concerned with the analysis of proteins and other elements of cell biology, and their exploitation to develop therapeutic agents.

Introduction cont. • Genomics: Determination of the DNA sequence of genes and through the specialty of functional genomics, the identification of the functional role of these genes in cellular biology. • Proteomics: The study of all the proteins expressed within the cell. This includes determining the number, level, and turnover of all expressed proteins, their sequence, and protein interactions within the cell and across the cell membrane. • Transcriptomics: Study of mRNA molecules, which are involved in the transcription of DNA codes and their transport from the nucleus to the cell. • Glycomics: Study of cellular carbohydrates. • Metabolomics: Study of the small molecules generated in the synthetic and degradation pathways of cellular metabolism. • Pharmacogenomics: The identification of genetic markers that assist in predicting whether a patient will respond well to a therapy.

Gene Biology • Cell: In almost all cells making up a living organism, there is an identical set of codes that regulate the function of the cell. This is encoded as one or more strands of the DNA molecule. The entire complement of DNA molecules of each organism is known as its genome. The overall function of the genome is to drive the generation of molecules, mostly proteins, which will regulate the metabolism of a cell and its response to the environment The genome is the same in almost every cell in the human body. For instance, a liver cell and a brain cell have the same DNA content and code in their nucleus. What distinguishes cells in one organ or tissue from one another is that different portions of their DNA are active. • DNA Structure: Each molecule of DNA may be viewed as a pair of chains of the nucleotide base molecules adenine(A), thymine (T), cytosine (C), and guanine (G). The two DNA strands join at each base-pairing, where A binds to T and C binds to G. DNA is able to undergo duplication, which occurs through the coordinated action of many molecules, including DNA polymerases (synthesizing new DNA), DNA gyrases (unwinding the molecule), and DNA ligases (concatenating segments together).

Gene Biology cont. • Transcription: In order for the genome to direct or effect changes in the cytoplasm of the cell, a transcriptional program needs to be activated to generate new proteins in the cell. DNA remains in the nucleus of the cell, but most proteins are needed in the cytoplasm of the cell where many of the cell's functions are performed. Thus, DNA must be copied into a transportable molecule called ribonucleic acid (RNA). A gene is a single segment of the coding region that is transcribed into RNA. RNA is generated from the DNA template in the nucleus of the cell through a process called transcription. • RNA: The RNA sequence of base pairs generated in transcription corresponds to that in the DNA molecules using the complementary A-T, C-G, with the principal distinction being that the nucleotide uracil (U) is substituted for the thymine (T) nucleotide. Thus, the RNA alphabetic ACUG instead of the DNA alphabet ACTG. The specific RNA that codes for proteins is called messenger RNA(mRNA).

Gene Biology cont. Flow of genetic information, from DNA to RNA to protein. This simplified diagram shows how the production of specific proteins is governed by the DNA sequence through the production of RNA.

Gene Biology cont. Protein Synthesis Illustrations

Gene Biology cont. • Intron/Exon and Splicing: Genes are not necessarily continuous. Instead, most genes contain exons (portions of the gene that will be placed into the mRNA) and introns (portions that will not appear in the mRNA but are 'spliced out' during transcription). Introns are not inert, however, and some functions have been recently discovered for them, such as promoter-like control of the transcription process. Further, introns are not always spliced consistently. If an intron is left in the mRNA, an alternative splicing product is created. Various tissue types can flexibly alter their gene products through alternative splicing. • Protein Synthesis: After the splicing process, the mRNA molecule that has been generated is actively exported through nuclear pore complexes into the cell's cytoplasm. The cytoplasm is where the cellular machinery acts to generate the protein on the basis of the mRNA code. Specifically the ribosomal complex, which is a complex containing hundreds of proteins and special transfer RNA (tRNA) molecules, are directly involved in protein manufacture. A protein is built as a polymer or chain of amino acids, and the sequence of amino acids in a protein is determined by the mRNA template.(DNA) GCT TGC AGA GCG  (mRNA) GCUUGC AGA GCG  (protein chain) alanine cysteini argenine alanine*

Gene Biology cont. • Protein Processing: Once the protein is formed, it has to find the right place to perform its function, whether as a structural protein in the cytoskeleton, or as a cell membrane receptor, or as a hormone that is to be secreted by the cell. There is a complex cellular apparatus that determines this translocation process. One of the determinants of the location and handling of a polypeptide is a portion of the polypeptide called the signal peptide. This header of amino acids is recognized by the translocation machinery and directs the ribosome-mRNA complex to continue translation in a specific sub-cellular location, for example constructing and inserting a protein into the endoplasmic reticulum for further processing and secretion by the cell. • External/Internal Factors: Initiation of the transcription process can be caused by external events or by a programmed event within the cell. External factors such as piezoelectric forces, heat shock or stress, and the appearance of new micro- or macronutrients. Finally, there are pathological internal derangements of the cell that can lead to transcriptional activity. Self-repair or damage-detection programs may be internal to the cell, and can trigger self-destruction (called apoptosis) under certain conditions, such as irreparable DNA damage. There may be a deletion mutation of a repressor gene causing the gene normally repressed to instead be highly active.

Knowledge Extraction • Genome science is rich in sequence data but poor in functional knowledge. The volume of data must somehow be sifted and linked to human biology before it can have any meaning. • The central hypothesis (or hope) of these methods is that, with improved techniques, one can analyze larger data sets and discover the 'true' biological functional pathways in gene regulation, and identify the characteristics of disease that most accurately predict the nature and course of disease. Relative growth of Medline and GenBank. The cumulative growth of molecular biology and genetics literature (light grey) is compared here with DNA sequences (dark grey). Articles in the GS (molecular biology and genetics) subset of Medline are plotted alongside DNA sequence records in GenBank over the same time period

Sample Knowledge Discoveries • Treatment: Specifically, bioinformatics allows us to identify genes that indicate a patient's susceptibility to disease, assists in developing an understanding of the cellular pathways involved in generating the illness, and as a consequence provides an opportunity for the development of highly targeted therapies. Subcategories of B-cell lymphoma determined by microarrays correspond clinically to duration of survival. On the left is a dendrogram (similar to a decision tree) that has been constructed across the samples of B-cell lymphoma, using an unsupervised learning technique. The top branch essentially defines an even split between the categories GCB-like DLBCL and activated B-like DLBCL, but this distinction was never before made clinically. On the right are Kaplan-Meier survival curves of the patients from whom the samples were obtained. Patients whose cancer matched the Activated B-like DLBCL gene expression profile had a significantly worse prognosis

Sample Knowledge Discoveries cont. • Microorganisms identification: The identification of microorganisms has historically relied on culturing organisms or morphological identification in specialized laboratories. However, the ability to identify microorganisms genetically is enabling the detection, identification and characterization of infective pathogens to be done near the patient, whether at the hospital bedside, in general practice or at home. • Pharmacogenomics: Bioinformatics analysis of genomic, pathological and clinical data from clinical trials can identify which sub-populations react well or poorly to a given drug  personalized 'molecular' medicine. • Drug discovery: once the entire genome of an infective microorganism is available, it can be examined for potential molecular target sites for attack by specially designed drugs. • Gene Therapies: For patients with genetically based chronic illnesses like cystic fibrosis, gene therapies are being pursued that should eventually offer the possibility of directly interacting with the defective genes to moderate, repress or disable the biochemical processes that result in the disease state.

Summary • Biosurveillance • Introduction • Error Reporting • Infectious Disease Surveillance • Web and Biosurveillance • Bioinformatics • Introduction • Gene Biology • Knowledge Extraction • Sample Knowledge Discoveries

Biosurveillance and Bioinformatics: A Comprehensive Overview