Pandemics: Historically Slow "Learning Curve" Leading to Biomedical Informatics and Vaccine Breakthroughs
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Published online: 2021-04-21
290
© 2021 IMIA and Georg Thieme Verlag KG
Pandemics: Historically Slow “Learning
Curve” Leading to Biomedical Informatics and
Vaccine Breakthroughs
Casimir A. Kulikowski
Department of Computer Science, Rutgers University, USA
Summary shortcomings to deal with complex socio-economic, political, to the key sequencing technologies and biomedical informatics
Background: The worldwide tragedy of the severe acute and technological disruptions together with the many ethical that enabled the Human Genome Project, and only now, 20
respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic challenges presented by pandemics. years later, are having an impact in ameliorating devastating
vividly demonstrates just how inadequate mitigation and Objectives: The principal goal is to review the history of biomed- zoonotic infectious pandemics, including the present SARS-
control of the spread of infectious diseases can be when faced ical information and healthcare practices related to past pan- CoV-2 event through unprecedently rapid vaccine development.
with a new microorganism with unknown pathogenic effects. demics in order to illustrate just how exceptional and dependent In the future these advances will hopefully also enable more
Responses by governments in charge of public health, and all on biomedical informatics are the recent scientific insights into targeted prevention and treatment of disease. However, past
other involved organizations, have proved largely wanting. human immune responses to viral infection, which are enabling and present shortcomings of most of the COVID-19 pandemic
Data infrastructure and the information and communication rapid antiviral vaccine development and clinical management of responses illustrate just how difficult it is to persuade enough
systems needed to deal with the pandemic have likewise severe cases – despite the many societal challenges ahead. people – and especially political leaders – to adopt societally
not been up to the task. Nevertheless, after a year of the Methods: This paper briefly reviews some of the key historical beneficial risk-avoidance behaviors and policies, even as these
worldwide outbreak, hope arises from this being the first antecedents leading up to modern insights into epidemic and become better understood.
major pandemic event in history where genomic and related pandemic processes with their biomedical and healthcare infor-
biosciences – relying on biomedical informatics – have been mation intended to guide practitioners, agencies, and the lay Keywords
essential in decoding the viral sequence data and producing public in today’s ongoing pandemic events. Pandemic histories, slow biomedical learning curve,
the mRNA and other biotechnologies that unexpectedly rapidly Conclusions: Poor scientific understanding and excessively immunology and vaccines, SARS-CoV-2, genomic
have led to investigation, design, development, and testing slow learning about infectious disease processes and mitigating epidemiology, biomedical and public health informatics, ethics
of useful vaccines. Medical informatics may also help support behaviors have stymied effective treatment until the present
public health actions and clinical interventions - but scalability time. Advances in insights about immune systems, genomes, Yearb Med Inform 2021:290-301
and impact will depend on overcoming ingrained human proteomes, and all the other -omes, became a reality thanks http://dx.doi.org/10.1055/s-0041-1726482
I The Excessively Slow with plagues. Only in the past 300 years
have sciences, technologies, and practices
micro-organisms including those in sym-
biotic microbiomes and co-existing species
Human “Learning Curve” in of medical, nursing, and epidemiological despite increased biomedical awareness
the History of Pandemics public health gradually developed suffi-
ciently to help understand and manage ep-
and understanding of these problems over
recent decades [1].
From the earliest technology of written idemics and pandemics rationally. Yet, indi-
records to today’s sophisticated web-based vidual vaccination and hygienic practices,
biomedical sciences and technologies, as well as effective adherence to preventive 1 Early Historical Information on
humans have dealt poorly with the largely societal behavioral norms continue to fall
unexplainable and frequently unexpected short in containing the myriad of unpre- Pandemics
scourge of epidemic and pandemic spreads dictably virulent zoonotic infections that The specific effects of illnesses – including
of infectious diseases. Tales from ancient plague human populations. This is largely infectious, inflammatory, and recognizably
times from all the world describe suffering, because of deep and widespread ignorance, chronic conditions – can be traced to ap-
death, and traumatized survival but contain misunderstanding, and misinformation proximately 2,500 years ago when we begin
little clear useful information about how about the rapidly evolving complex and to read in the surviving written sources
physicians or other healers dealt effectively changing ecologies of mutation-prone how Hippocrates gives in the book “Of the
IMIA Yearbook of Medical Informatics 2021291
Pandemics: Historically Slow “Learning Curve” Leading to Biomedical Informatics and Vaccine Breakthroughs
Epidemics” a detailed, reasoned account of on the traditions of Herodotus, the “father impacting health and maintaining balance
clinical observations of the effects of what of history”, who included many medical between the various bodily humors. On the
appears to be epidemic outbreaks on islands accounts and stories in his writings [9]. other hand, malnutrition was recognized
just off the coast of his native Ionia. He also Hippocrates was the first to wean medicine as an important factor in increasing the
was the first to recognize how symptoms from the biases of Olympian religious beliefs vulnerability of people to disease. Lung
appear to be contagious from person to which led people to think about the causes diseases, including pneumonia, pleurisy,
person – strikingly among athletes in close and healing of maladies in terms of godly in- coughs, and colds as well as declining,
proximity to each other while wrestling in terventions in the earlier Asclepian tradition consumptive physical conditions, and skin
gymnasia. In contrast, in earlier Homeric lit- [10]. In contrast, Hippocrates resorted most- lesions, often come up in the Hippocratic
erature, and for Greek authors before Hippo- ly to empirical remedies for a wide range of writings, as does leprosy, infections of the
crates, epidemic simply meant “who is in his illnesses based on reasoned interpretations liver, digestive disorders due to parasites,
country” from epi=on and demos=people. of observations about patients, also devel- diarrheas, kidney and bladder conditions,
So, Hippocrates was the first to have used oping precepts of minimal treatment: to do and eye infections such as conjunctivitis
the word epidemic with the modern medical the least harm with medical interventions and trachoma, as well as glaucoma [13, 15].
meaning of a “set of syndromes occurring in the natural course of disease. These have Modern interpretations of what might have
in a given place for a given period” [2, 3]. immortalized his name for posterity when been the causal infectious agents behind the
Thucydides is the first historian to describe the Hippocratic Oath for physicians became great Plague of Athens based on the descrip-
a sequence of transmission from distant and gradually accepted as the standard for eth- tions in Thucydides include Yersinia pestis,
exotic lands to Greece, and through its port ical behavior in clinical matters [11, 12]. typhus, typhoid, and Ebola or some other
of Piraeus to Athens, when he eloquently The empirical and rational Ionian school of infection leading to a viral hemorrhagic
describes the great plague that ravaged the medicine was an innovative and challenging fever. Results from DNA (deoxyribonucleic
city and killed Pericles during the siege by the departure from the previous highly inter- acid) analysis of material taken from teeth
Spartans in the history of the Peloponnesian ventionist medical philosophies that had in mass burials from the pandemic period
War [4]. He tells of the early attempts by developed from the anatomically informed detected the presence of Salmonella enterica,
physicians to care for the infected, but later and sophisticated Egyptian medical practices supporting a typhoid fever hypothesis [16].
abandoning patients once they were unable which were often surgical, and which most The reported black fluid exuding from the
to help, and the incredibly large death toll – commonly were followed in Greece before bodies of the infected, the frequent contagion
estimated at 25% of the population of the city. and during the time of Hippocrates, and of those caring for the sick, the relative lack
This led to the disintegration of social order interpreted in religious terms [13]. of infections among the besieging Spartans
with crime and misbehavior running rampant, The Hippocratic sources include discus- outside the long walls that connected Athens
and the abandoning of ritual funerals, so that sions about the role of environmental con- to its port of Piraeus, as well as indications
bodies of the dead were either left where they ditions such as humidity and “miasmas” in that central African monkeys had been
fell, or just thrown into piles on one another, the air coming from natural swamp environ- imported at the time with the enormous
and burnt [5]. References to plagues and ments (common in the days before extensive quantities of ivory needed for the Pallas
pestilences can be found in many other and drainage projects) or, during epidemics, from Athena statue in the Parthenon, all suggest
even earlier sources, such as the Bible and putrefaction of corpses, and blamed these the plausibility of an Ebola-like causative
other records from the Near and Middle as the cause of contagion [14]. This was agent, though this has been impossible to
East [6, 7], as well as from India and China. explained through the contemporary theories prove due to non-survivability of RNA (ri-
Related to potential pre-historic origins, a of “humors” involving the flow of different bonucleic acid) viral material [17].
recently posted as yet unreviewed pre-print types of fluids and gases within and through During the Hellenistic period, extant
reporting on comparative genomic studies the bodies of individuals, which were as- sources suggest that Hippocratic innovative
conjectures that a corona virus-like epidemic sumed to be essential to the maintenance medical investigations and practices came
may have driven adaptation in East Asian of life, and which, when badly disrupted or mainly from Alexandria in Egypt, which
populations from 25,000 to 5,000 years ago unbalanced, were thought to cause illnesses. produced a wealth of medical and surgical
[8]. However, little recorded information Person-to-person contact as a factor in epi- scholarship. After the Roman conquests
has survived about the ways in which people demic spread is mentioned by Thucydides in of Greece and the Middle East, the Greek
systematically and medically coped with his book on the Peloponnesian Wars, but it is physician and philosopher Galen (who
such disasters beyond minor palliatives for conflated with religious contamination, fol- became the personal doctor to the emperor
suffering, and praying to gods to save them lowing the traditional thinking. While crowd- Marcus Aurelius) wrote extensive medical
from the incomprehensible waves of invis- ing in cities is mentioned by him during the treatises within the Hippocratic tradition,
ibly caused illness, death, and destruction. siege of Athens, it was not explicitly noted adding considerable clinical observation of
Western medicine has been largely in- as a possible factor in epidemic spread, specific diseases. His work became the basis
fluenced by Greek Hippocratic medicine as even though lifestyle, diet, and exercise are for much subsequent medical knowledge
transmitted through Roman sources that built mentioned frequently in Greek medicine as through the Middle Ages and beyond. He
IMIA Yearbook of Medical Informatics 2021292 Kulikowski wrote about the Antonine Plague that spread and dramatized with eyewitness descrip- But it was the purely empirical obser- throughout the empire and Rome itself, and tions of bizarre happenings, human misery, vations of relative immunity to smallpox which is now considered to have most likely and suffering, they created the structure for (variola in Latin), in milkmaids who had been smallpox [18]. The next major plague the plague classics of the eighteenth century contracted the related cowpox viral infection, across the Roman Empire during its crisis of and by tracking the contagion’s complex that had inspired Jenner in 1796 to experi- usurpations and invasions during the third and crooked paths anticipated trends of ment with a variant of the older practice of century is now argued to have been caused nineteenth century epidemiology”. That “variolation” which had been used in China, by an Ebola-like virus [19]. The Justinianic people living in poverty would frequently India and the Middle East since before the Plague due to Yersinia pestis was the next be blamed for disease due to their abject and 16th century and been experimented with extensive pandemic that came from Africa insalubrious living conditions, unsanitary in England and its North American colonies and the East, and led to so much death, war, practices, and the contempt with which since the early 18th century [31]. Variolation and destruction, that it has traditionally been they were held by most of the powerful consisted of the transfer from individuals considered a major cause of the depopulation and the educated who wrote about these who had been infected with smallpox of the of the Roman and Persian empires (deaths matters is emphasized in [28]. Another powdered scab material or the fluid from amounting to at least 30% or more of the major scourge, smallpox, was a pandemic pustules into superficial scratches made populations), contributing to the disintegra- disease already recognized in ancient Egypt in the skin of others who hoped to receive tion of civil societies, decimation of armies, around 1,000 BCE [7], which, becoming immunity this way without contracting a and subsequent conquest of much of the endemic throughout the Mediterranean and serious or fatal case of the disease. Unfortu- Middle East by Islam [20], then becoming all of Europe, was much later transmitted nately, the procedure required much care in endemic, and in a subsequent wave contrib- by Europeans to the Americas, ravaging the titrating the amounts of material transferred uting to the fall of the Umayyad Caliphate pre-conquest populations and facilitating – and much luck in not transferring too much [21]. Recent phylogenetic reconstructions the colonization and control of the “New so as to produce a full-blown case of small- suggest that multiple variants of Y. pestis World” continents [29]. pox. By transferring the skin material from spread across Western Europe [22], while a different but apparently related infection other genomic analyses of remains from and seeing its repeated success in protecting contemporaneous burials have downplayed against severe cases of smallpox, despite the significance of the pandemic [23]. The 2 Gradual Progress in considerable resistance from the medical surviving Eastern or Byzantine Empire Understanding Immunological and profession of the day, the efficacy of the new reorganized healthcare in its cities and Epidemiological Processes in the vaccination method became recognized. Jen- gave rise to the first hospitals [24]. These ner’s persistence paid off in the U.K. and led practices transferred to the Latin Western Modern Era to the introduction of vaccination programs Europe and were the precursors within From the 16th to the mid-19th centuries, grad- which became accepted around the world – a Christian healing tradition of modern ual but steady, and occasionally quite unex- and named after the cows that when milked hospitals [25]. Yet, despite advances in pected notable advances in the sciences and transmitted the cowpox to the maids, even healthcare, little new knowledge was avail- technologies for medicine took place. These though it is likely that the cows may have able to deal with the greatest pandemic of advances were based on the observation of contracted the virus from horses [32]. all time that came from the East during the natural phenomena and experimentations in Throughout the 19th century, scientists Middle Ages, which saw the spread of the order to test theories generalizing the appli- sought a better understanding of the caus- Black Death or bubonic and pneumonic cability of insights about diseases in general, es of infectious diseases, which was not plagues caused by Y. Pestis, carried by fleas epidemics in particular, and the effectiveness achieved until Louis Pasteur’s research from rats and humans. The Black Death is of a few of the highly empirical treatments showed that the growth of micro-organisms estimated to have killed more than a third tested. Rational and causal explanations of was responsible for spoiling beverages, of the population of Europe, and continued physical and biological phenomena slowly such as beer, wine, and milk, leading him to be endemic with repeated outbreaks until helped develop better understanding of to invent the process that bears his name: the early 19th Century throughout most re- physics, chemistry, and some of the basics of pasteurization, which kills most bacteria gions of the world [26]. Cohn [27] tells of life and its processes. The underlying causes and molds in liquids by heating to between how “physicians now directed their plague of epidemic and pandemic disease based on 60 and 100 °C [33]. He collaborated with writings to the prince and discovered their “germ theory” [30], however, were not un- Claude Bernard, the preeminent physiologist most ‘valiant remedies’ in public health: covered until the 19th century, when improved who introduced the scientific method in strict segregation of the healthy and ill, microscopes and more sophisticated methods medicine, including blind trials for testing cleaning streets, latrines, and addressing the of investigation led to a rapid succession of proposed interventions. In a number of long term causes of plague – poverty. Those discoveries that still provide the major founda- fermentation experiments, Pasteur showed outside the medical profession joined the tions for the understanding of microorganisms that contamination with microorganisms chorus. Relying on health board statistics and their role in epidemiology. was required for fermentation — refuting IMIA Yearbook of Medical Informatics 2021
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Pandemics: Historically Slow “Learning Curve” Leading to Biomedical Informatics and Vaccine Breakthroughs
the prevailing concepts of spontaneous toxins into the cell interior. Burnett later producing specific genomic information
generation, and suggesting that contami- proposed that clonal proliferation of a cell relevant to the current COVID-19 pandem-
nation by “germs” could cause infections line selected by an antigen could explain ic. Researchers at the time were the first to
in animals and people, inspiring Lister to the antibody response. In the 1970’s it was benefit from the recently completed Human
propose and develop antiseptic procedures shown in mouse experiments that T-cells first Genome Project – which had critically relied
in surgical practice. Pasteur was a tireless check to see whether an infected cell belongs on advances in biomedical informatics – to
investigator and went on to discover the to itself, whether the infection is viral or achieve rapid human and animal genome
causes and treatments of chicken cholera, bacterial and only then goes about killing it. sequencing with chronological changes
swine erysipelas, and rabies, all of which Detecting “self ” is accomplished via a major indicating mutations in viral strains. This
were frequently fatal endemic zoonotic histocompatibility complex (MHC) Class I led to identifying the pathways of zoonotic
maladies from close contact of humans with protein which serves as a carrier enabling the virus transmission and pathogenesis as the
farm animals and pets. He conducted daring detection of viral peptides (small fragments epidemic spread [38]. A novel coronavirus
experiments testing a vaccine for anthrax of a viral protein). A special type of T cell resulting from several independent zoonotic
using the saliva of rabid dogs, and got into – the CD4 T or “helper” cell – provides yet strains was implicated in human cases, and
heated disputes with Robert Koch, the another pathway for controlling infection by hospitals were found to be among the epi-
discoverer of anthrax bacteria on issues of stimulating B cells to synthesize antibodies, centers for super-spreading events, with trav-
vaccine preparation and contamination.To- while dendritic cells present antigens to T elers transmitting the virus from mainland
wards the end of the 19th century, scientists cells and initiate an immune response. All China to Hong Kong, Taiwan and Vietnam,
gradually began to develop an understanding these are part of the adaptive immune sys- and then globally. Civets and raccoon dogs
of the mechanisms of immune inflammatory tem which attacks specific pathogens, while sold in open markets were identified as likely
responses to viral infection. An article in the an evolutionarily older innate system uses reservoirs for human infection, and closure
journal Cell [34] discusses these historical immune system dendritic cells and macro- of markets helped suppress the expanding
advances in bioscience, which accelerated phages to combat pathogens less specifically outbreak relatively quickly [39].
dramatically throughout the 20th century, through toll-like receptors or TLRs. TLRs
leading to the genomic revolution enabling recognize molecular patterns corresponding
investigation and tracking of zoonotic epi- to more general classes of pathogens. Inter- 3 The SARS-CoV-2 Pandemic and
demic and pandemic transmission processes ferons and other chemicals are released once
within and between species through their a pattern has been recognized, and serve as Biomedical and Health Informatics
interactions in a wide range of shared envi- preliminary anti-viral responders. Biomedical informatics, a field of com-
ronments.Metchnikoff in the 1880’s carried The above mechanisms can be interpreted puter-based technological and scientific
out experiments with starfish observing the through the metaphor of “cells-as-factories”. endeavor that has existed for little over half
recruitment of mobile (immune) cells to Viruses, with a rare exception, do not have a century, has been the essential catalyst for
the site of an induced injury, while Ehrlich bacterial-like virulence factors or toxins. Be- advanced biomedical research with a major
around this same time was theorizing about ing intracellular, viruses disrupt the body’s impact through the US National Library of
how plasma cells with “side chains” (now function either by direct destructive effect on Medicine’s online computer-based literature
known to be unique proteins) could attach target cells and organs or by inducing patho- and data resources [40], and those of its Na-
themselves to specific types of viruses and genic host responses. The cell can be looked tional Center for Biotechnology Information
“consume them” – phagocytosis. Von Beh- on as a factory. A virus may use up the cell’s [41] which made the results of the Human
ring and Shibasaburo’s experiments tested energy; shut off the synthesis of required Genome Project freely and openly available
how immunity to toxins and venoms might materials; compete for the cell’s ribosomes, to the public worldwide, thereby significantly
arise from serum producing an “antitoxin”, which are necessary for building proteins; or accelerating genomic, proteomic, and other
while Ehrlich coined the word “antibody” compete for the cell’s polymerases and in- molecular science data and information
to describe the chemical substance released hibit its innate defense system. Some viruses through its extensive informatics infrastruc-
into the bloodstream by cells in response to have the capacity to integrate into the cell’s ture. The viral pandemics of the present
the invading “antigens” from microbes. It genome and thus cause indirect damage, century, then, are the first where methods of
took until the 1940’s for the Danish physi- leading, for instance, to malignancy – for data-and-knowledge intensive biomedical,
ologists Bjorneboe and Gormsen to discover which immunotherapies are increasingly healthcare, and public health informatics
that it was white blood B-cells, originating effective [35]. As with bacterial virulence, are all available to support the monitoring,
in the bone marrow, which corresponded to the factors responsible for the intensity analysis, modeling, and management of
one type of antibody. Another type of cell, of viral infection affect both zoonotic and strategies being developed and deployed for
named a “T-cell” from their origin in the non-zoonotic agents [36]. both clinical and epidemiological purposes,
thymus, were discovered to be the “killers” About 20 years ago, the severe acute making informatics a “critical strategy”
of virally infected cells which they accom- respiratory syndrome coronavirus (SARS- for helping in the control of the present
plish by breaking into a cell, and introducing CoV) epidemic [37] was the first event COVID-19 pandemic [42].
IMIA Yearbook of Medical Informatics 2021294
Kulikowski
From a clinical perspective, most pub- track of numerous and rapid changes in succumb even when on ventilator devices.
lished literature describes early attempts to medical knowledge and practice, including Early results from The Netherlands and
gather data and monitor the progression of those for communicable disease outbreaks. France have implicated a specific gene
the pandemic and its effect on hospital set- However, the many required changes appear TLR7 which, when deleted, led to type
tings. It is still very tentative and primarily to have difficulty in keeping up with the rise I interferon expression being blunted,
suggestive about the many telemedicine of so many novel organisms that can cause with the consequence of severe disease
implementations with which informatics can pandemics, as witnessed by the ongoing ensuing;
help significantly augment, or when possible addition of emergency codes as well as 3) The possibility of autoimmune diffuse
even replace, in-person clinical consultations country-specific coding exceptions [45]. symptoms being triggered by a SARS-
that are risky to patients and practitioners This adds complications to the efforts at reg- CoV-2 infection affecting the brain, heart,
alike, and more generally to assess the ularizing coding and their knowledge bases and other organs, as well as producing
technological informatics support needed by various standards-setting organizations blood-clotting for reasons presently not
by hospitals, clinics, and other healthcare such as HL7 FHIR, which has had to cope understood.
practices. Some aspects of using information with the difficulties in switching from ICD-9
technology in the first reported site of the to the current ICD-10 (and the developing Thus, even with the wealth of new insights
pandemic in Wuhan, China, are described ICD-11) codes, which are distinct coding about viral and other microorganism mech-
in [43], emphasizing the rapid deployment schemes [46]. Since epidemiological studies anisms within cells, and their impact on
of shelter hospitals specifically designed depend so critically on consistency mappings immunology and vaccine development [48],
to take in the patients with COVID-19, between standards for codes, the reported these insights have not yet translated into
equipped with information exchange and difficulties already experienced by changing enough discoveries about their effects at the
electronic health record capabilities to deal coding practices due to mandatory adoption tissue and organ levels to help understand the
with the need to deploy electronic capa- of ICD-10 codes [47] need to be recognized physiological consequences of Covid-19 in
bilities and communication for healthcare as a serious vulnerability of all clinical records a way that can bridge biomechanistic with
practitioners managing the many emergency and informatics systems that substantially statistical observations in the many courses
admissions of infected patients. Few details impacts the analyses of pandemic trends and of illnesses and their complications that
are given, however, of the specific systems’ outcomes. There is also the evident danger SARS can take. Governments and health
capabilities and deployment strategies, of misclassifications in recorded patient his- institutions worldwide were unready to cope
other than general references to the needs tories essential for follow-up care of patients with SARS-CoV2 ahead of time [49, 50]. So,
for physicians and managers to carry out recovering from infection. to try to contain the spread of the disease they
monitoring, assessment of the distribution, Despite the considerable and rapid in- had to depend primarily on traditional social
severity, testing and tracing, and clinical crease in knowledge about infectious disease measures relying on individual compliance:
care of the patients – with privacy issues of mechanisms at the cellular and molecular lev- use of masks or other types of personal pro-
the latter also mentioned. During the Ebola els in the past years, Mukherjee, who started tective equipment (PPE), such as face shields
(2014) and Zika (2015) epidemics, where his career as an immunologist – emphasizes for all, and body suits for practitioners in
risk communication and management were in [34] that the COVID-19 pandemic and direct contact with ill patients, and behaviors
critical, researchers associated with the the often devastating and lethal post-infec- such as maintaining social distancing to min-
World Health Organization (WHO) noted tion complications illustrate today’s highly imize exposure of self and others, and avoid-
a “subtle retreat of national agency” [44] incomplete understanding of the pathophys- ance of large, dense gatherings, since many
when international guidance was obtained. iological consequences of immune responses people might be asymptomatic carriers and
However, in the present pandemic, there has to the virus. He outlines three critical sets of potential disease-spreaders whose numbers
been a reversal of this trend. All countries issues that need to be pursued to help control can, at this point, only be guessed at, given
have managed their national emergencies the virus pandemic: the very dynamic and poorly documented
differently according to the political, 1) Determining the strength and durability evolution of the pandemic as new variants
economic, social, and legal constraints of of immune response to the virus, which of the virus continue to be discovered [51].
their own societies. The great variability in would clarify whether re-infection is From a public health informatics perspec-
genetic pools, environments, and resources likely and when, and just how long does tive, a variety of decision support systems
together with highly contrasting historical a person really remain infectious even if have been developed to identify high-risk
experiences, cultural predispositions, and asymptomatic; areas for zoonotic disease outbreaks [52],
wealth-health divides have all contributed to 2) Explaining the differences that contrib- as have web-based tools for summarizing
radically different and often hard-to-explain ute to startlingly different courses of the information about the pandemic spread
infection control patterns around the world. disease with some patients recovering [53]. In healthcare informatics there is a long
The World Health Organization has modified quickly and without many or any appar- history of computer-based clinical decision
and expanded its International Classification ent complications while others develop support systems, or CDSSs [54], many de-
of Disease (ICD) coding in order to keep very severe respiratory symptoms and veloped with AI techniques over the past 50
IMIA Yearbook of Medical Informatics 2021295
Pandemics: Historically Slow “Learning Curve” Leading to Biomedical Informatics and Vaccine Breakthroughs
years [55]. A wide range of these CDSSs are and assess the candidate vaccines [59]. This and dependent for its analytical methods on
linked to electronic health records (EHRs) is of especial concern in terms of differential epidemiology, which studies the incidence,
which provide some degree of improvement impact in different subpopulations, especial- prevalence, and determinants of injury,
in clinical process outcomes [56], but they ly since so many people and their political disability, and disease in populations [64].
are unable to help with clinical management leaders have downplayed the severity of the Epidemiology in turn, has benefited over
of the novel and poorly-understood viral pandemic’s threat to health, with resulting the years from considerable experience in
infections like COVID-19 for which critical mortality rates being considerably above the the application of statistical methods based
data on the spectrum of disease progression, expected numbers as seasonally adjusted on demographics, and the ways in which
outcomes, and comorbidities is still lacking. deaths are becoming quite significant as of populations can be stratified and analyzed
Only after the current pandemic has abated this writing in early 2021. As result, there is an in observational studies and experiments
will it be possible to discover the critical increasing call for better communication and designed for controlled studies of medical
epidemiological factors about how quickly even compulsory behavioral controls, such interventions in healthcare situations rang-
and for how long does immunity persist as heavy fines for non-mask wearing in lo- ing from the clinical to the introduction of
after a person recovers from COVID-19, and cations of major infection, and lockdowns of vaccination or other preventive measures
whether and for how long they might remain businesses, schools, and other public venues. through programs at regional and national
contagious, as well as understanding of viral Reminders of the historically well-attested levels throughout the world [65].
load and transmission effects on type and deadliness of the influenza pandemic after Because of the great diversity of muta-
severity of disease, and correlation of these World War I [60] do not seem to have per- genic pathogens which can lead to pandem-
with immune reactions in individuals of sisted in popular historical memory enough ics [66], records of the different infectious
different age, gender, and ethnic groupings – to have had an influence in developing risk- disease outbreaks now include their detailed
all of which requires ongoing investigations averse behaviors in people who are routinely genomic epidemiological variants from the
[57]. As result of the above limitations, public used to much milder seasonal influenza out- rapid whole-genome sequencing methods
health measures continue to rely on applying breaks – ignoring the fact that these can also and the bioinformatics analytics constantly
general population-level travel restrictions be highly risky and fatal when new strains being improved and used in surveillance sys-
together with requested quarantining of sus- appear, such as those of Swine Flu [61]. tems [67]. Genomic epidemiology is defined
pected infectious individuals or those who A gripping and detailed description as “the use of pathogen genome sequencing
may have been exposed, especially if they of how the current COVID-19 pandemic to understand infectious disease transmission
have travelled from “hot spots” in the out- unfolded in its early phases (up to about and epidemiology” and with results obtained
break. These, restrictions, however, have been August 2020), eloquently covering the many directly from clinical samples in real time,
applied relatively haphazardly by different worldwide missteps in the responses to it, the promise of personalizing molecular diag-
governments at different times responding to and the extremely disruptive and often lethal noses is on the horizon [68]. Yet, developing
national socio-political-economic pressures. impacts on health and all aspects of life in adequate data infrastructures for supporting
The many countries and regions where quar- societies around the globe can be found in such genomic epidemiology at scale for
antining is optional or not enforced even when the book by the physician and sociologist public health purposes has lagged behind the
required, means that these measures are likely Nicholas Christakis [62]. research advances and their usually siloed
to be largely ineffective in controlling the databases which are frequently unavailable
pandemic worldwide given the unreliability, – as are the methodologies, especially those
frequent indifference, and even risk-seeking used by private companies.
of many people.
The development of vaccines benefiting
II Data Infrastructure and With the COVID-19 pandemic respon-
sible for rapid and unexpected spread of
from bioinformatics methods and genomic Informatics for Pandemics infections, deaths, overwhelming of med-
data and knowledge, on the other hand, has
been proceeding at an unheard-of pace.
and Developing Vaccines ical facilities, and lockdowns of societies
and their economies in early 2020, the U.S.
Whereas traditionally it has taken two to four in the Age of Genomic National Academies were tasked to produce
years to develop a vaccine (if this proves pos-
sible at all), for COVID-19 by November 2020 Epidemiology a Consensus Study Report on the Genomic
Epidemiology Data Infrastructure Needs,
successful results in remarkably rapid vaccine Public health was the motivation for some of subtitled Modernizing Pandemic Response
trials have been reported [58], with a spectrum the earliest systems for medical documenta- Strategies [69]. The first highlighted conclu-
of vaccines having different properties in tion in the 19th century, and computer-based sion is that “Current sources of SARS-CoV-2
terms of mechanisms of action and require- healthcare-related informatics developed genome sequence data, and current efforts to
ments for delivery. The multiple phases of after World War II [63]. Public health is integrate these data with relevant epidemio-
testing needed to estimate subgroup-specific aimed at maintaining good health and pre- logical and clinical data, are patchy, typically
efficacy means that it will take some time venting disease in communities, regions, passive, reactive, uncoordinated, and under-
before reliable data are available to compare and countries, and as such is closely related funded in the USA”. The report points out
IMIA Yearbook of Medical Informatics 2021296
Kulikowski
how available data were unrepresentative, include the Global Alliance for Genomics [77]. Many are based on mathematical models
biased, and inadequate to answer questions and Health for genomic data sharing within a for infectious disease spread [78], which date
about viral evolution and transmission, and, human rights framework; the COG-UK in the back to the 1920’s [79], with recent systems
most importantly, how genome sequence United Kingdom to guide health interventions incorporating insights from genomic science
variants might be related to virulence, and policies; the European COVID-19 Portal and bioinformatics methods for epidemiolog-
pathogenesis, clinical outcomes, and the for rapid collection and sharing of genomic ical modeling and analysis [80].
effectiveness of countermeasures. These data; Galaxy COVID-19 for compiling best In the European Union, the coordination
inadequacies in data infrastructure that practices, infrastructure, and workflows to of strategies for vaccine development and
were needed to prepare for the COVID-19 support genomic analyses of SARSCoV-2 public health among the member nations was
pandemic, vividly demonstrate the failure of data; and the Public Health Alliance for announced by the European Commission in
those (mainly political appointees) in charge Genomic Epidemiology, a global coalition November 2020 [81]. Six contracts were
of public health in the USA to heed the warn- working to develop consensus standards, concluded to allow the purchase of a vaccine
ings of experts and learn from those who led share best practices, and advocate for open with the pharmaceutical companies Astra-
the very (relatively recent) successful efforts science and data sharing in public health Zeneca, Sanofi-GSK, Johnson & Johnson,
in controlling the earlier SARS and Ebola microbial bioinformatics. BioNTech-Pfizer, Curevac, and Moderna.
pandemics before they could spread widely The application of bioinformatics tools AstraZeneca’s vaccine candidate, developed
and intensely worldwide. for research on COVID-19 is comprehen- in collaboration with Oxford University,
The report from the National Academies sively described in [70], listing methods already entered large-scale Phase II / III clin-
[69] lists a number of data sources and ini- and software available for fast sequence ical trials after achieving promising Phase I
tiatives for SARS-CoV-2, within the USA detection and annotation, providing access / II results in safety and immunogenicity by
and internationally. These included the U.S. to pandemic-related literature, and data to the fall of 2020. The agreement was financed
Centers for Disease Control and Prevention’s assist research and drug design. Covidex with the Emergency Support Instrument, and
(CDC’s) SARSCoV-2 Sequencing for Public [71], an AI neural ranking model using a the Commission continues discussing similar
Health Emergency Response, Epidemiology, keyword search infrastructure designed to agreements with other vaccine manufactur-
and Surveillance (SPHERES) consortium, co- compete in the TREC-COVID text retrieval ers. A contract between Sanofi-GSK and the
ordinating a large-scale nationwide genomic challenge over COVID-relevant literature in European Commission entered into force
sequencing effort across the United States the open research dataset compiled by the following the contract’s formal signature,
and the National Center for Biotechnology Allen Institute for AI (AI2) is one of many and once proven to be safe and effective
Information (NCBI) at NIH as primary re- references involving advanced bioinformatics against COVID-19, the contract will allow
pository for all genomic sequencing. A major approaches. Others include the web appli- all EU Member States to purchase up to
international effort is the Global Initiative cation Pangolin [72] which uses a dynamic 300 million doses of the vaccine. Sanofi and
on Sharing All Influenza Data (GISAID) nomenclature scheme for assigning global GSK also indicated they will try to provide
now adapted to include SARS-CoV-2 data to outbreak lineages, COPASI [73] for model- a significant portion of their vaccine supply
record how viruses evolve and spread during ling the dynamics of pandemics, COVIDSIM through a collaboration with the COVID-19
outbreaks. Nearly every major SARS-CoV-2 [74] for building epidemiological models of Vaccines Global Access facility, or COVAX
study uses GISAID. The Nextstrain software viral spread (which had a strong political [81] which has been developed by the Global
tool is an open-source platform for exploiting impact on UK policy in the decision to im- Alliance for Vaccines (GAVI), the Coalition
the potential of genomic data from a variety plement school and other lockdowns) [75], for Epidemic Innovations (CEPI), and the
of infectious disease pathogens to support ep- and CoV-GLUE [76] for tracking accumu- World Health Organization (WHO) to pro-
idemiological research and outbreak response lating nucleotide changes. With these and vide access to the COVID-19 ACTS Tools
with a GISAID-enabled interface of publicly the many other systems, apps, and software Accelerator to all people in a timely manner,
available sequence data from every continent. referenced in [70], the article makes a strong but with lower and middle-income countries
It has powerful analytic and visualization point about the critical need for better meta- especially in mind.
tools for exploring data at various scales (e.g., data to help coordinate and integrate all the BioNTech-Pfizer and Moderna have
global, continent, country, region), identi- bioinformatics tools in a coherent way. This produced a new class of vaccines based on
fying major clades of the virus. Nextstrain results from the frequent inconsistencies that microRNA [82], which acts as a data carrier
can address questions about which regions invariably arise from an overabundance of and informs the body on how to make pro-
of the genome are most variable, estimate possible choices of different assumptions, teins that trigger immunity to COVID-19,
the rate of infection, and identify sequences parameter settings, and bioenvironmental and although having difficulties of preservation
on the phylogenetic tree by features such as societal population constraints - potentially and transportation issues due to the ultra-low
gender and age of those infected. The National with many confounding variables. Models temperatures needed for maintaining vaccine
COVID Cohort Collaborative (N3C) gathers designed to interpret and predict different efficacy. The development and deployment of
clinical data for carrying out translational outcomes from the wide range of available medical informatics studies, as well as apps
informatics research. International initiatives methods for analyzing data are discussed in and systems for dealing with the COVID-19
IMIA Yearbook of Medical Informatics 2021297
Pandemics: Historically Slow “Learning Curve” Leading to Biomedical Informatics and Vaccine Breakthroughs
pandemic have been rapid and extensive the heterogenous distributed sources would evolutionary game theory models recently
[84-87], while facing problems of acceptance be difficult [94]. The American Medical In- [100], or introduced with cross-species-ori-
and mistrust, especially when dealing with formatics Association issued an Open Letter ented popular arguments for evolutionary
problems of contact-tracing [88]. Profession- protesting against these actions and making development of trust among humans [101].
al societies in healthcare informatics have recommendations to stay with the well-tested In terms of public health from ancient times,
supported these informatics efforts [42, 89]. public systems of the CDC [95]. On the other one can note early efforts to ensure cleanli-
Ethical challenges faced by informatics for hand, the provision of considerable funding ness of environments and uncontaminated
public health are discussed in [90], where from the US Congress through the CARES water supplies [102], as well as distinct be-
three main themes are covered: (1) public Act for a number of emergency measures to havioral roles for individuals - traditionally
health reporting and data sharing, (2) contact counter the pandemic, including the rapid women - who devoted their lives to healing
tracing and tracking, and (3) clinical scoring development of vaccines under the title of and health-caring duties [103]. These are
tools for critical care, with corresponding “Operation Warp Speed” proved to be very best known in the West as developing into
proposed actionable recommendations for successful in helping stimulate unexpectedly the religious orders of sisters or brothers,
broader change beyond the pandemic for rapid vaccine development and funding badly whose members administered medications
public health organization and policy reform. needed supplies such as respirators and other and nursed the sick adhering to standards of
Non-standardized, ad-hoc reporting and inad- hospital equipment and medications, even caring for others as often enunciated in their
equate coordination and integration of data though the political factors had a strong effect vows [104]. The influence of Hippocratic
across administrative boundaries are identi- on competing pandemic containment strate- rational medical traditions in the Hellenistic
fied as major causes of failure in public health gies [96]. Meanwhile, the WHO received the Middle East, its admixture with traditional
responses, and while the value of tracing support of Bill Gates, who worked with drug religious practices, and diffusion through the
infections is undeniable, the automated (often manufacturers and provided funding through Roman empire is discussed in Kottek and
covert or undisclosed) tracking of patients the Gates Foundation to speed up vaccine Horstmanshoff [105]. Strong awareness of
and their contacts for enforcing quarantines development [97]. In South Asia, issues of the central importance of personal hygiene,
or other restrictions has significant potential policy implementations and difficulties with public or group practices of washing, and
for privacy abuse by authorities [91, 92]. The resources accounted for highly differing out- relationship to religious rituals for purification
recommendations for clinical scoring of pa- comes in different countries [98]. Africa had or cleansing upon entry into temples or homes
tients with severe COVID-19 disease in ICUs very few cases of COVID-19 reported early is known in almost all major cultures, in the
involved the need to incorporate such tools as in the pandemic, possibly attributable to the East especially from the Buddhist traditions
integral components for critical care to help many fewer connections to the rest of the in India and China [106], and in the Islamic,
with decisions for admission triage, ventilator world in its equatorial zone, with populations Sikh, and other world religious traditions
allocation, and cardiopulmonary resuscitation considerably more dispersed than in other [107]. These issues of cleanliness and religion
[93]. At the same time the authors point out world regions, more impacted with malaria are considered as part of the WHO guidelines
the inadequacies of many scoring algorithms endemically, and with less diabetes and heart on Hand Hygiene in Health Care [108]. The
which do not take into account changes in disease. All of these problems have contrib- argument has also been made that the need
resource-availability, patient preferences, or uted to difficulties in tracking the pandemic for personal hygiene precedes human history
disability factors with comorbidities. despite sophisticated geospatial modeling and has evolved from very early in animal
In the United States, inadequacies in with satellite data [99]. species evolution through beneficial effects of
response to the pandemic have been widely adaptive behaviors, and in humans specifically
reported to result from deliberate policy by to avoid infectious diseases [109]. For the
politicians and their appointees who chose current worldwide spread of COVID-19, the
to pay no attention to the warnings, and then application of social and behavioral science
hobbled the Center for Disease Control and III Historical Cultural approaches to assist in responding to the
Prevention (CDC) – the lead US agency for
gathering and analyzing epidemiological data
Norms for Hygiene and pandemic is discussed in [110].
In the US literature, the history of public
and coordinating epidemic countermeasures Public Health: The Problem health from ancient to modern times was
– while systematically denying the severity
and even the existence of a pandemic in
of Unreliable Humans first covered most notably by Rosen [111]
in his monumental and comprehensive book
its first months of recorded spread across The history of pandemics illustrates how, like from 1958, in which he took a progressive,
the world. The scientific and hospital data with all catastrophic natural disasters, humans highly socioeconomic-centered perspective
collection and tracking systems previously as members of groups and societies exhibit a towards educating practitioners of the field
professionally managed by the CDC were wide range of behaviors in adhering to social about the antecedents of their discipline. He
switched to a private company with the stated norms and acting rationally cooperatively describes the impact on population health in
reason being that the CDC pointed out that or not with other members of their group, the 19th century following dislocations during
providing 100% of hospital data daily from as studied cross-culturally in the context of and after the Napoleonic Wars, resulting
IMIA Yearbook of Medical Informatics 2021298
Kulikowski
from rapid advances in industrialization, matic representation of data and ask herself and technological advances outlined in
commerce, science, and technology (espe- would The Queen understand the point that this article. Education with up-to-date in-
cially for transport, lighting, and heating), was being made by the data” [115]. Consider- formation about infectious diseases, their
which all led to unprecedented scales of ing the difficulties, we still face in today’s age transmission, and control over the past 200
crowding in cities with primitive sanitation, of data science for visualizing the impact of years, has strived to enlighten and encour-
encouraging epidemic disease which could COVID-19 on society through summarizing age rational behavioral reactions to crises
not be ignored. This spurred European and statistical illustrations that laypersons can and disasters in all their forms including
American physicians and scientists to search understand, hers was a pioneeringly relevant public health and pandemic events, and
for the underlying causes, resulting in the achievement that deserves to be much better higher degrees of education among popula-
bacteriological discoveries of Pasteur and known and recognized than it is. Nightingale tions do seem to accomplish this [121]. Yet,
Koch. They also led to the emphasis on clean also asked the Belgian statistician Quetelet, the experiences of governments and other
water supplies and adequate sewage disposal founder of the behavioral sciences [116], organizations during the current COVID-19
and treatment, or the highly influential “san- about possible ways of quantitating malnu- pandemic are hardly encouraging, and so
itary idea” and the gathering of systematic trition – and he came up with the Body Mass there have been increasingly urgent calls by
statistical data on living and health conditions, Index, which is still used today, though usually enlightened medical authorities emphasiz-
primarily in France and in Britain, where the for measuring the opposite effect: obesity. ing the need to better inform people about
clear correlation between wealth and health Improvements in public health from how to continue observing best behavioral
was demonstrated [112]. At the same time, the end of the 19th through the 20th century practices to preserve public health so as to
hygienic, medical, and nursing practices for were set back by the global disasters of the avoid the most restrictive and economically
the control of sepsis or infection in hospitals first and second World Wars, including the damaging social measures such as lock-
and surgeries were gradually implemented sharp recurrence of humanity’s old plague downs – since, despite the rapid develop-
following Semmelweis’ demonstrations that of tuberculosis (TB) [117] and the “Spanish ment and expected availability of vaccines,
hand washing prior to delivery of infants was Flu” pandemic from 1918-1919 which saw human behavioral unreliability will still
critical to avoid postnatal fevers and maternal about 500 million people infected, and 50 enable contagion for some time before
infection and death [113] – basic procedures million deaths, making it the most widespread vaccination becomes sufficiently effective
which are still the mainstay of contagion pandemic of the modern era [118]. The world without relying on the non-plan of unethical
prevention today. The role of contamination wars, however, also gave greater urgency to disregard for public health measures in the
of water supplies during cholera epidemics biomedical research, and accelerated medical expectation that natural herd immunity will
in London was demonstrated by John Snow, discoveries for controlling infections through be achieved [122]. In a keynote addressed
whose On the Mode of Communication of antibiotics [119] and trauma care methods to the American Informatics Association,
Cholera led to the recognition that it was not [120], as well as the vaccination developments Dr. Anthony Fauci, director of the National
person-to-person transmission or miasmas in mentioned earlier. In consequence the current Institute of Allergy and Infectious Diseas-
the polluted air that caused the disease. The major challenge to pandemic control or ame- es (NAID) not surprisingly emphasized
importance of worker health for competitive lioration remains human behavior which is the key role that informatics plays in the
industrial economies, and of military health unpredictably unreliable. production and dissemination of scientific
for their armies led to many improvements in knowledge and of information that will
healthcare practices, and much social change. encourage needed public health practices
These both combined in the remarkable suc- [123]. It is in this sense that the biotechnol-
cesses by Florence Nightingale (whose birth
bicentenary was celebrated in 2020 as the IV Conclusion: Pandemic ogies of vaccination and informatics have
been serving – and will continue to serve
Year of the Nurse) for dramatically improv- Workarounds for Behavioral – as workarounds for the unreliability of
ing military hospital sanitation during the human behaviors in managing the complex
Crimean War, turning nursing into an effective Unreliability - Informatics personal and societal decisions and actions
and essential healthcare profession that was
respectable [114]. In relation to informatics
and Education Based on that pandemics impose on people.
This places biomedical informatics
“her contribution to statistical thought, partic- Scientific Discoveries and during pandemics at a critical ethical center
ularly applied to healthcare, was astonishing.
She, for example, was the first person to use
Biotechnologies of debates about the tradeoffs between the
degree to which Hippocratic practices ought
pie charts in health sciences. She used pie Pandemics throughout history have been to be adhered to by physicians, nurses, and
charts for a reason. They fulfilled her belief and continue to be among the most devas- healthcare practitioners, and the challenges
that statistical data should be easily accessible tating and unpredictable challenges faced of taking responsibility for decisions and
to the average intelligent person. She liked to by humankind. The reactions of people have actions involving human trust when auto-
apply what she called privately “the Queen invariably proven confused and wanting, mated systems in the rapidly developing
Victoria test”. She would look at a diagram- even today with the biomedical scientific Internet of Things (IoT) and AIs routinely
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