Diagnoses Without Names: Challenges for Medical Care, Research, and Policy

Foreword
	References
Preface: Introduction—When A Diagnosis Has No Name
	The Definition of Diagnosis
	The Purposes of Diagnosis
	Can We Quantify and Use Uncertainty?
	Lessons from the Workshop
Acknowledgments
Contents
Contributors
Part I: What Is a Diagnosis?
	1: Chasing My Cure: Lessons Learned from My Rare Illness
		Introduction
		My Diagnostic Journey
		Defining Castleman Disease and Advancing the Field
		Conclusion
		References
	2: A Pragmatic Approach to Diagnostic Categorization
		Introduction
		What Are the Goals of Diagnosis?
		Consequences of Diagnosis
		What Are the Kinds of Diagnostic Categories?
		How Does Diagnosis Happen?
		What Are the Consequences of Not Having a Suitable Diagnostic Category?
		Factors Contributing to Diagnostic Difficulties
		General Recommendations for Diagnostic Change
		Examples
		Conclusions
		References
	3: How Diagnoses Are Assigned
		Classification in Medicine
		Disease, Illness and Sickness
		Pattern Recognition
		Development of Clinical Expertise
		The Diagnostic Process
		The Manifest Continuum
		When the Illness Has No Name
		The Problem with Assigning a Label
		Recommendations for Management
		Conclusions
		References
	4: Toward Molecular Diagnoses for Autoimmune Rheumatic Diseases
		Introduction
		Molecular Clustering in Autoimmune Rheumatic Disease
		Patients with Symptoms Who Do Not Meet Current Classification Guidelines: Lessons from Incomplete Lupus Erythematosus (ILE) and Undifferentiated Connective Tissue Disease (UCTD)
		Uncertain Disease Classification in Understudied Populations
		Conclusion
		References
Part II: Purposes of Diagnosis
	5: Diagnostic Uncertainty in Drug Development
		Introduction
		Defining Diagnostic Uncertainty in Drug Development
		Addressing the Lack of Representativeness in Clinical Trials
			Real-World Evidence
			Clinical Trial Optimization
		Keeping the End in Mind: The Patient at the Center of the Drug Development Process
		Conclusions
		References
	6: Confronting the Inevitability of Diagnostic Uncertainty Across Multiple Legal Domains
		Introduction
		Preliminary Thoughts Prompted by the Pandemic
		Contested Vital Signs, Pre-diseases, and Beyond
		Emphasizing Etiology and Prognosis
		Demanding Diagnostic Prowess
		Expertise and Etiology
		Perils in Prognostication
		Inadvertent Consequences of Undue Inventiveness
		Looking Beyond the Courtroom
		Final Musings About Trans-scientific Enterprises
		References
	7: The FDA and the Drug Development Process
		Introduction
		Stages of Drug Development and Review
			Investigational New Drug Application (IND)
			Phase 1
			Phase 2
			Phase 3
			New Drug Application (NDA)
			Phase 4: Postmarketing Requirement and Commitment Studies
		What Does FDA Approval Mean?
		Accelerated Approval
		Drug Development Designations
		Summary
		References
Part III: Assigning
	8: Diagnosis of Systemic Lupus Erythematosus in the Age of Precision Medicine
		Introduction
		SLE
		Can Genomics and Transcriptomics Be Used to Diagnose SLE?
		Gene Expression Studies and Organ Involvement
		Summary and Conclusions
		References
	9: The Impact of Antinuclear Antibody Testing on the Naming and Misnaming of Disease
		The Problems of ANA Determination
		Symptomatology
		The Issue of Nomenclature
		References
	10: In the Box or Out of the Box
		References
	11: Ever-Evolving Disease Classification Criteria for Clinical Trials and Studies: The Case of Systemic Lupus Erythematosus
		Introduction
			What Is the Difference Between Disease Diagnosis and Classification? And Why Do We Need Classification Criteria for Clinical Research and Trials?
		The Evolution of Classification Criteria for Systemic Lupus Erythematosus
			Cases Below the Threshold
		Summary
		References
	12: Prognosis: A Framework for Clinical Practice When Patients Have ‘Symptoms with No Diagnosis’
		Diagnosis in Clinical Practice
		Challenge 1: The Benefits and Hazards of Searching for a Diagnosis
		Challenge 2: How to Classify Patients with Symptoms that Do Not Have a Diagnosis?
		Challenge 3: Explaining Symptoms When There Is No Diagnosis – The Example of Chronic Pain
		Challenge 4: How Do We Care for the Sick Individual in a Measured World?
		Planning the Future
		References
	13: When the Illness Has No Name: Focus on Clinical Trials in Systemic Lupus Erythematosus
		Chapter
		Do All Subjects Enrolled in SLE Clinical Trials Have SLE?
		Do Classification Criteria Ensure the Purity of the Study Enrollment?
		Do SLE Study Subjects Actually Have Their Stated Disease Activity?
		Are Study Subjects Taking Their Medications?
		What Steps Can Be Taken to Promote Certainty in SLE Clinical Trials?
			Ensure Patients Have SLE
			Enrich the Study Population with Informative Patients
			Promote Compliance and Adherence
		Conclusions
		References
	14: The Epidemiology of Systemic Lupus Erythematosus
		Epidemiology
		Identifying Individuals Who May Have SLE
		Defining Individuals with SLE
		Real-World Experiences
		How Many Have SLE? It Depends
		Future Directions
		Back to John Snow
		References
Part IV: Diagnoses
	15: Managing and Tolerating Diagnostic Uncertainty
		Introduction
		Conceptualizing Diagnostic Uncertainty
		Managing Diagnostic Uncertainty
		Managing Uncertainty: The Meaning and Necessity of Tolerance
		References
	16: Is There a Textbook for Non-textbook Patients?
		Is There a Textbook for Non-textbook Patients?
			Theme: Delays in Diagnosis
			Theme: Not Believed by Doctors
			Theme: Not Believed by Family Members/Family in Denial
			Theme: Women Symptoms Are Not Taken Seriously
			Theme: Symptoms
			Theme: Power Struggle with Doctors
			Theme: Treatments Don’t Work
			Theme: Mental Health
			Theme: Advice to Doctors
			Theme: Advice to Patients
	17: The Changing Role of Uncertainty in Physician-Patient Relationships
		Concepts
		The Evolution of Physician-Patient Relationship
		The Role of Uncertainty in the Physician-Patient Relationship
		Looking to the Future
		References
	18: Syndromes in Search of a Name: Disorders of Consciousness, Neuroethics, and Nosological Humility
		Introduction: Terry’s Story
		The Origins of the Vegetative State
		From Phenotype to Mechanism
		Naming Wisely
		The Place of Time
		What’s in a Name?
		New Nosologies, Pragmatism, and Disability Rights
		Coda
		References
	19: Reflections on the Conference by a Physician-Patient
		My Interest in this Conference
		Thinking as a Physician
		Thinking as a Patient
		The Key Lessons
		References
	20: Clinical Ambiguity in the Intelligent Machine Era (Treats Breaks and Discharges)
		Introduction
			Healthcare Megatrends
			Democratizing Technologies
			Ambiguity and Common Sense
		Probability Science
			Knowledge and Decision-Making
		Data Science
			Knowledge Representation
			Deconvoluting Data Complexity
		Computing Science
			Making Machines Intelligent
			Reasoning and Abstraction
			Reliability and Transparency
			The Digital Image Advantage
		Cognitive Human-Intelligent Machine Parallels
			Confidence
			Information Processing
			Learning
			Bias
			Context
			Intuition and Expertise
		Limitations of Current Healthcare AI Applications
			Intelligibility
			Reproducibility
			Data Quality
		Lessons Humans Can Learn
			From Autonomous Driving Vehicles
			From Natural Languages and Semantics
			From Resolving Lexical Ambiguity
			From Common Sense Challenges
				Difficult Questions and Answers
		Conclusions
		References
	21: Shame, Name, Give Up the Game? Three Approaches to Uncertainty
		Chapter
		Uncertainty as Threat
		Uncertainty as Classification Problem
		Uncertainty as Part of Process
			Research Agenda
		Conclusion
		References
Others Who Spoke
	Others Who Spoke at the Workshop Concurred with and/or Added New Thoughts on Several Topics
		Reference
Index