The Clinical Pathologist's Role In Genomics: Data Managent ...

The Clinical Pathologist’s Role in Genomics: Data Management, Quality Assurance,

and Consultation

presented by Daniel Schwartz, MD, FCAP

SS114 Bringing Context and Consistency

to the Genomic Revolution September 22, 2004

3:30 – 5:00 PM

College of American Pathologists 2004. Materials are used with the permission of the faculty. SS114 Bringing Context and Consistency to the Genomic Revolution

CAP ’04 – The Pathologists’ Meeting™ September 19 - 22, 2004

Phoenix, AZ

Disclosure Statements

All speakers must disclose to the program audience any financial interest or relationship with the manufacturer(s) of any commercial product(s) that may be discussed in the educational presentation or with the manufacturer of a product that is directly competitive with a product discussed in the presentation. In addition, all speakers must disclose whether non-FDA approved uses of pharmaceutical products or medical devices are included in the presentation The College of American Pathologists does not view the existence of these interests or uses as implying bias or decreasing the value to participants. The CAP, along with the Accreditation Council for Continuing Medical Education (ACCME), feels that this disclosure is important for the participants to form their own judgment about each presentation. The following speakers have financial interests/relationships or non-FDA approved uses to disclose:

Daniel Schwartz, MD, FCAP – Gene Logic, Inc.

The following speakers have no financial interests/relationships or non-FDA approved uses to disclose:

The following speakers have not provided information on financial interests/relationships or non-FDA approved uses:

Learning Objectives

Upon completion of this course, participants should be able to:

• Describe the information that is generated by gene arrays • Discuss the limitations and opportunities of gene arrays in terms of mechanisms

of disease and describe some of the bioinformatics tools, their use and limitations, including contributions and applications of a standardized pathology terminology (SNOMED CT to data collection and interpretation and pathology archives as valuable genomic and proteomic resources

The Clinical Pathologist’s Role in Genomics:Data Management, Quality Assurance, and ConsultationDaniel Schwartz, MD, FCAP

September 22, 2004

College of American Pathologists 2004. Materials are used with the permission of the faculty. SS114 Bringing Context and Consistency to the Genomic Revolution 1

Copyright 2004 Gene Logic Inc. Page 1

The Clinical Pathologist’s Role in Genomics:Data Management, Quality Assurance, and

Consultation

Dan Schwartz, MD, MSIS, FCAPGene Logic Inc.

Gaithersburg, MD

September 22, 2004


The clinician’s view of genomics

Genomics: “The large-scale investigation of the structure and function of genes.” * Note the emphasis on large-scale.Most common concern: Expression data on 30,000+ genes.Less commonly noticed: Large quantity of clinico-pathologic data on tissues expressing those genes.How can that data be:• Managed?• Verified?• Conveyed meaningfully to non-clinicians?

*Drug Discovery and Development Magazine


September 22, 2004



Perceptions: Why these issues are overlooked…

Diagnosis: Necessary, familiar, personally rewarding, intellectually stimulating.Molecular biology: Fascinating, new, challenging, sexy.Data management: Boring, doesn’t require professional expertise, very unsexy.Quality assurance: Reviewing other people’s work is less stimulating than primary diagnosis.• Medicolegal issues are also raised

Consultation: Why me? This isn’t my area of expertise or interest.

Copyright 2004 Gene Logic Inc.

…and why they shouldn’t be:

Genomic data are meaningless without the appropriate clinicopathologic context of samples from which they were derived.• Clinicians can and should be part of any human genomic research

or application.Data management issues are incredibly challenging once you dig into them.It is a pleasure and a privilege to learn from, and to teach, experts in other fields:• Molecular biologists• Software engineers and database analysts (among others)• Bioinformaticians• Many others

Your research colleagues will be infinitely grateful for your input (though they may not know it yet).


September 22, 2004


Copyright 2004 Gene Logic Inc.

Clinical data management in genomics

Which data points should be captured?What is the meaning of a data point in anatomic pathology?How should this data be:• Conceptualized?• Extracted? (And from where?)• Stored?

Why is it important to maintain a consistent system?How can consistency be achieved?


Pathology data

Define a set of clinical features, anatomic descriptors, laboratory values, observations, examinations, etc. to be stored in association with each sample.The set may (probably will) vary with the type of sample.Define mandatory vs. optional data.Define which units data are to be reported in.• Especially important when working with multiple accrual sites

Data types are not limited to the traditionally “pathologic.”W/R/T genomics, pathologists are medical experts, not just pathology experts.


September 22, 2004



An example of a minimal data set

Sample: Adenocarcinoma of colonData:• Anatomic site (optional: which part of colon?)• Pathomorphology (adenocarcinoma – subclassify?)• Pathologic stage (which system?)• Grade (can this be standardized?)• Other diseases (present; past?)• Medications (present; past?)• CEA (serum; tissue by immunohistochemistry?)• History of prior chemo/radiotherapy (or, not accept sample?)• Family history (what are the relevant diseases?)• CT scan, barium enema, other radiologic info (how to

capture? pre-op, post-op, on primary, for mets?)• Outcome data (response to chemotherapy? survival? other?)• Text-based descriptions have great secondary value


Context vs. sample

Patient (“donor”) has adenocarcinoma of colon.Sample is from the uninvolved area of the colon (i.e. morphologically normal).How do you capture this information?• Or, do you consider it important?

An added complication: Cancer arose in a setting of longstanding ulcerative colitis.• How can you capture that as well?• How do you convey to your colleagues that this is

important information to consider?


September 22, 2004



Anatomic Pathology data storage: CodingOrderly data storage = effective data retrieval.Implies the need for a standardized system for:• Extracting pathology information, and… • Coding it as data.

This system must include:• A way to “tease out” the relevant information from:

− What is known about a sample− What is known about the context in which it was obtained

• A way to encode this info so it can be found easily• A way to ensure that the same coding schema is uniformly employed by

all codersMethod for extracting information will vary among institutions: prospective vs. retrospective, batch vs. one-off, report review vs. real-time, pathologist vs. non-pathologist.Which coding system to use is a matter of style and comprehensiveness.• A controlled vocabulary is essential.


Why use a controlled vocabulary?

Standardizes terminology:• Allows effective storage of data in tables

• Allows effective searching for data in database

• The alternative is free-text

Limits the way a concept can be expressed• A good thing: Similar concepts are coded the same way

(usually)

• A bad thing: Medical concepts don’t always fit into neat pigeonholes

Limits the size, complexity, and operational overhead of the database itself• Quicker database response times


September 22, 2004



Coding system: SNOMED-CT

Among coding systems, SNOMED-CT is a very good choice. But it is not the only choice.• Homegrown systems can work in some situations.

Consider the use of only a small subset of SNOMED concepts (“microvocabulary”).• Represent only concepts in use: diminished complexity.• Included concepts will depend on level of granularity needed.

Often many ways to represent the same concept in SNOMED.• Sometimes subtle differences from one to the next.• Usually, one concept will have many synonymous descriptions.

− You may need to choose the description that will be used –and then communicate it to end-users.


Microvocabulary examples and issuesCID 36195005 has synonymous descriptors:• Hyperplastic nodule• Nodular hyperplasia• Nodular regenerative hyperplasia

Which description should be used, so that end-users can search for it?The morphologic descriptor “nodular hyperplasia” is used in thyroid, prostate, and other organs.• Associate the same [concept + description] for different

diseases with a variant of the same general morphology?• Or, should different concepts be used for different

diseases, even though their morphologies are similar?• Fundamentally: Are you coding a disease, a morphology,

or do you need both to adequately convey meaning?


September 22, 2004



Philosophical issuesIs a tonsil normal or diseased?Is morphologically normal colon from a patient with ulcerative colitis normal or diseased?What about familial adenomatous polyposis coli?Is morphologically normal tissue adjacent to a tumor really “normal?”Is frontal lobe tissue from a schizophrenic patient "normal"?Are low malignant potential tumors best classified as malignant or benign (if you classify tumors at all)?Is the duodenum anatomically distinct enough from the jejunum/ileum to be coded separately?Is leiomyoma a tumor of myometrium or of uterus?How many different flavors of carcinoma should have distinct codes for one organ?In general: How “granular” should coding be?


Creating and maintaining a system

There is an art to this.Creating a system like this can be slow and painful – but the long-term payoff is great. A simple spreadsheet can be an excellent tool for ensuring coding consistency.


September 22, 2004



Coding spreadsheet: Unfiltered


Coding spreadsheet: Partial filtering


September 22, 2004



Coding spreadsheet: Complete filtering


Microvocabulary maintenance

There must be administrative oversight of the lexicon - an individual, a committee, etc. - to ensure standardization.There must be a method for updating the lexicon and promulgating updates to users.There must be a method to ensure user access to the lexicon and tools to implement it.There must be an error-checking mechanism, and someone authorized to use it to find and fix errors.


September 22, 2004



Microvocabulary maintenance

There is no BEST answer, just many GOOD answers; agree on one and stick with it.• If you wish to merge your data with that of another

organization or researcher, you must:− Agree on standards in advance.− Have a way of coordinating lexicon updates.

Add concepts and/or change descriptions carefully.• Are you sure that construct (context + sample

properties) has never been coded in your DB before?

Remove terms with GREAT care if ever at all: can break referential integrity of database!


Pathology Quality Assurance

How do you know that the tissue submitted for analysis is what it purports to be?Answer: Don’t take anyone’s word for it; check for yourself.• Majority of errors are clerical and easily fixed.• Samples should be handled with same respect as

clinical specimens.• You will save your colleagues much head-scratching.

Review of a slide is essential:• Tissue directly adjacent to analyte.• Pre-analytic frozen section of actual analyte.


September 22, 2004



The QC process

Accessioning checks• State of tissue• Correlation of data (donor ID, tissue blocks,

inventory, pathology reports)• Quantity of tissue

Pathology report review and data entry• Coding (SNOMED-CT or other)• Categorization• Text annotation• Other, as needed by your institution


Sample QC Process: Accessioning Checks

Site Patient ID• Unique identifier

assigned by collection site (if applicable)

Sample Matches• Identify any samples

from same patient• Tumor-normal matches

Donor Demographics- Age - Gender- Race / ethnicity

Required Data• Date of collection• Time from surgical excision

to freezing• Organ / anatomic tissue site• Tissue category• Tissue / pathologic diagnosis • Patient primary and

secondary diseases• Tissue preparation method

(Frozen, OCT, Paraffin, RNA, etc.)

• Weight of sample

Review Sample Information for:


September 22, 2004



Sample QC: Slide review

Review representative slide(s)• Correlate with report• Further text-based annotation • Image capture and storage has tangible benefit

Criteria for rejection: The 100% standard• If the pathologist is not 100% certain that the

tissue to be analyzed is correctly identified and of adequate quality, it is rejected.

• Never “unreject” a sample.• Be an independent arbiter.


When is a sample acceptable?

Pathology report available and interpretable.All identifications are in line.Pathology report matches slide review.Slide shows tissue of interest is adequate in quantity and quality.If any ambiguities, hold sample until resolved.


September 22, 2004



Post-QC retrospective review

Feedback to collection sites (if applicable)• Clarification of ambiguities• Review of rejections• Refinement of sample acquisition protocols

Post-publication checks: Lookbacks• Genomics/bioinformatics• User requests• New samples from previous patients• New clinical data available• Previous samples when new, similar samples are encountered

Periodic, broad-based review of dataQuality Assurance Committee


Quality Assurance Committee

Meet regularly.

Request participation of senior investigators across disciplines.

Review questions from any source, regarding quality of samples and/or clinical data.

Be empowered to take corrective actions.• Remove samples

• Recode samples

• Institute process improvements


September 22, 2004



Consultation

The “gray zones” of pathology (and medicine in general) may be difficult territory for non-physicians.• Even SNOMED-CT can’t neatly bin every medical

situation.• Textual annotation is very helpful – if anyone reads

it. And even then it may not be understood.• It’s up to the pathologist to make the case for

understanding the subtleties of clinicopathologic information……

• ….and then to follow up by providing appropriate explanation and support.


Active vs. passive consultation

One mode is to wait for questions to arrive.• Ever heard of the Maytag® repair man?

The clinical pathologist should actively engage researchers to anticipate problems before they arise.Pre-formed “sample sets” are one answer.…but in the long run, giving people fish is less effective than teaching them how to fish (in the gene pool…?)


September 22, 2004



Other forms of outreach

Correlate microarray data with immunohistochemical data (as a service).Teach “Pathology 101” to individuals with no formal pathology background.Know more about genomics than your colleagues know about pathology. Understand their concerns and issues.For this purpose, don’t draw sharp boundaries between medical specialties. You are the medical expert.


Summary

The clinical pathologist has a vital and necessary role to play in genomics.This role will evolve from ad hoc to formalized to (potentially) reimbursable.The role of the pathologist is not as boring as it might at first appear…• …and there is ample opportunity for learning on

the fly.

The pathologist will be well-served to understand basic issues of genomics and database design/management.


September 22, 2004



Thank you!

Questions and comments?

The Clinical Pathologist's Role In Genomics: Data Managent ...

Documents

Transcript of The Clinical Pathologist's Role In Genomics: Data Managent ...