Diagnoses Without Names Challenges for Medical Care,

Research, and Policy

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Editors
Michael D. Lockshin Mary K. Crow
Weill Cornell Medicine Weill Cornell Medicine
Hospital for Special Surgery Hospital for Special Surgery
New York, NY, USA New York, NY, USA

Medha Barbhaiya
Weill Cornell Medicine
Hospital for Special Surgery
New York, NY, USA

ISBN 978-3-031-04934-7    ISBN 978-3-031-04935-4 (eBook)

https://doi.org/10.1007/978-3-031-04935-4

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To all the patients whose experiences taught
and will continue to teach all of us.
Foreword

The author has no conflict of interest to report.

For many centuries, persons dedicated to helping others who are sick have sought
ways to classify and group illnesses in an attempt to better diagnose and treat them.
Eventually, medical science focused on the classification of diseases came to be
called nosology, derived from the Greek words nosos (disease) and -logia (-study of).
The related field nosography sought to enable diagnostic labels for conditions and
syndromes. A diagnosis is a consensus label that synthesizes a patient’s subjective
and objective findings. The label, with no formal boundaries, can describe symptoms
(chronic pain syndrome), physical findings (asthma), laboratory tests (infections), or
molecular biology (the newly described lupus-like VEXAS syndrome).
Diagnostic labels are time-limited and evolve as cumulative medical and scien-
tific knowledge leads to greater insights. For example, in the nineteenth century, the
science of microbiology transformed the concept of infectious diseases and the
electrocardiogram changed the concept of heart attack. In the twentieth century,
medical imaging such as roentgenographs (now called radiographic images), fol-
lowed by computerized tomography, magnetic resonance imaging, and positron
emission tomography, revolutionized concepts of and priorities for assigning diag-
noses. In the twenty-first century, improved ways to accumulate large datasets
related to cell biology, such as cytometry by time of flight (CyTOF); gene expres-
sion, such as single cell RNA sequencing; large-scale genotyping; and other
approaches have led to more sophisticated ways to subset, cluster, redefine, and
identify new diagnoses. New illnesses such as HIV disease, antiphospholipid syn-
drome, alpha-gal syndrome (tick bite-induced red meat allergy), and immunoglobu-
lin 4-related diseases (IgG4-RD) have reset doctors’ vocabularies.
Importantly, not all patients’ illnesses fall within definitional rules. Physicians
once acknowledged uncertainty in medical charts. Rule out diagnoses (R/O MI, rule
out myocardial infarction) and vague, symptom-based diagnoses (FUO, fever of
unknown origin) were commonly accepted diagnoses in mid-twentieth century med-
ical charts. Assuming they were honestly applied, tests and treatments were reim-
bursed for all patients, whether or not the diagnosis was certain, until the 1980s.
Then, new administrative rigor required doctors to chart diagnoses and based reim-
bursement policies on diagnosis-related group (DRG) codes. Also, in the 1980s,
increasing rigor of patient selection for clinical research and clinical trials led to
development of specific, but often conflicting, diagnostic criteria that exclude patients

vii
viii Foreword

whose diagnoses are uncertain. More recently, DRG codes have given way to the
International Classification of Diseases (ICD) codes, currently 19,000 items. ICD
codes can reflect uncertainty or ambiguity, but physicians who code for uncertainty
find their requests for tests and treatments denied, doctors now rarely document
uncertainty in medical records. Doctors, patients, insurers, clinical and basic scien-
tists, public health administrators, lawyers, published press, media, social media, and
public conversation use different diagnosis definitions for different purposes. When
they ignore diagnostic uncertainty, they speak of different things.
This book began with an idea expressed by Dr. Michael Lockshin in the 1980s
(in press interviews, in talks to medical audiences, and later in books for lay audi-
ences) that contemporary medical discourse poorly serves and systematically
ignores patients whose diagnoses are uncertain. The persistence and seeming
increasing acceptance of the idea led to a recent workshop, When a diagnosis has no
name: Uncertainty and opportunity, sponsored by The Barbara Volcker Center at
the Hospital for Special Surgery. At the workshop, stakeholders from diverse fields
discussed their views and priorities regarding diagnostic uncertainty. A summary
paper briefly and without specific participant attribution outlines the workshop’s
points, conclusions, and recommendations [1].
This book is a product of the workshop. Workshop participants provide here the
details of their data, opinions, and priorities, with three goals: to bring forward an
open, all stakeholder-based conversation on diagnostic uncertainty; to develop a
vocabulary for diagnoses acceptable to all; and thereby to improve science, com-
munication, and patient outcomes. Better understanding of disease pathogenesis is
leading to improved molecular classification of human disease, such has been
reported in immune-mediated inflammatory diseases [2]. Hopefully, these scientific
and clinical advances, paired with better collaboration among physicians, scientists,
patients, healthcare regulators, third party payers, and legislators, will build on the
framework outlined in this book, to achieve the common goal of improving patients’
lives worldwide.

References
1. Lockshin MD, Crow MK, Barbhaiya M. When a diagnosis has no name: uncertainty and
opportunity. ACR Open Rheumatol. 2021. https://doi.org/10.1002/acr2.11368.
2. Schett G, McInnes IB, Neurath MF. Reframing immune-mediated inflammatory diseases
through signature cytokine hubs. N Engl J Med. 2021;385(7):628–39. https://doi.org/10.1056/
NEJMra1909094. PMID: 34379924.

S. Louis Bridges

Physician-in-Chief and Chair of the Department of Medicine and Division of
Rheumatology, Hospital for Special Surgery (HSS), New York, NY, USA
Chief of the Division of Rheumatology at New York-­Presbyterian/Weill
Cornell Medical Center (WCM), New York, NY, USA
Franchellie M. Cadwell Professor of Medicine at HSS, Joseph P. Routh
Professor of Rheumatic Diseases in Medicine at WCM, New York, NY, USA
Preface: Introduction—When A Diagnosis Has
No Name

Diagnosis, the founding principle of medicine, underlies all aspects of patient care:
evaluation, intervention, prognosis, communication, research, and public policy.
In common conversation, a diagnosis name is binary (present or not) and unam-
biguous; it describes a known pattern of symptoms, laboratory tests, and biological
phenomena. When patients’ findings do not fit definitions, their diagnoses are
uncertain. As a result, they lose access to laboratory tests and treatments; they are
excluded from administrative and public health documents and from research stud-
ies; they lose dignity in their interactions with physicians, friends, and families.
To bring attention to diagnostic uncertainty, in April 2021, the Barbara Volcker
Center at the Hospital for Special Surgery convened a 2-day virtual workshop,
“When A Diagnosis Has No Name,” that asked experts representing the fields of
patient care, basic and clinical medical research, industry, federal regulatory agen-
cies, insurers, medical philosophy, public media, law, hospital managers, and
patients to analyze diagnostic uncertainty. The goal was to improve medical care,
research, and administration. The workshop deconstructed the concept of diagnostic
uncertainty, debated the definitions and purposes of diagnosis, and made recom-
mendations regarding uncertainty.
The workshop asked stakeholders to answer four questions:

• What is your definition of “diagnosis”?

• For what purposes do you use diagnosis names?
• Why are diagnoses uncertain?
• Can we quantify and use uncertainty in patient care, science, and
administration?

The workshop participants’ responses are the chapters in this book.

The Definition of Diagnosis

Diagnosis names rest on quantitative and qualitative interpretations of published

patterns of symptoms, physical findings, and laboratory tests. In different medical
fields, there are no specific rules regarding the evidence required to assign a diagno-
sis name; different stakeholders use different criteria to assign the same diagnosis

ix
x Preface: Introduction—When A Diagnosis Has No Name

name. Existing criteria seldom weigh endogenous or exogenous variables that influ-
ence disease expression. In both the patient’s course and the science that underlies
use of a diagnosis name, definitions of diagnoses change over time. Diagnoses are
not binary; they are time-restricted points on an analogue scale.
Broadly defined diagnoses, which include long-term evaluations, new techno-
logical methods, and large databases of patients, are important for individual patient
care. Narrow, exclusionary, and time-limited diagnoses are needed to perform stud-
ies and generalize diagnosis-based information for patient groups.

The Purposes of Diagnosis

Stakeholders use different definitions for different purposes (Fig. 1).

Lawyers, practicing physicians, and patients use inclusive biologically based
definitions to describe disease mechanisms and to personalize treatments for indi-
viduals. For these stakeholders, molecular mechanisms more than clinical pheno-
types justify use of a diagnosis name (Table 1).
To minimize variability, researchers use sociologically-based exclusionary defi-
nitions to study typical but not atypical patients (those who fail to meet diagnostic
or classification criteria). Administrators use exclusionary definitions to create poli-
cies for populations of patients, classify illnesses, and count patients for public
Response to Rx

Overall evel of
classification

Non-specific
Response to

certainty for
Mechanism

Symptoms
prevention

Biomarker
laboratory

laboratory
Nosologic

Molecular
Example

Specific

Signs

class

Trauma Fracture High

Infection Poliomyelitis High
Genetic Down syndrome High
Deficiency Rickets Moderate
Neoplastic Breast cancer Moderate
Exogenous Pneumoconiosis Moderate
Degenerative Alzheimer Low
Immunological Lupus Low
Psychiatric Schizophrenia Low

high
moderate
low
uncertain

Fig. 1 Estimated levels of certainty for data elements that, summed, result in relative certainty for
each nosologic class. Estimates are those of the author; they are not based on systematic study of
this topic. They suggest that diagnoses of traumatic, infectious, and genetic nosologies have the
highest likelihood of certainty; of deficient, neoplastic, and exogenous nosologies have intermedi-
ate likelihood of certainty; and of degenerative, immunological, and psychiatric nosologies have
least likelihood of certainty
Preface: Introduction—When A Diagnosis Has No Name xi

Table 1 Assumed purposes for which different stakeholders use diagnosis names, listing which
types of patients are included or excluded in their counting of patients and the types of questions
they ask of the data
Definition
Stakeholder Purpose Includes Excludes Questions
Basic scientist Standard definition upon Typical Atypical Nosology
which to base studies and Etiology
rules Mechanism
Clinical scientist Standard definition upon Typical Atypical Categorization for
which to base studies and identification,
rules prognostication
Intervention to
understand
mechanisms
Treatment trials
Epidemiologist Standard definition upon Typical Overlap, Risk identifiers
which to base studies and and change Data for public health
rules atypical analysis
Public health policy
making
Educator, media, Standard definition upon Typical Overlap, Clarity of
editor which to enhance public and change communication
understanding atypical
Administrator Standard definition upon Typical Overlap, Funders of science
which to base studies and and change Funders of care
rules atypical Public health
planning
Hospital
administration
Social services
Legal services
Lawyer Assign responsibility None None Negotiate definition
Clinician Create hypothesis upon Typical None Efficient
which to base interventions and improvement of
and billing atypical patient health
Patient and All of the above Typical None Efficient
family and improvement of
atypical health

reimbursement, intervention, research, and public health policies. Most public dis-
courses prioritize sociologic over biologic purposes for using a diagnosis name1.
To assign diagnoses, physicians evaluate data in nine domains: symptoms, signs,
non-specific laboratory tests, specific laboratory tests, response to therapy, preven-
tion, biomarkers, biologic mechanisms, and molecular signatures (Fig. 1). Data in
each domain vary in their objectivity or subjectivity. Objective data points like
positive blood cultures or biopsies yield diagnoses with high certainty, and those

1
The experience of the SARS-CoV2/COVID-19 epidemic, in which, even though the etiology was
the same, patients varied widely in phenotype and biotype, stimulated many participants to reeval-
uate the rules by which they make diagnoses and assign them levels of certainty.
xii Preface: Introduction—When A Diagnosis Has No Name

with subjective data points like pain yield diagnoses with low certainty. By weigh-
ing relative objectivity and subjectivity of the data points, it is possible to rank nine
nosologic classes according to likelihood of certainty. Thus trauma, infection, and
genetic classes have the highest likelihood of certainty; deficiencies, neoplastic, and
exogenous classes have moderate likelihood of certainty; and degenerative, immu-
nologic, and psychiatric classes have least likelihood of certainty.
Workshop participants identified four causes of diagnostic uncertainty:

• Diagnostic and classification criteria set qualitative rules about who has a diag-
nosis. (In an administrative sense, patients with otherwise identifiable disease
who do not have specified abnormalities do not have that diagnosis.) Criteria set
quantitative thresholds (a patient whose blood test is abnormal but below a
threshold does not have the diagnosis). Because criteria do not offer alternative
diagnoses, patients’ diagnoses have no names.
• An illness’ concatenation may not provide criteria-defining information because
symptoms did not appear within a criteria-defined time frame or because a future
discovery will explain what is not yet understood.
• Heterogeneity, in which symptoms occur in atypical order or with atypical mani-
festations, leads to exclusion of patients from diagnosis definitions without pro-
viding alternative diagnosis names.
• Stakeholders select different times of onset—susceptibility, trigger factor, first
symptoms, first medical consultation, or first fulfillment of criteria—when they
use a diagnosis name. In medical offices, physicians use unofficial names such as
“pre-diagnosis” or “incomplete diagnosis” to converse among themselves, but
patients who do not meet consensus criteria are ineligible for study or benefits
available to those who do.

Can We Quantify and Use Uncertainty?

New biological science can provide molecular explanations for disease mecha-
nisms; new computer and statistical methods can reassign diagnosis names for pop-
ulations; AI mining of large data sets that can compare atypical patients with typical;
and natural language processing can scan EMRs. Uncertainty can be quantified, and
diagnoses can be assigned probabilities of sensitivity and specificity. Individual and
groups of patients can be stratified by probability of diagnoses.
These are the challenges: stakeholders must speak a common language; they
must include the role of uncertainty when they make decisions; and they must con-
sider diagnoses to not be binary truths but somewhat ambiguous, time-dependent
points on an analogue scale.
Preface: Introduction—When A Diagnosis Has No Name xiii

Lessons from the Workshop

Diagnostic uncertainty is anomaly that causes both problems and opportunities in

patient care, science, and administration.
The workshop identified these problems:

• Uncertainty results when diagnoses do not have standard definitions, when ill-
nesses vary over time, when exogenous factors modulate phenotype, and when
narrowly defined biologic processes explain features of illnesses of different
nosologic classes.
• Uncertainty impedes prognostication, documentation, interventions, communi-
cation, public policy, and social identities for patients.

The Workshop identified these opportunities:

• Communicate more effectively by distinguishing sociologic and biologic defini-

tions of diagnoses (or selecting a common vocabulary)
• Create diagnosis policies, in democratic groups, that include all relevant medical
specialties, patients, and public stakeholders
• Quantify diagnostic uncertainty and stratify patient groups by degrees of certainty
• Accept that not all diagnoses are binary, but are points in time in an illness journey
• Simultaneously mine large data sets that contain undiagnosed and excluded
patients to validate in the real world hypotheses generated by studies on narrowly
defined patients
• Provide to patients whose diagnoses are uncertain equal access to benefits avail-
able to others

New York, NY, USA Michael D. Lockshin

Acknowledgments

The Barbara Volcker Center for Women and Rheumatic Diseases sponsored the
conference that was the source of this book. Wanda Napolitano, Senior Events &
Marketing Coordinator, Professional Education, Hospital for Special Surgery, ably
handled the logistics of the conference and the book.

xv
Contents

Part I What Is a Diagnosis?

1 Chasing My Cure: Lessons Learned from My Rare Illness������������������   3
David C. Fajgenbaum
2 A Pragmatic Approach to Diagnostic Categorization���������������������������� 11
Miriam Solomon
3 How Diagnoses Are Assigned�������������������������������������������������������������������� 19
Pat Croskerry
4 Toward Molecular Diagnoses for Autoimmune
Rheumatic Diseases������������������������������������������������������������������������������������ 33
Judith A. James and Catriona A. Wagner

Part II Purposes of Diagnosis

5 Diagnostic Uncertainty in Drug Development���������������������������������������� 45
Paola Mina-Osorio
6 Confronting the Inevitability of Diagnostic Uncertainty
Across Multiple Legal Domains���������������������������������������������������������������� 59
Lars Noah
7 The FDA and the Drug Development Process ���������������������������������������� 69
Allan Gibofsky

Part III Assigning
8 Diagnosis of Systemic Lupus Erythematosus in the Age
of Precision Medicine�������������������������������������������������������������������������������� 77
Sule Yavuz and Peter E. Lipsky
9 The Impact of Antinuclear Antibody Testing on the Naming
and Misnaming of Disease������������������������������������������������������������������������ 89
David S. Pisetsky
10 In the Box or Out of the Box �������������������������������������������������������������������� 97
Jane E. Salmon

xvii
xviii Contents

11 Ever-Evolving Disease Classification Criteria for Clinical Trials

and Studies: The Case of Systemic Lupus Erythematosus�������������������� 101
Karen H. Costenbader
12 Prognosis: A Framework for Clinical Practice When Patients
Have ‘Symptoms with No Diagnosis’ ������������������������������������������������������ 115
Peter Croft
13 When the Illness Has No Name: Focus on Clinical Trials
in Systemic Lupus Erythematosus ���������������������������������������������������������� 125
Richard Furie
14 The Epidemiology of Systemic Lupus Erythematosus �������������������������� 133
S. Sam Lim

Part IV Diagnoses
15 Managing and Tolerating Diagnostic Uncertainty���������������������������������� 141
Paul K. J. Han
16 Is There a Textbook for Non-textbook Patients?������������������������������������ 149
Jillian Rose
17 The Changing Role of Uncertainty in Physician-Patient
Relationships���������������������������������������������������������������������������������������������� 157
Andrew Schafer
18 Syndromes in Search of a Name: Disorders of Consciousness,
Neuroethics, and Nosological Humility���������������������������������������������������� 163
Joseph J. Fins
19 Reflections on the Conference by a Physician-Patient��������������������������� 177
Jerome Groopman
20 Clinical Ambiguity in the Intelligent Machine Era
(Treats Breaks and Discharges) ���������������������������������������������������������������� 185
D. Douglas Miller
21 Shame, Name, Give Up the Game? Three Approaches
to Uncertainty�������������������������������������������������������������������������������������������� 209
Vera Wilde
Others Who Spoke �������������������������������������������������������������������������������������������� 219
Index�������������������������������������������������������������������������������������������������������������������� 223
Contributors

Karen H. Costenbader Harvard Medical School, Division of Rheumatology,

Inflammation and Immunity, Brigham and Women’s Hospital, Boston, MA, USA
Peter Croft Primary Care Centre Versus Arthritis and Centre for Prognosis
Research, School of Medicine, Keele University, Keele, Staffordshire, UK
Pat Croskerry Dalhousie University Medical School, Halifax, NS, Canada
David C. Fajgenbaum Department of Medicine, University of Pennsylvania,
Philadelphia, PA, USA
Joseph J. Fins Division of Medical Ethics, Weill Medical College of Cornell
University, Weill Cornell Medical College, New York, NY, USA
Adjunct Faculty, The Rockefeller University, New York, NY, USA
Visiting Professor of Law and Solomon Center Distinguished Scholar in Medicine,
Bioethics and the Law, Yale Law School, New Haven, CT, USA
Richard Furie Zucker School of Medicine at Hofstra/Northwell, Division of
Rheumatology, Northwell Health, Great Neck, NY, USA
Allan Gibofsky Weill Cornell Medicine, Hospital for Special Surgery, New
York, NY, USA
Jerome Groopman Medicine Harvard Medical School, Experimental Medicine,
Beth Israel Deaconess Medical Center, Boston, MA, USA
Paul K. J. Han Division of Cancer Control and Population Sciences, Division of
Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
Judith A. James Arthritis and Clinical Immunology, Oklahoma Medical Research
Foundation, Oklahoma City, OK, USA
Departments of Medicine and Pathology, University of Oklahoma Health Sciences
Center, Oklahoma City, OK, USA
S. Sam Lim Department of Medicine, Division of Rheumatology, Emory
University School of Medicine, Atlanta, GA, USA
Department of Epidemiology, Rollins School of Public Health, Emory University,
Atlanta, GA, USA

xix
xx Contributors

Peter E. Lipsky Ampel BioSolutions and RILITE Research Institute,

Charlottesville, VA, USA
Michael D. Lockshin Weill Cornell Medicine, Hospital for Special Surgery,
New York, NY, USA
D. Douglas Miller Medical College of Georgia, Augusta, GA, USA
Paola Mina-Osorio Aurinia Pharmaceuticals Inc., Rockville, MD, USA
Lars Noah Levin College of Law, University of Florida, Gainesville, FL, USA
David S. Pisetsky Duke University Medical Center, VA Medical Center,
Durham, NC, USA
Jillian Rose Hospital for Special Surgery, New York, NY, USA
Jane E. Salmon Department of Medicine, Hospital for Special Surgery, Weill
Cornell Medicine, New York, NY, USA
Andrew Schafer Department of Medicine, Weill Cornell Medical College, New
York, NY, USA
New York-Presbyterian Hospital/Weill Cornell, New York, NY, USA
Miriam Solomon Philosophy Department, Center for Bioethics, Urban Health and
Policy, Temple University School of Medicine, Philadelphia, PA, USA
Catriona A. Wagner Arthritis and Clinical Immunology, Oklahoma Medical
Research Foundation, Oklahoma City, OK, USA
Vera Wilde Berlin, Germany
Sule Yavuz Department of Medical Sciences, Rheumatology, Uppsala University,
Uppsala, Sweden