Proposed Terms

Below the reader will find:

(A) First, a draft list of proposed definitions by Richard Scheuermann, Werner Ceusters, and Barry Smith for the meeting titled: Signs, Symptoms and Findings: First Steps Toward an Ontology of Clinical Phenotypes (September 3-4, 2008).

(B) Then, emails with comments pertaining to the proposed definitions from a few of those who participated in the meeting.

(C) Based in part upon these comments, a paper titled "Toward an Ontological Treatment of the Initiation, Realization, Recognition and Representation of Disease: Some Terminological Proposals" [1] was produced by Richard Scheuermann and Barry Smith and distrubuted to those who participated in the meeting for further comments. So, finally, the reader will find emails with comments pertaining to this paper from a few of those who participated in the meeting, along with comments from Barry Smith.

Draft List of Proposed Definitions

Diseases, Signs and Symptoms: Draft List of Proposed Definitions

We use ‘bodily feature’ to designate biological qualities, processes or structures of an organism such as blond hair, coughing, swelling.

We use ‘clinically normal’ to designate bodily features of a human being that are typically not associated with pain or other feelings of illness, with dysfunction, or with other indications of enhanced morbidity.

We use ‘homeostasis’ to designate the state in which the bodily processes of the organism are regulated in such a way as to (1) maintain bodily features within a certain homeostatic range and (2) respond successfully to departures from this range caused by external influences. During homeostasis the organism continually assesses its current state to determine if its bodily features fall within this range.

Homeostatic Range =def. The range of types of bodily features whose maintenance is continuously sought by an organism in the state of homeostasis.

Normal Homeostasis =def. Homeostasis of a type that is clinically normal for a human being of a given type and age in a given environment.

Abnormal Homeostasis =def. Homeostasis of a type that is not normal.

Disorder =def. A bodily structure in a human being that is clinically abnormal.

Etiological Process =def. A biological process in a human being that leads to a disorder.

Pathological Process =def. A biological process in a human being that is caused by a disorder.

Acute Pathological Process =def. A pathological process terminating with a resolution of the disorder and a return to normal homeostasis.

Acute Disorder =def. A disorder that leads to an acute pathological process.

Chronic Pathological Process =def. A pathological process that results from an adaptation on the part of the patient to a level of abnormal homeostasis.

Chronic Disorder =def. A disorder that, in the absence of intervention, would typically lead to a chronic pathological process.

Progressive Pathological Process =def. A pathological process that deviates increasingly from homeostasis in such a way that the re-establishment of homeostasis is precluded.

Progressive Disorder =def. A disorder that, in the absence of intervention, would lead to a progressive pathological process.

[2] Types of Pathological Process

Physical Examination =def. A sequence of acts of observing eliciting responses, and measuring the bodily features of a patient, occurring in the context of a clinical encounter.

Sign =def. A bodily feature of the patent that is observed in a physical examination and is hypothesized by the clinician to be a disorder or a manifestation of a disorder.

Symptom =def. A quality of the patient that is observed and can be observed only by the patient and is of the type that can be hypothesized by the patient as a manifestation of a disorder.

Laboratory Test =def. A laboratory assay that has as input a specimen derived from the patient, and as output a result that represents a quality of the patient.

Laboratory Finding =def. The representation of a quality of a patient that is the output of a laboratory test.

Clinical Finding =def. A representation of a bodily feature of a patient that is recorded by a clinician because the feature is hypothesized to be of clinical significance.

Clinical Phenotype =def. A constellation of those types of bodily features that are associated with a disorder at each stage of its development.

Clinical Picture =def. A representation of a clinical phenotype as instantiated in a given patient that is inferred from the constellation of laboratory and clinical findings available to the clinician about a given a patient at any given stage.

Diagnosis =def. The conclusion of an interpretive process that has as input a clinical picture of a given patient and as output an assertion to the effect that the patient has a disorder of such and such a type.

Email Comments Based Upon Draft List of Proposed Definitions

From: Xia, Ashley (NIH/NIAID) [E] [3] Sent: Tuesday, September 02, 2008 10:54 AM Subject: RE: Signs Symptoms and Findings Workshop: Definitions Proposed for Discussion

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Hi Richard

I would like to suggest to add a concept of Homeostatic Profile. The current concept of Homeostatic Range is good for a single measure of a sign, symptom or finding. Homeostatic Profile is good for a collection of homeostatic ranges of a homeostatic state.

Ashley

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From: Kent Spackman [4] Sent: Tuesday, September 02, 2008 2:00 PM Subject: RE: Signs Symptoms and Findings Workshop: Definitions Proposed for Discussion

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I haven’t spent much time examining these proposed definitions, but thought I would give you my initial ‘off-the-cuff’ reaction in the form of questions (see attached). There may be good answers to some of these questions – in fact I hope there are. But I suspect I can generate a number of additional difficult questions on further reflection. The general ‘gist’ of the terms is easy to grasp, of course, but I think it would be unwise to underestimate the degree of difficulty of getting good definitions – and getting consensus about the meanings.

I would prefer to back up a step and try to answer two questions: 1) What are the fundamental types of things for which we need ontological categories? (Do we really need to differentiate “signs” from “symptoms”?) 2) What are the criteria by which we can judge whether we have good categories and good definitions? And I’d like to propose one important criterion. It is: the degree to which ordinary clinicians can understand and reproducibly apply the definitions.

Kent Spackman

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From: Sivaram Arabandi [5] Sent: Tuesday, September 02, 2008 3:00 PM Subject: Re: Signs Symptoms and Findings Workshop: Definitions Proposed for Discussion

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I can see that the discussion is already getting off the ground and want to add a couple of thoughts. The workshop and the definitions of terms here (like 'Normal Homeostasis', 'Disorder' etc) are focused with the context 'human beings'. However the terms themselves are equally applicable in the more general sense to all animals. It may be useful to provide a broader definition because of the interplay between humans and animals (infectious diseases and their accompanying signs and symptoms - eg. rabies) as well as translational research.

Sivaram

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From: Anita Burgun-Parenthoine [6] Sent: Tuesday, September 02, 2008 4:14 PM Subject: Re: Signs Symptoms and Findings Workshop: Definitions Proposed for Discussion

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Thanks for sharing these questions. I have two comments: - phenotypes (as well as observable entities) may be normal. It's interesting to mention that in MPO the synonyms for normal phenotype are 'viable' and 'fertile'.... - As Kent already said, some distinctions are difficult to get. For example, the distinction between chronic disorder and progressive disorder is difficult in practice as many chronic diseases end up with complications. Looking forward to the workshop, Anita

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From: John Armstrong [7] Sent: Tuesday, September 02, 2008 5:34 PM Subject: RE: Signs Symptoms and Findings Workshop: Definitions Proposed for Discussion

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Richard,

From the content of the document you distributed involving disorders, findings, signs, symptoms, and processes, I gather that we will be facing some difficult conceptual issues related to classifying subsumption relations for which there do not appear to be intuitive child-parent links (e.g. those relating findings and disorders.) This is a constant challenge we face at Lead Horse Technologies, whether we are browsing SNOMED-CT or developing and editing our own, proprietary ontologies. There are approaches aimed at solving this dilemma, used by us and others, but they often can involve labor intensive curation and constant editing. If it’s not too late, I’d like to propose that topics discussed at the workshop this week include the idea that dilemmas like the one described here may be approached through tying the curation of intraontological relations not to intelligent design but to evolution – that is, linking the curation of subsumption relationships to actual clinical enquiries received from practicing clinicians rather than to the efforts of ontology development professionals such SNOMED-CT editors. This would boil down to applying a wiki-approach to ontology evolution and it is one that we are working on at Lead Horse. Food for discussion, even if only over a glass of wine.

Thanks, and I’m looking forward to the workshop. John

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From: Colombo Gianluca [8] Sent: Tuesday, September 02, 2008 7:34 PM Subject: R: Signs Symptoms and Findings Workshop: Definitions Proposed for Discussion

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Dear all, it is a pleasure to contribute to the discussion.

We would like to bring up two general points, and then proceed to a more detailed discussion of the proposed definitions.

First of all, a remarkable aspect of the diagnostic activity is that certain observations are performed, in order to reconstruct the state of a patient; the state itself is not fully/directly observable (e.g. diabetes cannot be observed per se); the observables collected during the diagnostic activity are interpreted by the clinician, according to some explicit theory and/or his experience, in order to fully reconstruct such state. We therefore deem important to disinguish between what is observed and what is inferred/reconstructed. Also the methodology/istrumentation for the observation, and the criteria for the inference/reconstruction play an importat role. Second, looks like that the notion of disorder plays a pivotal role. A disorder must ncessarily be an anomaly of structure. What is the rationale behind this choice?

Best, Gianluca Colombo and Daniele Merico

HERE ARE OUR COMMENTS:

Signs, Symptoms and Findings: Draft List of Definitions Proposed for Discussion

We use ‘bodily feature’ to designate biological qualities, processes or structures of an organism such as blond hair, coughing, swelling.

We use ‘clinically normal’ to designate bodily features of a human being that are typically not associated with pain or other feelings of illness, with dysfunction, or with other indications of enhanced morbidity. How is dysfunction defined?

We use ‘homeostasis’ to designate the state in which the bodily processes of the organism are regulated in such a way as to (1) maintain bodily features within a certain homeostatic range and (2) respond successfully to departures from this range caused by external influences. During homeostasis the organism continually assesses its current state to determine if its bodily features fall within this range.

Homeostatic Range =def. The range of types of bodily features whose maintenance is continuously sought by an organism in the state of homeostasis.

Normal Homeostasis =def. Homeostasis of a type that is clinically normal for a human being of a given type and age in a given environment.

Abnormal Homeostasis =def. Homeostasis of a type that is not normal.

Disorder =def. A bodily structure in a human being that is clinically abnormal. 1) Why a structure, and not a quality or process? What is the rationale? 2) A disorder can be both a cause and an effect? From the poin of view of etiology, it aperas to be neuter.

Etiological Process =def. A biological process in a human being that leads to a disorder. Why introducing the notion of etiological process but not of etiological factor?

Pathological Process =def. A biological process in a human being that is caused by a disorder. 1) Why is a pathological process interesting? Is it the connection between the disorder and the symptoms/signs, or the patient’s malaise, or morbidity? 2) A biological process ensuing a disorder may be physiological rather than pathological (e.g. wound healing), if pathological implicitly means “associated with pain or other feelings of illness, with dysfunction, or with other indications of enhanced morbidity” (quoted from clinically normal).

Acute Pathological Process =def. A pathological process terminating with a resolution of the disorder and a return to normal homeostasis.

Acute Disorder =def. A disorder that leads to an acute pathological process.

Chronic Pathological Process =def. A pathological process that results from an adaptation on the part of the patient to a level of abnormal homeostasis.

Chronic Disorder =def. A disorder that, in the absence of intervention, would typically lead to a chronic pathological process.

Progressive Pathological Process =def. A pathological process that deviates increasingly from homeostasis in such a way that the re-establishment of homeostasis is precluded.

Progressive Disorder =def. A disorder that, in the absence of intervention, would lead to a progressive pathological process.

Physical Examination =def. A sequence of acts of observing eliciting responses, and measuring the bodily features of a patient, occurring in the context of a clinical encounter.

Sign =def. A bodily feature of the patent that is observed in a physical examination and is hypothesized by the clinician to be a disorder or a manifestation of a disorder.

Symptom =def. A quality of the patient that is observed and can be observed only by the patient and is of the type that can be hypothesized by the patient as a manifestation of a disorder.

Laboratory Test =def. A laboratory assay that has as input a specimen derived from the patient, and as output a result that represents a quality of the patient.

Laboratory Finding =def. The representation of a quality of a patient that is the output of a laboratory test.

Clinical Finding =def. A representation of a bodily feature of a patient that is recorded by a clinician because the feature is hypothesized to be of clinical significance.

Clinical Phenotype =def. A constellation of those types of bodily features that are associated with a disorder at each stage of its development. 1) Is there a relevance criterion in the association? Since the Clinical Phenotype refers to bodily feature, any feature may be included. 2) A bodily feature can be a structure; hence a structure can be a clinical phenotype; in other ontologies/works, it is usually preferred to define a phenotype as a property bore by a structure (f. Bard et al., Nature Reviews Genetics 2004).

Clinical Picture =def. A representation of a clinical phenotype as instantiated in a given patient that is inferred from the constellation of laboratory and clinical findings available to the clinician about a given a patient at any given stage. Why are Clinical Picture and Clinical Phenotype two distinct concepts? Why is only the former related to Laboratory/Clinical Findings and not simply Bodily Features? Does that imply being observable (directly, or by means of instrumentation) in antithesis to being reconstructed/inferred? Or is the difference related to significance according to the clinician? Indeed, Clinical Findings must be of clinical significance for the clinician (but not Laboratory Findings).

Diagnosis =def. The conclusion of an interpretive process that has as input a clinical picture of a given patient and as output an assertion to the effect that the patient has a disorder of such and such a type. If a disorder is neuter with respect to causes and effects, is a diagnosis neuter to causes and effects as well? Declining this definition on a specific example, is Diabetes Mellitus Type-I a diagnosis? Is Diabetes Mellitus Type-I a disorder? Or is rather the absence of insulin-producing beta cells of the pancreas the disorder? Or is it the absence of insulin the disorder? Or is it the abnormally high level of glucose in the blood? Glucose is a blood component, and thus is a bodily structure.

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From: Lou Gldberg [9] Sent: Wednesday, September 03, 2008 8:44 AM Subject: Re: Signs Symptoms and Findings Workshop: Definitions Proposed for Discussion

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Homeostatic and homeostasis are old and venerable terms and everyone more or less knows what they mean but they are misleading. None of the states they refer to are static in any way. Alternate terms that have been suggested are homeodynamic and homeokinetic.

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From: Zhangzhi Hu [10] Sent: Wednesday, September 03, 2008 9:42 AM Subject: Re: Signs Symptoms and Findings Workshop: Definitions Proposed for Discussion

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Just throw in my 2 cents:

- We should add "Etiology" besides "Etiological Process", just like there is Homeostasis as opposed to "homeostatic process" (already a GO term, GO:0042592)".

- We also should add Prognosis as opposed to Diagnosis.

- Perhaps we also consider Progression and Remission...

- Also there seems to be already a Symptoms Ontology, but not sure about its content:

http://ieeexplore.ieee.org/xpl/freeabs_all.jsp?tp=&arnumber=1647635&isnumber=34552

Zhangzhi

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From: Sivaram Arabandi [11] Sent: Fri 09/05/08 10:07 AM Subject: Fwd: Re: FYI: An attempt to integrate draft list of definitions into an existing medical record

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I too found the workshop very stimulating and ended up doing a lot of background reading on my entire flight back to Cleveland! I thoroughly enjoyed the discussions and the consensus approach to resolving the challenges. Here are a few thoughts:1. I feel that 'clinical-finding' and those that are clinically significant i.e. 'clinically-significant-finding' are not one and the same - instead they have a subclass relationship.

2. Common to encouraging adoption of new products/technologies, be it in the patient-centric side or in the population-centric research/studies side, is the fact that the users need to have control of the data i.e. data portability. This is an area where using Ontologies to provide common, reusable models and RDF for data persistence provides the separation between the application layer and the data layer and give the user ownership of data. This is a problematic area for current EMRs and once a user/practice/hospital starts using a specific implementation of EMR, they are essentially locked down.

3. I particularly liked the idea of breaking down the concepts behind symptoms and signs into their component parts - what was found, who found it, how was it found etc.. to define them at a very granular level. These can then be used, globally or locally, to define what one considers as symptoms or signs in a flexible way. 4. One thing that I was not sure of was 'What are the boundaries for the Phenotype ontology?' - how far should we go in identifying the symptoms and signs and lab findings and associating them with the disorders/diseases? Is this the place to define 'these are the clinical findings associated with a particular disorder'?

Sivaram

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On Sep 4, 2008, at 11:49 PM, Ogbuji, Chimezie wrote:

Thanks for the excellent workshop. I thoroughly enjoyed the discussions and found them very insightful. I was sufficiently encouraged and motivated that I spent the 2 hours in-flight re-factoring the Computer-based Patient Record ontology I've been slowly developing, over a period of over a year, to incorporate the terms and definitions from the draft list distributed to the participants. The exercise was was very insightful for me and in the end, the combination of the definitions and the conversations we had about them helped fill certain holes that I have had for some time in the ontology. The updated OWL file is attached for anyone interested. I defined a namespace for the terms that I re-used from the term list. In the absence of a better option, I used the workshop URL as the basis for this namespace: http://bioontology.org/wiki/index.php/DallasWorkshop

Below are the terms I incorporated, the others either already had an existing term in the ontology from the prior version or I ran into difficulty incorporating them: pheno:bodily-feature pheno:aggregate-bodily-feature pheno:clinical-phenotype pheno:laboratory-test-finding pheno:abnormal-homeostasis pheno:normal-homeostatis

Embedded within the OWL assertions were a few editorial comments that identify some interesting issues I ran into during the re-factoring process: For pheno:bodily-feature, the criteria that restricts instances of this defined class to only include those that are 'of' an organism was not axiomatized since, I was not sure what relation, specifically, what role restriction, would be relevant to represent this criteria. For pheno:clinical-phenotype, the criteria that there is an association with a disorder was not axiomatized since I was not sure what relation would be relevant as a general, permanent association between a constellation of phenotypes and a disorder. For clinical-finding, the criteria regarding the clinician's hypothesis of clinical significance is also not axiomatized. This seemed (to me) part of a more difficult problem of capturing modal logic, which would seem necessary to represent beliefs. I have also included a screen shot of the classes from within Protege to show where they fell in the larger framework into which they were re-factored. Thanks again, for a wonderful workshop!

Chimezie (chee-meh) Ogbuji

Email Comments Based Upon "Toward an Ontological Treatment..." Paper

From: "Hogan, William R" [12] Sent: 10/14/2008 Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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Bill: 1. Under examples of acquired genetic disease, you cite malignant colon cancer. However, a physical object like a tumor is not a disposition. Thus, I would have thought malignant colon cancer to be an acquired genetic disorder, not an acquired genetic disease, the disease being the disposition toward unregulated cell division and the lumps of cells that result being another disorder that can lead to other dispositions (e.g., disposition to abnormal colonic transport).

Barry's Response: We (actually me, since I didn't check this with Richard yet) view the cancer as the disposition, the disorder is whatever it is in the cell(s) in virtue of which they have this specific disposition toward unregulated cell division of this specific sort; the tumor is another disorder which is a consequence of the realization of the disease. Not every disorder serves as physical base for a disease; the tumor in question does not (typically) do so. (Does it ever?)

Bill: 2. I am not sure that your definition of infection rules out normal flora, colonization, or carrier status. I know that you inserted the word "pathogenic", but the situation I am concerned about is that normal flora (at least in humans) are a common source of bacterial infections.

Barry's Response: E.G., normal flora invade the weakened lung of smokers; but then they are not normal -- because they are in the wrong place.

Bill: One common usage of 'pathogen' is to refer to types of organisms some of whose instances cause infectious diseases in humans.

Barry: One common usage of 'drug' is to refer to types of chemical substances some of whose instances are packaged, sold and administered to patients. Penicillin is a drug in this sense. But it is a loose sense, which a good ontology needs to guard itself against. E.g. because there are non-drug penicillin varieties (wild type penicillin expandase?)

Bill: Thus, the definition of "infection" as currently stated would apply to every human, and I don't find such a definition particularly helpful.

Barry: because every human has many pathogens within his or her interior? If so, I think we are safe, since we say that there is infection only if the pathogen contributes to a disorder, and a disorder (we say) has to be clinically signifant.

Bill: I think that the terms pathogenic/pathogen therefore may require some explication (I don't know whether you have a page limit), and obviously care will be required not to be circular (i.e., can't define pathogen as organism that causes infection or infectious disease).

Barry: We are bending over backwards not to be circular.

Bill: Or rather the definition of infection could be modified slightly.

Attempt 1: pathogen = organism that disrupts normal homeostasis in its host organism, or leads to abnormal homeostasis. Not sure this one covers latency such as with Zoster virus. Or perhaps such latency does not qualify as infection because the virus is not pathogenic at that time. Pathogenicity according to this definition would be a quality of an instance of an organism that it may acquire/lose.

Barry: To talk of pathogens is to talk of organisms playing certain roles. To make this clear replace this with:

Attempt 1*: pathogen = organism that is within a host organism and either is disrupting normal homeostasis or ADD CLAUSE REGARDING LATENCY.

Bill:

Attempt 2: pathogen = organism with strong disposition to cause morbidity in a particular host. As opposed to weak disposition? I think attempt #1 with the idea that the latency of zoster viruses in ganglion cells does not equal infection is better.

Attempt 3: redefine infection: "...presence of a pathogenic organism -- in either a clinically abnormal quantity or location or both -- within the host organism..." It has to be clinically abnormal because for example, any bacteria in the urine of a pregnant woman requires treatment, but you only need to treat >100K CFUs (colony-forming units) in the urine of a non-pregnant woman. In this case, the Zoster latency qualifies as infection (which is my preference).

Barry: I believe the issue here is covered by our present definitions.

Bill: 3. Definition of sign: I am somewhat uncomfortable with its restriction to the physical exam (unless you define physical examination as including any imaging study). For example, see the following link for an example of an "echocardiographic sign": http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=481116

Barry: If Richard agrees, I would be happy to expand 'sign' to allow image-associated signs.

Bill: 4. Definition of symptom: I have difficulty with the "can be observed only by the patient" aspect of it. For example, we may say the patient has a symptom (which you define as a type of quality) of fever or rash, and the clinician can subsequently observe those things (qualities) also.

Barry: I would be happy to drop this.

Bill: 5. Definition of physical exam: perhaps say "observing and measuring" as opposed to just "measuring".

Barry: Fine with me.

Bill: 6. Definition of clinical finding: I would include laboratory finding in the scope of this definition.

Barry: Surely the laboratory findings can at least include much more, e.g., at the molecular level, that would not be classed as clinical?

Bill: 7. Possibly missing term - physical exam finding: representation of a sign (as sign is currently defined), or representation or output of a physical examination.

Barry: Fine with me.

Bill: 8. Clinical manifestation: I would add at the end of the definition "...including the signs and symptoms themselves."

Barry: Logically redundant, in fact, but I suppose I could go along with it.

Bill: 9. Clinical phenotype: I would change "bodily qualities" to "bodily features" in the definition. It seems to encompass both structures and their qualities, which is what the defined class of "bodily feature" as stated earlier in the paper comprehends.

Barry: We hope to clean up this whole aspect in the next version.

Bill: 10. Discussion: the diagnostic process is an iterative one. The clinician is forming hypotheses during history taking, testing them during additional history taking, forming new hypotheses a result, testing those hypotheses during physical exam, forming new hypotheses as a result, etc. It is such a canon of how medicine is taught that exclusion of the iterative nature of the diagnostic process from this paper may alienate clinicians. However, I understand that including it in this paper is not straightforward and perhaps not even necessary to the purposes of the paper. However, simply paying homage to the iterative nature of the diagnostic process--including that the response to a particular treatment is often itself a diagnostic sign--in a single sentence may be sufficient to avoid rejection of the rest of the paper due to its exclusion.

Barry: I agree.

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From: "Hogan, William R" [13] Sent: 10/18/2008 Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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Bill: Yes, "clinically abnormal" in the definition of disorder plus the use of disorder in the definition of infectious disease covers all my concerns. Thus, I agree that the definition as it stands is fine. Tumors, by virtue of their physical mass, often cause all sorts of clinically abnormal problems, such as blockage of bile ducts, blockage of the bowel, seizures, pain, fractures, etc, etc. Whether any of these things are diseases is then the issue. Since a disease is a disposition to undergo pathological processes, I would say then that tumors do in fact (sometimes, but not always) serve as the physical basis of diseases. Have I gone wrong in this line of reasoning? I don't think it impacts any definitions, regardless.

Yes, some laboratory findings are not clinical. I think it would be helpful for the definition of clinical finding to include those lab findings that are clinical but I don't see an easy way to do it. To create the term clinical laboratory finding immediately creates a potential for multiple inheritance: clinical lab finding is_a lab finding and clinical_lab_finding is_a clinical finding. I don't feel strongly enough about it to pursue it further.

Barry: I think we can avoid the multiple inheritance if we recognize two senses of 'clinical' (or rather, find a way to distinguish two terms): clinical as a temporal attribute of a disease process (meaning, roughly, LATE), and clinical as an attribute of an examination, meaning, roughly, relating to what doctors do with patients in their clinics.

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From: "Jacuzzo, Leonard" [14] Sent: 10/9/2008 Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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Leonard: Homeostatic Range =def. – The range of types of bodily features whose maintenance is continuously sought by an organism in the state of homeostasis (e.g. 65 – 110 mg glucose/dL serum).

This seems strange to me. Is it a range of types, or is it a range for a given type? The examples seems to be of a range for a given type and not a range of types. I am not sure what a range of types would be, but I am thinking that there is a range of types of furniture in the sense that types of furniture range from stools to dressers or something.

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From: "Cowell, Lindsay" [15] Sent: 10/9/2008 Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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Linsay: Would the following cover an eating disorder? (maybe it does not matter for infectious disease, but it might for diseases in general).

Disorder =def. – A physical structure or portion of bodily substance that is clinically abnormal (e.g. a tumor, an infected cell, a prion molecule in the brain, a mutation in genomic DNA, endotoxin in blood).

Barry: Sure. Something wrong in the brain.

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From: "James, Andrew" [16] Sent: 10/20/2008 Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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I still have some reservations about homeostasis and the use of the term abnormal homeostasis, etc. I have always considered homeostasis as a process that is either successful or not. The organism either maintains the normal state or does not. I have embedded a description of homeostasis taken from Dorland's Medical Dictionary. There is an adjective, homeostatic. Our use of the term 'homeostatic range' seems appropriate but I'm not sure about the terms "normal homeostasis" or "abnormal homeostasis". I consider the term "homeostasis" refers to a process not a state. I would be very interested to hear from the biologists and cellular physiologists in our group. What is the experts' appraisal of our use and definition of these terms.

  "The tendency of a biological system to maintain relatively constant
  conditions in its internal environment while it continuously interacts
  with and adjusts to changes on the outside. Though homeostatic
  mechanisms, the human body maintains body temperature, the osmotic
  pressure of the blood, and many other things within a normal range."

I am concerned that we are distorting reality to solve our problem of defining diseases as acute, chronic. or progressive. Daniele suggested the use of the term "state" which I find appealing. There is a baseline state that is the norm for humans, and then multiple abnormal states.

I agree treatment of symptoms and signs as a first step. While it may be futile to make a clear distinction between symptoms and signs, I accept that a term can be used as a symptom in one specific context and as a sign in another specific context. I am still troubled by our apparent inability to define those 'symptoms' related by a third party on behalf of the patient. once again, the suggestions of describing the source of information may solve this problem. My colleagues view the information provided by parents about their child as 'observations made by the parent that are subjected to interpretation by the parent as symptoms of a disease'. The same can be said for information provided by caregivers (children, others) of the elderly, and friend/acquaintance/bystanders when a person has collapsed in a public place.

The definition for clinical history taking concerns me because it appears to exclude a major component of paediatric practice.

I think we should be consistent in out use of words. We should use organism when defining biological entities, and patient or person when defining entities that hinge upon the involvement/participation of humans. Furthermore, I recommend we use person rather than patient. The word patient may be viewed as somewhat pejorative. Furthermore, many of the entities that we define may exits in a person who has not sought medical and therefore, does not have a physician. How can this person be a patient if he is not under the care of a physician?

Finally, I think the definition for Clinical Phenotype is actually the definition for Disease phenotype. If this is true, then the definitions for Clinical Picture and Diagnosis need some minor changes.

Below is a more detailed discussion of these comments with my suggestions for change highlighted with MS Word's tracking tool.

I think the following sentence, located at the top of page 3, is incomplete: "We then say that the patient has two distinct disease instances of the same disease type. These successive bouts are the differentiated by their etiology in the sense that their respective physical bases are caused by distinct processes ." I assume "the' should be "then'.

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A More Detailed Discussion of Above Comments (Andrew James)

Predisposition to Disease of Type X =def. – A disorder in an organism that causes an increased risk of developing the disease X. [the word developing seems a better choice from a biological perspective – acquisition suggests a takeover]. Do we mean that there is always a state of predisposition that must be changed by another event? I assume the answer is yes. Does one also have a predisposition to disease X because one has the genotype for disease X? Huntington’s Disease is a constitutional genetic disorder that does not become clinically apparent until later in life. Is the pre-clinical phase of Huntington’s Disease also an instance of predisposition to Huntington’s Disease simply because the individual has the Huntington’s genotype? No additional event is required for Huntington’s Disease to develop.

Clinical History Taking =def. – An interview in which a clinician elicits a clinical history from a patient.

This definition denies the existence of paediatric history taking [obtaining a history from a parent]. There are other instances in which the patient’s history is obtained from a third party [an elderly person, a mentally incompetent person, an unconscious person]. Therefore, the definition is either incomplete, or too constrained. Suggest a minor amendment as follows:-

Clinical History Taking =def. – An interview in which a clinician elicits a clinical history from a patient, or a parent, guardian, or person who is authorized to make health care decisions on behalf of the patient. [Note: this definition does not include a friend, or the bystander, who provides a brief clinical history on behalf of a person who collapses in a public place].

Clinical Phenotype =def. – A constellation of those types of bodily qualities that are associated with a disease at each stage of its development.

This definition appears to be that of the phenotype of a disease. There is no mention of either history taking or physical examination by a physician. How can this be a clinical phenotype? It appears to be the phenotype of a disease. Suggest the following change of name;

Disease Phenotype =def. – A constellation of those types of bodily qualities that are associated with a disease at each stage of its development.

If Clinical Phenotype is renamed Disease Phenotype, then Clinical Picture should be renamed Clinical Phenotype, and the definitions of both Clinical Phenotype and Diagnosis need minor revision to consistent with the definition of Disease Phenotype.

Clinical Picture =def. – A representation of a clinical phenotype as instantiated in a given patient that is inferred from the constellation of laboratory, image and clinical findings available to the clinician about a given a patient at any given stage. The renamed and revised definition for Clinical Picture follows:

Clinical Phenotype =def. – A representation of a disease phenotype as instantiated in a given patient that is inferred from the constellation of clinical, laboratory and image findings available to the clinician about a given a patient at any given stage of the disease.

Diagnosis =def. – The conclusion of an interpretive process that has as input a clinical picture of a given patient and as output an assertion to the effect that the patient has a disease of such and such a type. The renamed and revised definition for Diagnosis follows:

Diagnosis =def. – The conclusion of an interpretive process that has as input a clinical phenotype of a given patient and as output an assertion to the effect that the patient has a disease of type X.

Suggest a minor revision of the following definitions:

Physical Examination =def. – A sequence of acts of measuring bodily features of a patient performed by a clinician.

Clinical Finding =def. – A representation of a bodily feature of a patient that is either the output of a clinical history taking and/or a physical examination, or an image finding. [the ordering simply reflects the usual process flow for obtaining a history, performing a physical examination and then obtaining x-rays].

Infection =def. – A disorder of a type which involves the presence of a pathogenic organism within a host leading to pathogen persistence and/or pathogen duplication.

Secondary Infection =def. – A disorder consisting in the presence of a pathogenic organism within a host that leads to infection in virtue of a predisposition to disease that exists in virtue of a prior infection with a different pathogenic organism (e.g. cryptosporidiosis in AIDS patients)

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From: "Peters, Bjoern" [17] Sent: 10/31/2008 Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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Bjoern Peters (BP): You define 'bodily feature' on page 1, which I like, and mimics, but then go on to use 'bodily structure' and 'bodily substance' in the definition of 'disorder'. Is this an intended differentiation? I thought bodily feature would work well there.

Barry Smith (BS): Yes. Disorders relate only to bodily structures in the general sense which includes bodily substances (thus, disorders are always independent continuants); bodily features include also qualities and processes.

BP: Page 2 has a typo: 're-gained at a level that is judged to be clinically abnormal' should probably read 'normal' instead of 'abnormal'.

BS: No. It is correct; in cases of chronic disease the patient regains homeostasis but it is outside the threshold of normal homeostasis and, so, clinically abnormal.

BP: I would prefer 'homeostatically abnormal' or something like that to 'clinically abnormal'.

BS: Your preferred phrase does not convey a clear idea in English, unfortunately.

BP: But, more importantly, I do not like the elucidation. You say later that diseases of unknown causes can have 'clinically abnormal' bodily features (which is fine), but in the elucidation you refer to the clinician setting thresholds of significance. I was hoping that in the realism-based view of diseases, clinicians only come in on the diagnosis side of things, and they may find something to be clinically abnormal which they consider clinically normal the next day due to changing knowledge.

BS: That is absolutely right; clinicians cannot make something abnormal that is in fact normal, just by consensus decision; for the realist there are the usual possibilities, e.g.: the patient lies / exaggerates and so the clinician makes an error; the clinician makes an error due to her own misperception or bad reasoning; the clinical consensus is in error and misclassifies. Why do you think the assessment of deviation from homeostatis is not on the diagnosis side of things?

BP: It took me a while to get the definition of 'genetic predisposition to Disease of Type X', as it is unclear which of the two dispositions the physical basis relates to. My proposed rewrite: "A predisposition to disease of type X whose physical basis for the increased risk of acquiring disease X is a constitutional abnormality in a patient's genome"

BS: I would now like to propose:

Predisposition to Disease of Type X =def. A disorder in an organism which is the physical basis for [rather than: 'which causes'] an increased risk of developing the disease X.

In conjunction with this, I think our existing definition,

"Genetic Predisposition to Disease of Type X =def. A predisposition to disease of type X whose physical basis is a constitutional abnormality in a patient's genome"

is clear enough. Do you agree?

BP: Regarding the definition of symptom, I believe that the 'only' in 'can be observed only by the patient' needs to be removed. Also, why is this 'quality of the patient' and not 'bodily feature of the patient'? That is why there are so many problems, as the same bodily why sign and symptom is not.

BS: I think we are going to find it very difficult to get consensus on the definition of 'symptom' and that we will in the end have to drop this term.

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From: "Peters, Bjoern" [18] Sent: 11/05/2008 Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes Response: "Ceuster, Werner" [19]

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Bjoern Peters (BP): I could argue some fine points, but can live with all responses, except for one: It still seems to me that the elucidation of 'clinically abnormal' suggests that, as clinical consensus changes, so would causes of disease.

Werner Ceusters (WC): Clinical consensus cannot change anything about the cause of diseases, except for iatrogenic ones that come into existence as a result of new sorts of treatments that themselves result from some consensus.

BP: The assessment of abnormality should clearly be left to clinicians.

WC: any assessment involves some sort of diagnosis and is thus a level 2 thing (level 1 = first order reality; level 2 = cognitive representation; level 3 = externally accessible concretization). Whether some entity is abnormal or not, is a level 1 thing. Assessments can be right or wrong. It is not because all clinicians, in consensus, think that P is the case, that P really is the case. The term 'clinically abnormal' is, however, indeed a bit misleading. Something is not clinically abnormal because judged so by a clinician. Even if there were no clinicians, there would still be clinical abnormalities in the sense of the document.

BP: However the abnormality that causes disease itself should not require a clinical consensus, or any clinician to exist.

WC: Absolutely.

BP: Is it true that you only include clinicians in the elucidation to avoid a statistical definition of normality and abnormality?

WC: The elucidation, as far as I read, is not part of the definition.

BP: If so, you could refer to thresholds set by an 'informed clinician', who knows of all disorders associated with a bodily feature.

WC: Such thresholds, as you would have it, are again level 2 entities. Thresholds for whether something is clinically abnormal or not do exist also at level 1. An informed clinician's assessment of level 1 thresholds would be probably better than an uninformed one, but it remains an assessment.

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From: "Peters, Bjoern" [20] Sent: 11/05/2008 Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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I agree with all of Werner's points, but I didn't think that is written in the paper. This is the section I am referring to. Clinically abnormal is classified as a primitive term, with the following informal elucidation, which I split it into three parts:

(1) "We use 'clinically abnormal' to characterize those bodily features of or in an organism that are causally linked to an elevated risk of pain or other feelings of illness, to dysfunction, or to enhanced morbidity, and which (unlike pregnancy or menopause) are not such as to belong to the life plan for an organism of the relevant type."

(2) "A clinician will judge a bodily feature to be clinically abnormal only where the elevated risk exceeds a certain threshold level of clinical significance. The determination of this threshold will reflect the training and experience of the clinician in question and thus may vary from clinical context to clinical context."

(3) "It is worth noting that this treatment of 'normality' is distinct from those statistical treatments which do not take account of overlap of parameter values used to distinguish between normal and abnormal or of distribution extremes."

Regarding (1), it is great, and all I would want to say, given how the term is used throughout the paper.

Regarding (2), it is minimally confusing. Being generous, I can accept that this is no longer talking about 'clinically abnormal', but about the judgment of a physician thereof which is a completely different entity. That does make the 'clinically' part of the label suspect though, and I don't think it helps to understand the term better.

Regarding (3), what is this? Does it refer to the treatment of 'normality' for (1) or (2)?

Did you consider 'physiologically abnormal' or 'pathological' instead of 'clinically abnormal'?

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From: "Scheuermann, Richard" [21] Sent: 11/05/2008 Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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Response to Bjoern Peters' comments above:

Indeed, part 1 is the key part of the elucidation. A bodily feature can be clinically abnormal without being assessed by anyone including a clinician. We added 'clinically' to address the cases in which a bodily feature would be considered abnormal but not associated with pain, illness or dysfunction (e.g., the bearded lady); we are not interested in these kinds of abnormalities here.

Part 2 was designed to address the variability inherent in how a bodily feature is judged by different people at different points in time in different context. This does not change anything stated in part 1, it just clarifies how judgement can play a role in the assessment of the clinical abnormality.

Part 3 is added to make the point that the approach is not based on statistics, which is problematic for the reasons stated.

We reserved pathological and physiological to refer to processes. A 'pathological process' is one of the bodily features that would be clinically abnormal; another abnormal bodily feature would be a 'disorder'.

Thanks to all for the careful evaluation. I suspect that we will definitely need to do a little wordsmithing in order to make these points more clearly.

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From: "Cowell, Lindsay" [22] Sent: 11/24/2008 Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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Lindsay Cowell: In general, I think the draft is well written and the definitions good. I have just a couple of comments/questions:

1. Disease is defined (partly) as the disposition to undergo certain pathological processes. It seems we should also take into account diseases that result from the inability to undergo certain normal processes. So there is the absence of a process where there should be one.

Barry Smith: We will fix that.

Lindsay: 2. A predisposition has as its physical basis a disorder, which is a physical structure, according to the definitions. And this makes sense I think. But in the bit of clarifying text that follows the definition, you say that a predisposition is a disposition to acquire further dispositions and that diseases may be predispositions. These two statements seem to be a mixing of independent and dependent continuants.

Barry: You are right, we will fix that.

Lindsay: 3. It might be better to say that the predisposition confers on the organism the disposition to acquire further dispositions (or disorders), and that diseases may result in such predisposing disorders.

Barry: Yes.

Also, I would say that the definition still works even in the case where processes are absent, since such absence will be a problem only where a situation is thereby created wherein other (pathological) processes are present. Thus I added an extra example as follows:

Disease =def. – A disposition (i) to undergo pathological processes that (ii) exists in an organism because of one or more disorders in that organism (e.g. epilepsy as a disease that disposes to the occurrence of seizures (pathological process) due to an underlying abnormality in the neuronal circuitry of the brain (physical basis); AIDS is a disease that disposes to opportunistic infections that take advantage of a weakened immune system).

Is this satisfactory?

Lindsay: Maybe. I guess the question is whether in all cases, the inability for a normal process to unfold results in a pathological process, and even if yes, is the disease only realized through the pathological process? The example I was thinking of (and I will try to think of others) is SCID (severe combined immunodeficiency). There are different underlying disorders, but the one I am thinking of is mutations in the RAG1 or RAG2 genes. In this case, the process of V(D)J recombination cannot be realized, so B cells and T cells do not develop and the patients cannot mount adaptive immune responses. In this case, because the patients' immune responses are not normal, we can say that the disease is realized in a pathological immune response, so you are right, the definition still works. But what I was thinking at the time, and what I still have as a question, is maybe in this case the disease is realized through the fact that V(D)J recombination does not happen. (And the pathological immune response is the realization of a different disease, the infectious disease.)

There may be other diseases in which there is no ensuing pathological process (like the pathological immune response) and so are better examples of my concern. Or maybe there is no need for my concern because there is always some pathological response. I am not sure.

Barry Smith: My hypothesis is that, if there is no pathological process (including for example slowed growth), then we would not talk of disease.

A potential counterexample might be a case of congenital failure organ formation in the process of development. Are there cases such as this, properly classified as diseases, where the ONLY consequence is that a given organ does not form?

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From: "Smith, Barry" [23] Sent: 11/27/2008 Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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Barry Smith: Returning to Bjoern's issues with our tripartite definition of clinically abnormal (see below). I agree with Bjoern that it would be much nice if we could just use Part (1). Unfortunately, 'elevated level of risk' is a continuous function, and there are some very low levels of elevation (a tiny pin prick) which will not be judged to be clinically significant. Part (2) is introduced to do justice to the need to create a threshold between the insignificant and the significant levels of elevatedness.

I propose a modified version below, simplified in light of Bjoern's recommendation, that is designed to remove the appearance of subjectivity from our original statement, and to eliminate the interpretation according to which clinical abnormality might come into existence because clinicians adopt certain beliefs.

At 03:33 PM 11/5/2008, Bjoern Peters wrote:

Bjoern Peters: I agree with all of Werner's points, but I didn't think that is written in the paper. This is the section I am referring to. Clinically abnormal is classified as a primitive term, with the following informal elucidation which I split it into three parts:

(1) "We use 'clinically abnormal' to characterize those bodily features of or in an organism that are causally linked to an elevated risk of pain or other feelings of illness, to dysfunction, or to enhanced morbidity, and which (unlike pregnancy or menopause) are not such as to belong to the life plan for an organism of the relevant type."

(2) A clinician will judge a bodily feature to be clinically abnormal only where the elevated risk exceeds a certain threshold level of clinical significance. The determination of this threshold will reflect the training and experience of the clinician in question and thus may vary from clinical context to clinical context.

(3) It is worth noting that this treatment of 'normality' is distinct from those statistical treatments which do not take account of overlap of parameter values used to distinguish between normal and abnormal or of distribution extremes."

(1) is great, and all I would want to say, given how the term is used throughout the paper. (2) is minimally confusing. Being generous, I can accept that this is no longer talking about 'clinically abnormal', but about the judgment of a physician thereof which is a completely different entity. That does make the 'clinically' part of the label suspect though, and I don't think it helps to understand the term better. (3) So what is this? Does it refer to the treatment of 'normality' for (1) or (2)?

Barry Smith: We use 'clinically abnormal' to characterize those bodily features of or in an organism that i) are causally linked to an elevated risk of (pain or other feelings of illness or of death or of dysfunction), ii) are unlike pregnancy or menopause in being not such as to belong to the life plan for an organism of the relevant type, iii) are such that the elevated risk exceeds a certain threshold level.

This would replace (1) and (2).

OK?

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From: "Peters, Bjoern" [24] Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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Bjoern Peters: I like it.

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From: "Ceuster, Werner" [25] Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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Werner Ceusters: Seems OK. Still requires a note in the paper that 'clinically' is not related here to 'clinician'.

Barry Smith: I would like to move to a position where 'clinical' means 'pertaining to what goes on in the clinic' (so: 'clinical exam', 'clinical manifestation' ...). Can we find an alternative for 'clinical' in the term 'clinically abnormal'?

Werner Ceusters: Do you need an adjective? What other sorts of abnormality are there? I can think of normal variants (non-canonical, non-pathological ones).

Perhaps we need these dimensions:

1) in line with the life plan 2) associated with more risk 3) pathological (the risk is realized)

Combinations would then be:

+--: canonical ---: normal variant -+-: harmful variant -++: pathological

Examples of special combinations would be:

++-: pregnancy +++: menopause

Would there be:

+-+? --+? (psychopath) ?

Barry Smith: There might be:

mechanically abnormal, chemically abnormal, and musically abnormal.

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From: "Peters, Bjoern" [26] Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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Bjoern Peters: 'clinically abnormal' should encompass '-+-' and '-++' in Werner's scheme, right? I thought about labels for a while, and am not happy with the following, but thought it was worth sharing, if only to inspire to do better:

'health risk associated abnormality'

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From: "Scheuermann, Richard" [27] Subject: RE: Follow-up Information Regarding the Dallas Workshop on Clinical Phenotypes

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Richard Scheuermann: While I agree with the components of the elucidation, I find the wording rather awkward. Since this is an elucidation rather than a definition, couldn't we make it a little more intuitive for the average clinician scientist. How about something like this:

We use 'clinically abnormal' to characterize those bodily features of or in an organism that i) are causally linked to an elevated risk of pain or other feelings of illness, death or dysfunction), ii) are not part of the life plan for an organism of the relevant type (e.g. pregnancy or menopause), and iii) are such that the elevated risk exceeds a certain threshold level.

Also, Barry noted above:

"I would like to move to a position where 'clinical' means 'pertaining to what goes on in the clinic' (so: 'clinical exam', 'clinical manifestation' ...). Can we find an alternative for 'clinical' in the term 'clinically abnormal'?"

How about:

medically abnormal, abnormal condition, and pathologic?