The protocol summary should outline the research plan according to
factors the IRB and the ORA consider essential for review. The protocol
summary should be prepared according to the following outline. If your
research involves social and behavioral research, use the
Social/Behavioral Science (SBS) protocol summary.

Please note "N/A" or "not applicable" under any section that does not
apply to the proposed research -- **[do not leave any section
blank]{.underline}**.

**INTRODUCTION & OBJECTIVES**

1.  **[Background]{.underline}:**

The idiopathic inflammatory myopathies ((IIM)s are a heterogeneous group
of disorders characterized by limb girdle muscle weakness and
inflammation with or without cutaneous inflammatory disease. IIM include
polymyositis (PM), inclusion body myositis (IBM), dermatomyositis (DM)
and juvenile DM, each of which is considered a distinct
clinicopathologic entity.

Scientific advances in immunology and molecular biology over recent
years have led to increased knowledge of disease mechanisms and to the
development of new and more specific biologic therapies for patients
with chronic inflammatory diseases. In patients with chronic idiopathic
inflammatory myopathies, or myositis, there is a clear need for improved
treatment due to the persisting impaired muscle function in most
patients treated with the current regimens of high-dose corticosteroids
and immunosuppressive drugs such as methotrexate or azathioprine.
Currently recommended treatment is mainly based on uncontrolled studies
and case reports; few controlled trials have been conducted in patients
with myositis. A significant barrier to the conduct of studies has been
the lack of standardized validated outcome measures but that has been
developed during the last years through a collaborative myositis network
called the International Myositis Assessment and Clinical Studies Group
( IMACS).

*Need and Relevance - Limitations of myositis classification criteria.*

A significant and fundamental problem in clinical studies is the
classification criteria for inflammatory myopathies. Three different
criteria have been proposed (Bohan & Peter 1975, Tanimoto 1995,
Hoogendijk 2004) but the criteria of Bohan and Peter are the most often
used in clinical studies. Several limitations of these criteria are
recognized. Some criterion are not specified or operationally defined,
for example, the biopsy criterion is considered too inclusive and may
allow patients with some forms of muscle dystrophy to be included in a
group of inflammatory myopathies. These criteria also misclassify
patients with IBM, which was not known when these criteria were
proposed, as having PM.

Since the 1980s, a variety of discoveries could impact the subsetting of
myositis. The biology of muscle in PM/DM has advanced with careful
immunohistochemical characterization (Engel & Arahata 1986) (Dalakas
1991). Magnetic resonance imaging (MRI) can now visualize muscle
inflammation and myositis-specific autoantibodies could be helpful for
diagnostic purposes but are not included in the Bohan and Peter criteria
(Love et al 1991).

Other criteria for inflammatory myopathies have been put forward. Engel
and Arahata proposed immuno-histopathology based criteria (Engel &
Arahata 1986). The Tanimoto criteria added arthritis, systemic
inflammatory signs, muscle pain and tenderness to the Bohan and Peter
criteria, to also distinguish myositis patients from other myopathies
and neuropathies (Tanimoto et al 1995). The American Academy of
Dermatology has published recommendations for diagnostic evaluation of
the skin manifestations in DM (Drake et al 1996). For IBM,
classification criteria have been developed and because this phenotype
is unresponsive to immunosuppressive treatment, patients with IBM should
be regarded as a separate entity in clinical trials (Griggs et al 1995).
The Bohan and Peter criteria have also been used for children with
myositis. A group of paediatric rheumatologists has started to revise
the criteria for this group (NETWORK FOR JUVENILE DERMATOMYOSITIS).

At the European Neuromuscular Centre (ENMC) workshop on trial design in
adult idiopathic inflammatory myopathies in 2003 (Hoogendijk et al 2004)
more extensive muscle biopsy findings were added to the criteria and two
new subsets of inflammatory myopathies were proposed:

a\) Non-specific myositis (in patients with non-specific
perimysial/perivascular infiltrates, but without biopsy features
diagnostic of PM or DM), and

b\) Immune-mediated necrotizing myopathy (characterized by absence of
inflammatory infiltrate) (Hoogendijk et al 2004).

The ENMC participants recommended revision of the current criteria to
exclude other diseases, to include information relevant to understanding
underlying pathogenesis and to facilitate the comparison of studies.

In summary, there is a consensus to revise the classification criteria
for IIMs. Furthermore, most workers in the field believe that this
should be a collaborative effort of specialists in neurology,
rheumatology, paediatric, dermatology, pathology and epidemiology and
that it should be international to insure greatest acceptance.

2.  **Study objectives:**

To develop and validate classification criteria for idiopathic
inflammatory myopathies (IIM) and major subgroups of the IIM in adults
and children for basic and clinical research, especially clinical
trials, and to document the reliability of these new criteria. To test
the reliability of these new criteria.

This will be accomplished through a multi-center, international,
multi-disciplinary study known as the International Myositis
Classification Criteria Project (IMCCP). Each participating center in
the IMCCP is asked to perform a retrospective chart review of patients
at their center with the IIM and with mimicking conditions. Each center
is being asked to contribute 10 -15 IIM patients and 10 - 15 patients
with mimicking conditions (in which myositis was a consideration in the
diagnosis of the patient or the patient has a condition that might be
considered in the differential diagnosis of myositis). Following a first
round of data collection, an additional 10 - 15 IIM patients and 10 --
15 with mimicking conditions may be requested from each participating
center. If enrollment goals are not achieved, participating sites will
be re-contacted to see if they can enroll additional patients (with a
maximum of 60 per site). The total number includes 1000 myositis
patients (4 major subgroups of PM, DM, IBM and Juvenile DM, and then
other miscellaneous subgroups) and 1000 comparator patients (700 adults
and 300 pediatric) without myositis

3.  **Location: (if applicable)**

This is a multi-center retrospective chart review. Study patients will
be identified from the clinical practices of the Departments of
Dermatology, Rheumatology or Neurology at the Hospital of the xxxxxxxx

**STUDY DESIGN**

4.  **Research design & methodology**:

The design of this study is a retrospective chart review of IIM patients
identified by CPT codes. There are no experimental therapies used in
this protocol as it is strictly observational. In addition, no patients
are excluded from the study because of particular medications they are
taking. No additional laboratory work will be performed. Patients with
greater than 30% missing variables on chart review may be contacted for
additional information. Verbal informed consent and HIPAA consent will
be obtained. Subjects with charts that contain greater than or equal to
70% completeness will not be contacted and HIPAA authorization will be
waived. Subjects with additional records at other physicians who agree
to participate in our study will be mailed a medical records release
form to be filled out and signed permitting the Department of xxxxxxxx
to obtain more extensive medical records.

5.  **Duration**

The subjects will be identified by CPT codes and the review is expected
to be completed in 6-12 months from initiation. However there may be
further prospective sampling based upon the results obtained.

Once a list is generated from CPT codes, a systematic review of charts
from the Departments of xxxxx will commence. Data requested by the IMCCP
that is not contained within the charts will be obtained through patient
contact via telephone or by medical records from another physician.

**SUBJECT SELECTION & WITHDRAWAL**

6.  **Inclusion & exclusion criteria**

Inclusion: i. The subject has been diagnosed for at least 6 months

ii\. The physician is certain of the diagnosis -- only cases with known
idiopathic inflammatory myopathy or, as comparators, known non-IIM cases
(but in which myositis was considered in the initial differential
diagnosis) are chosen

iii\. The patients in whom most complete data are available

iv\. The most recent cases are chosen first -- these would likely result
in more consistent evaluations and therapy.

Patients with IIM may include adult or juvenile-onset DM, or PM, IBM,
and immune-mediated necrotizing myopathy. DM patients may include
amyopathic and hypomyopathic DM. Patients without myositis, but with a
mimicking condition may include, but not be limited, to the following
conditions:

□ Non-inflammatory inclusion body myopathy

□ Dystrophy, specify diagnosis

□ Metabolic myopathy

□ Mitochondrial myopathy

□ Drug or toxin associated myopathy

□ Infectious myopathy

□ Endocrine myopathy

□ Motor neuron diseases

□ Other neuromuscular disease

□ Other rheumatic disease

□ Other dermatologic disease

Exclusion: Patients without myositis, in which myositis was not
considered in the differential diagnosis. Patients with uncertain
diagnoses. Patients with a large degree of missing information resulting
in a very incomplete data collection form for the study.

7.  **Vulnerable populations**

    Since there is no intervention taking place in this study,
    vulnerable populations with a diagnosis of IIM are not excluded from
    this study unless further information is required that the patient
    is not able to render or consent is required for medical record
    release and the patient is not capable of consenting. Pediatric
    patients are included, but the risk of participation is minimal.

8.  **Subject accrual**

To obtain the needed data from 2000 subjects for this study, each center
will initially be asked to contribute 10 -- 15 subjects with myositis
and an equal number of comparator subjects. Preliminary statistical
analyses will be conducted after the completion of the first phase of
this study and if needed each contributing physician will be asked to
contribute up to 10 15 additional subjects with myositis and an equal
number of additional comparator subjects. If enrollment goals are not
achieved, participating sites may be re-contacted to see if they can
enroll additional patients (with a maximum of 60 per site).

We expect a maximum of 60 charts to be reviewed in each center. Since
there may be as many as 2000 subjects, obtaining a HIPAA authorization
waiver for subjects with greater than 70% chart completion is imperative
to decrease extraneous phone calls.

9.  **Subject recruitment & screening**

Subjects will be identified by CPT code diagnoses in the clinics of the
Departments of Dermatology, Rheumatology, Neurology or Pediatrics.
Charts will be reviewed for information contained in the IMCCP data
collection form. Missing variables will be obtained through patient
contact via telephone. Subjects with missing variables will also be
approached for permission to obtain medical records from other health
care providers.

No referrals from physician offices, clinics, programs, advertisements
or brochures will be involved and there will be no handouts, brochures,
flyers and advertisements.

All physicians and health care professionals in the Departments of
Dermatology, Rheumatology, Neurology and Pediatrics will be notified of
this study and will have the opportunity to affect the manner in which
their patients are invited to participate. If a physician does not want
a particular patient contacted, we will exclude that subject from the
study. Direct recruitment by a researcher who has not taken care of the
patient may occur by telephone when additional information is required
for the data collection form.

## Additional subjects will only be recruited if they are seen in clinic during the study period and their charts are referred for inclusion into this study. Otherwise, all subjects will be identified by CPT codes before study initiation. 

10. **Data and/or specimens**

    a.  [Data]{.underline}: The data collection form is attached to this
        protocol. Demographic, clinical muscle variables, skin
        variables, family history, onset of symptoms, other clinical
        variables, muscle biopsy results, laboratory results, EMG, EKG,
        and MRI results are among the data that will be collected. HIPAA
        identifiers (Name, MRN, age, elements of date) will only be used
        to cross-reference patients between the Departments of
        Dermatology, Rheumatology or Neurology so that patients are not
        included twice in this study. Name and phone numbers will be
        used to contact patients for additional information. Data will
        be collected on the data collection form, then entered into a
        website base proforma, Survey Monkey, to establish a preliminary
        database for the study. Linkage to identifying information at
        each individual study site will be destroyed after the
        coordinating center obtains a download of the database from
        Survey Monkey and performs checks for out of range or missing
        values. The identifying information will be destroyed upon
        resolution of queries from the coordinating center and upon
        completion of the study data, so that the same patient is not
        contributed twice during the study.

    b.  [Specimens]{.underline}: No additional specimens will be
        collected.

    c.  [Genetic testing]{.underline}: There will be no genetic testing.

**INVESTIGATIONAL AGENT**

11. **Drugs/devices: (if applicable)**

No drugs or devices are being tested in this study.

**STUDY PROCEDURES**

12. **Procedures:**

No procedures or interventions will take place in this study.

**STATISTICAL PLAN**

## 

## Sample size determination: 

We will request 200 patients per subgroup for a total of 1000 myositis
patients (4 major subgroups of PM, DM, IBM and Juvenile DM, and then
other miscellaneous subgroups) and then 1000 comparator patients (700
adults and 300 pediatric) without myositis. We assume that certain of
these will patients or comparators will not be evaluable for certain
classification criteria (for example, ones that involve biopsies,
autoantibody testing, and certain imaging data) due to missing data.
Based upon the expected enrollment of 150 evaluable patients in each of
the 4 major subgroups of myositis (PM, DM, JDM and IBM), and the
expected enrollment of 500 evaluable comparators (300 adults and 200
pediatric), the following power calculations support this level of
enrollment:

> Null Hypothesis: P1=P2 Alternative Hypothesis: P1\<\>P2. Continuity
> Correction Used.
>
> **Allocation Odds**
>
> **Power N1 N2 Ratio P1 P2 Ratio Alpha Beta**
>
> 0.98279 600 500 0.833 0.75000 0.85000 1.889 0.05000 0.01721
>
> 0.97234 150 300 2.000 0.75000 0.90000 3.000 0.05000 0.02766
>
> 0.94547 150 200 1.333 0.75000 0.90000 3.000 0.05000 0.05453
>
> Where N1 is a number of the total group or subgroup of myositis
> patients and N2 is the sample size of the total or subgroup of
> comparator patients and P1 and P2 are either sensitivity or
> specificity for the myositis groups vs. the comparators. The Odds
> Ratio is P2/(1-P2)/(P1/(1-P1)). The beta is the type 2 error and is
> 1-power. 

13. **Statistical methods**:

Since this is a multicenter initiative, the raw data will be compiled by
the steering committee and analyzed as aggregate data without any
patient identifiers. The sensitivity and specificity of the proposed
individual variables and combinations of variables to form new criteria
will be tested in 150 patients in a given subgroup of myositis and 500
comparator patients.

CART or Random Forests will be used to develop multiple rules and
determine which variables are regularly selected. Another approach will
be to randomly select a subset of cases and comparators (e.g. 50%),
develop criteria sets on the subset and apply them to the remainder and
to repeat this 5 to 10 times to confirm the most sensitive and specific
criteria. These will be selected at random and is the derivation set of
subjects. The ability of the criteria to distinguish between
inflammatory myopathies from comparator groups will be tested (construct
validity and convergent and divergent validity). The variables will also
be tested in subsets of inflammatory myopathies to assess their ability
to distinguish between subsets within the inflammatory myopathies. The
new study criteria will be assessed in comparison with the Bohan and
Peter criteria for myositis, which are the most often used criteria and
will thus be the "gold standard" against which the new criteria will be
compared for sensitivity and specificity and positive and negative
predictive value. New criteria will also be tested against other
published criteria of Tanimoto 1995 and Hoogendijk 2004. The ability of
the new criteria to distinguish between inflammatory myopathies from
comparator groups will be tested. The database will be managed by Dr.
Ingrid Lundberg and her associates at the Karolinska Institutet in
Stockholm, Sweden. The statistical analysis will be performed by Dr.
Peter Lachenbruch, Oregon State University, Corvallis, OR 97330.

.

**SAFETY & ADVERSE EVENTS**

14. **Potential risks:**

There is very low risk associated with this study. Patients may be at
psychological risk regarding breach of confidentiality (of PHI). It is
very unlikely that a breach of confidentiality will occur, but this is
always possible. Subjects are also at risk of misunderstanding the
purpose of the study and expecting a positive diagnostic or health
benefit from participation.

The alternative for this study is not to participate. There is no real
risk in this except perhaps guilt of knowing they are not contributing
to the advancement of scientific knowledge.

15. **Potential benefits:**

This study offers the possibility of developing standardized, validated
criteria for diagnosis and classification of patients with all forms of
myositis. It is the hope that criteria will emerge for various myositis
subsets that will enable a standardized approach across disciplines and
throughout the world for all research studies and therapeutic trials.

16. **Protection of subjects:**

> Subject with greater than 70% data collection variables complete will
> be waived of HIPAA authorization as no direct identifiers will be used
> after initial cross-referencing between the departments of
> Dermatology, Rheumatology and Neurology. Subjects with less than 70%
> data collection variables complete will be protected by obtaining
> verbal informed and HIPAA consent via telephone and by consenting to
> release of medical records through written documentation when
> necessary.

17. **Confidentiality & specimen/data storage**:

    a.  Data will be stored on password protected computers and on data
        collection sheets that will remain at the laboratory of Dr
        xxxxxxxx

    b.  After data collection is complete, personal identifiers will be
        removed before submission to the IMCCP.

    c.  Data will be submitted to the IMCCP using Survey Monkey
        (http://www.surveymonkey.com/).

    d.  Separate databases will be used for information containing
        protected health information with links to known identifiers
        kept in a separate, secure password-protected location. Linking
        data sets will be destroyed at the end of the study and no
        secondary use of the data will be attempted after study end
        without subsequent IRB approval.

18. **Data safety & monitoring: (if applicable)**

    a.  Stopping rules, unblinding, or subject withdrawal criteria do
        not apply.

19. **Risk/benefit ratio:**

    a.  There is minimal risk of harm anticipated in the proposed
        research as only a fraction of the study population will be
        contacted regarding this study. Further, no physical or
        psychological examinations or tests are needed. Thus, the
        benefit of this study to the individual subjects and society far
        exceed the potential risks.

**ETHICAL CONSIDERATIONS**

20. **Informed consent procedures:**

    a.  Patients with less than 70% of data collection variables
        contained within their chart will be contacted by telephone and
        informed consent and HIPAA authorization will be obtained
        verbally by xxxxxxxxx sub-investigator.

    b.  Written consent will be given by patients that consent to the
        study and require additional medical records released. If adult
        subjects are not competent to consent on their own behalf, their
        health care proxy will be contacted for consent or the subject
        will be excluded from the study. Competency will be assessed by
        prior medical records.

21. **Request for waived informed consent:**

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(1) Since this is a retrospective data collection without any
    intervention taking place, the research involves no more than
    minimal risk to the subjects. Since the most intrusive aspect of
    this study is either a telephone survey or a request for medical
    record release, a waiver of written informed consent seems
    reasonable given the sample size. Further, verbal informed consent
    and HIPAA authorization will be obtained for contacted subjects.

(2) The waiver or alteration will not adversely affect the rights *and*
    welfare of the subjects as those that are contacted will receive
    verbal consent. Since there is little data linking the subject and
    the research in this study, a written consent document may bear more
    risk and potential harm resulting from a breach of confidentiality
    than a verbal consent for contacted patients and a HIPAA waiver for
    patients with greater than 70% complete data collection variables on
    chart review.

(3) Given the potential sample size of this retrospective data analysis,
    practically, it would be difficult for the research to be carried
    out without the waiver for subjects with complete (\>70%) records.

(4) Whenever appropriate, the subjects will be provided with additional
    pertinent information after participation.

**STUDY FINANCES**

22. **Compensation to subjects for participation:**

    a.  There will be no compensation of cash payments, free
        hospitalization, medication, clinical testing, etc. given to
        patients in this study.

23. **Conflict of interest**

    a.  **No conflict of interest** exists for the principal
        investigator or any member of the study staff.

**PUBLICATION PLAN**

24. **Publication plan:**

There is intent to publish and present this research.