- We have developed the Multiple Sclerosis Patient Data Ontology (MSPD) to represent data from the patient data registry of the New York State Multiple Sclerosis Consortium (NYSMSC). MSPD is an application ontology that provides a set of classes for the annotation of both clinical measures and patient reported outcome data obtained from the enrollment forms used by the NYSMSC. To do so, we have adopted the paradigm established for representing assays in the Ontology for Biomedical Investigations. Our goal is to compare patient reported outcomes, such as self-reported disability and quality of life perceptions, to objective outcome measures in clinical practice, with reference to diagnoses and treatment modalities. We have begun an ontology-driven retrospective analysis of the patient records in the NYSMSC registry using an ontology term enrichment method in order to spot significant patterns in patient-reported and clinical outcomes in subsets of patients in the NYSMSC patient registry as compared to the NYSMSC patient population as a whole.
We have developed the Multiple Sclerosis Patient Data Ontology (MSPD)* to represent data from the patient data registry for the New York State Multiple Sclerosis Consortium (NYSMSC). MSPD is an application ontology that provides a set of classes for the annotation of both clinical measures and patient reported outcome data obtained from the enrollment forms used by the NYSMSC. Our goal is to compare patient reported outcomes, such as self-reported disability and quality of life perceptions, to objective outcome measures in clinical practice, with reference to diagnoses and treatment modalities.
Multiple sclerosis (MS) is an autoimmune demyelinating
disease of the central nervous system (CNS) affecting over 2
million people worldwide [
A patient reported outcome (PRO) is generally considered
to be an assessment of any aspect of a patient's health status
that comes directly from the patient without interpretation by a
clinician [
MSPD extends the Ontology for Biomedical Investigations
(OBI), which is an integrated ontology for the description of
biological and clinical investigations [
MSPD is an OWL2 ontology built using Protégé 4 and is
being developed according to OBO Foundry principles [
De-identified patient data from the NYSMSC patient
registry were annotated with a reasoned version of MSPD.
Data was handled in a HIPAA-compliant fashion per our IRB
approval. Ontology terms were assigned to patients’ ratings of
their perceived disabilities and current affective state based
upon thresholds used to determine whether responses to
particular Lifeware questions merited annotation. For the
results presented herein, the thresholds were set to annotate
fairly stringently, in most cases at the second highest score (on
scales of 1-4, 1-5, or 1-7), such that only stronger statements of
disability or negative affective ratings resulted in annotation.
Following annotation, subsets of patients were compared
according to gender to the population of patients as a whole
with determination of p-values based on the hypergeometric
distribution in a way similar to that developed for term
enrichment analysis for the GO [
A variety of processes are parts of the NYSMSC enrollment process. One subprocess involves the clinician preforming a comprehensive neurological examination, elements of which can be seen as assays of the patient’s neurological functioning. Another part of the enrollment process includes the patient evaluating aspects of their own neurological and motor functioning, rating physical limitations, and perceived disease progression. Along with these measures, patients are asked to indicate overall life satisfaction and to what extent they are bothered by certain moods and feelings. These self-assessments qualify as PRO and correlate to standard quality of life metrics. To represent theses aspects of the enrollment process we utilized the paradigm established by OBI for representing assays.
An OBI ‘assay’ is defined as “a planned process with the
objective to produce information about the material entity that
is the evaluant, by physically examining it or its proxies” [
Two hierarchical distinctions emerged in generalizing the types of assays present in the enrollment process for the NYSMSC data registry. One relates to distinguishing between who does the evaluating, either clinician or patient. We created two upper level classes: ‘clinician reported assay’ and ‘patient reported assay’. A ‘patient reported assay’ is “an OBI assay wherein a patient produces information about themselves as the evaluant” and a ‘clinician reported assay’ is “an OBI assay wherein a clinician produces information about a patient as the evaluant”. We further distinguish assays by what the information they produce is about. Assays are distinguished by producing data about functional impairments, such as perceived limitation with a limb, and information about affective judgments, such as being bothered by depression or pessimistic thoughts, as well as assays that produce externally verifiable facts such as date of birth and marital status.
The second hierarchy involves parthood distinctions based on the structure and composition of the enrollment forms. The ‘NYSMSC enrollment form assay’ represents the overall encompassing process of completing all portions of the enrollment form. It has two subparts, ‘NYSMSC clinician reported enrollment assay and ‘NYSMSC patient reported enrollment assay’. These in turn have multiple subparts that correspond to the numbered questions on the form, such as ‘timed ambulation assay’ and ‘limitation assay’.
Fig. 1 illustrates some of this structure in the ontology. As a result of making these two general distinctions amongst assay types, MSPD contains an asserted subclass hierarchy of general types of assays defined by what is being assayed, which are connected through parthood relations to assays that represent the enrollment forms themselves. This way of building MSPD gives us a clear separation between types of assays based who’s producing the information and what that information is about, versus the assay’s place in the structure of the enrollment form, and subsequently, the enrollment process itself. Not only do we believe this to be more ontologically precise, but it allows for more robust reasoning capability.
The definition for OBI assay requires the specified output be about a material entity. In this case that entity is a patient. But, when considering how to relate the information each assay produces to what aspect of the patient is being assessed, we needed to specify more than existence of the patient. A patient bears certain qualities and functions, such as his or her visual or cerebellar function, which ultimately are the entities of interest in these assays. These functions are realized during the assay process (when successful) as the patient is being evaluated. It is these realizations (functionings) that can be observed, measured, quantified in some cases, and used in making judgments about impairment. Thus, to relate the datum that each assay produces to the aspect of a patient’s functioning being evaluated, we utilized the following guideline for creating instance-level relations in MSPD assay classes: ‘OBI assay’ has specified output some (‘OBI measurement datum’ and (is about some (‘NYSMSC enrollee’ and
is bearer of some ‘BFO function’))) ‘OBI assay’ realizes some (‘BFO function’
and inheres in some ‘NYSMSC enrollee’)
For example, the ‘vision limitation assay’ refers to the part of the enrollment process wherein an enrollee is asked to rate how limited their vision is on a scale of 1 (“no limitation”) to 7 (“severe”). We take the output of the assay to represent a judgment the enrollee makes about their visual functioning. We assert that every output datum from this assay is about the enrollee who is the bearer of an instance of a ‘visual function’.
Likewise, the clinical reported component of the visual score in the EDSS assay, the ‘EDSS visual function assay’ produces a datum about the enrollee and the enrollee’s visual functioning. But, it is important to connect the functions, which are borne by the enrollee, to instances of their realizations in that particular assay since the clinician is measuring these realizations. We import the GO classes for various neurological and sensory processes, thus enriching the ontological representation by connecting these assays to the apparatus that GO provides for annotation to genes and molecular functions. ‘MSPD EDSS visual function assay’ realizes some (‘MSPD visual function’ and inheres in some
‘NYSMSC enrollee’) Fig. 1 illustrates some of the relations in MSPD.
A final structural component of the ontology relates to data
analysis tasks. To give our clinical collaborators the ability to
select and annotate subsets of patients based on varying and
unique criteria, we developed slasses that extended ‘OBI
conclusion based on data’, defined as “an information content
entity that is inferred from data” [
(‘OBI data item’ and is specified output of some ‘MSPD right lower limb limitations assay’)
An advantage of this design is that different instances of these conclusions can be created using the same datum. An assay that evaluates a patient’s limb functioning produces data that can be used to support various conclusions about limitation with that particular limb. The assay itself and the datum it produces are neutral with respect to whether limitation actually exists. But, a clinician or researcher can interpret the result and then decide if it supports such a conclusion.
We performed an analysis of 9331 patient records from the
NYSMSC data registry, selecting subsets of patients based on
gender, 6916 female and 2389 male. All data points for
patients in each subgroup were annotated with the ‘conclusion
based on data’ subclasses corresponding to the assays for both
PRO and certain clinical measures, such as EDSS scores. We
determined which data were annotated by setting a unique
threshold for each particular assay output. To eliminate patient
records where minimal or no disability was present, we set the
threshold high. Term enrichment was performed on each
annotated subset using the hypergeometric distribution method
established for the GO and used successfully for term
enrichment studies based on disease ontologies [
As Table 1 shows, terms related to patient reported limitations in limbs were associated with highly significant pvalues for over- or under-enrichment in the results for the two cohorts. Interestingly ontology terms annotated to the male cohort were significantly over-enriched while those for the female cohort were significantly under-enriched in all terms in the ontology that related to perceived limitations in limbs. This finding suggests that the male MS population experience or report limitations in limbs at a higher rate than female MS patients do, or alternately, that female patients under report such limitations. label limitation with limb conclusion limited lower limb function conclusion limitation in right limb conclusion limitation in right lower limb conclusion limited left limb function conclusion limited left lower limb function conclusion limitation in upper limb conclusion limited left upper limb function conclusion impaired pyramidal tract functioning conclusion
label limitation with limb conclusion limited lower limb function conclusion limitation in right limb conclusion limitation in right lower limb conclusion limited left limb function conclusion limited left lower limb function conclusion limitation in upper limb conclusion limited left upper limb function conclusion impaired pyramidal tract functioning conclusion
Also of interest, the conclusion based on data from the clinician reported component that most closely relates to limb functioning, the pyramidal tract functional score of the EDSS assay, showed only relatively minimal significance between each gender-based subgroup and the general population. This suggests that while male patients reported more limitation in limb functioning than female ones, the objective clinical measure of disability in MS patients did not correspond to these reports as strongly. That is to say, terms were only minimally enriched for the clinician reported measures, whereas they were highly enriched for the patient reported measures that related to limb functioning.
Thus far we have developed an ontology for representing aspects of the enrollment process in the NYSMSC patient data registry. Specifically, we have classes for representing assay processes and the data they produce. These assays are evaluations of both patient reported and clinical measures of quality of life, disease status, neurological impairment, and functional limitations. Classes were also developed to represent different types of conclusions that could be made using the available data so that thresholds could be individually established and easily changed for analysis purposes. The data produced from the assays are used to support conclusions indicating patient-perceived or clinician-measured impairment.
We used the ontology to perform a term enrichment analysis of subsets of patient records obtained from the data registry. We discovered that ontology terms annotated to male patients in the NYSMSC registry are highly over represented for terms related to limitation in limbs versus terms annotated to female patients, even though the corresponding clinical measures were only marginally over-represented.
The preliminary results presented herein are fairly striking, and we will work with our clinical collaborators to develop interesting questions to answer via annotation of the NYSMSC patient data and application of the term enrichment methodology. We recognize that there are a myriad of ways to select and group subsets of patient records. We are particularly interested in comparing patient cohorts treated with particular drugs versus cohorts treated in other ways. Through this work we hope to gain insight into the efficacy of particular treatment regimens as measured via both patient reported and clinical outcomes.
This work was supported by a National Multiple Society Pilot Project Grant, PP1970, and by the State University of New York at Buffalo.