**TEDDY QUALITY CONTROL**

**TABLE OF CONTENTS**

[I. INTRODUCTION 3](#introduction)

[II. OVERVIEW OF QUALITY CONTROL 4](#overview-of-quality-control)

[**A. Clinical Center Responsibilities
4**](#clinical-center-responsibilities)

[**B. Data Coordinating Center Responsibilities
4**](#data-coordinating-center-responsibilities)

[**C. Quality Control/ Quality Assurance Committee
5**](#quality-control-quality-assurance-committee)

[III. PROCEDURES & PERFOMANCE STANDARDS
5](#procedures-perfomance-standards)

[**A. Human Subjects Research 5**](#human-subjects-research)

[**B. Centralized Training 6**](#centralized-training)

[**C. Manuals and Form Development 6**](#manuals-and-form-development)

[**D. Certification for Data Collection
7**](#certification-for-data-collection)

[**E. Validity and Reliability Measures
7**](#validity-and-reliability-measures)

[IV. QUALITY CONTROL PROCEDURES 7](#quality-control-procedures)

[**A. General Monitoring Procedures 7**](#general-monitoring-procedures)

[1. Observation 7](#observation)

[2. Site Visits 8](#site-visits)

[**B. Communication with Participants
9**](#communication-with-participants)

[1. Model Scripts 9](#model-scripts)

[2. Documentation of Communications 9](#documentation-of-communications)

[3. Communications for Recruitment 9](#communications-for-recruitment)

[4. Communications for Results Notification and Study Details
10](#communications-for-results-notification-and-study-details)

[**C. Questionnaire and Interview Data
10**](#questionnaire-and-interview-data)

[1. Overview of Procedures 10](#overview-of-procedures)

[2. Onsite Quality Assurance 11](#onsite-quality-assurance)

[3. DCC Quality Assurance 12](#dcc-quality-assurance)

[4. Immunization Records 13](#immunization-records)

[5. Family History Data 13](#family-history-data)

[**D. Dietary Data 13**](#dietary-data)

[1. Overview of Procedures 13](#overview-of-procedures-1)

[2. Training & Certification 14](#training-certification)

[3. Onsite Quality Assurance 15](#onsite-quality-assurance-1)

[4. DCC Quality Assurance 16](#dcc-quality-assurance-1)

[5. Nutritional Biomarkers 17](#nutritional-biomarkers)

[**E. Physical Examinations 17**](#physical-examinations)

**TEDDY QUALITY CONTROL**

**TABLE OF CONTENTS**

[**F. Specimen Collection and Disposition
17**](#specimen-collection-and-disposition)

[1. Overview of Procedures 17](#overview-of-procedures-2)

[2. HLA Genotyping 18](#hla-genotyping)

[3. Shipping Confirmation 19](#shipping-confirmation)

[4. Autoantibody Laboratories 19](#autoantibody-laboratories)

[5. Stool Samples 20](#stool-samples)

[**G. Infectious Agent Quality Control
21**](#infectious-agent-quality-control)

[V. DATA MANAGEMENT 23](#data-management)

[APPENDIX A: SITE VISIT AGENDAS 26](#appendix-a-site-visit-agendas)

[APPENDIX B: SITE VISIT CHECK SHEETS
28](#appendix-b-site-visit-check-sheets)

# INTRODUCTION

The TEDDY study seeks to collect extensive data on genetic risk and
environmental exposures that may lead to the initiation of islet
autoimmunity as defined by the occurrence of autoantibodies and its
progression as defined by the diagnosis of Type 1 diabetes. The quality
of that data is essential to the ability to achieve study goals and test
study hypotheses. Accordingly, the TEDDY Steering Committee has created
a Quality Assurance/Quality Control Committee (QA/QC Committee) to
develop and monitor procedures and standards to ensure data quality.
These procedures provide an ongoing vehicle to rapidly identify
deviations that can be corrected so as to ensure the quality of data
over time and to document data quality in future publications.

For the TEDDY Study quality assurance/quality control measures are
contained in the manuals and procedures instituted to assure that the
data is collected in a standardized fashion by a well-trained staff who
take responsibility for the data quality and integrity overtime.

Components of QA/QC in the TEDDY Study include the following:

1.  Manual of Operations

2.  Appropriate instrument development and testing

3.  Centralized and/or local training requirements for each data
    collection task

4.  Certification requirements for appropriate data collection tasks

5.  Individual responsibility for performance

6.  Ongoing quality control monitoring that includes the following
    specific subset of quality assurance procedures designed to assess
    the quality of the data collection and processing tasks.

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A.  Observation

B.  Site Visits

C.  Repeat Measurements

D.  Quality Analysis-Data review, consistency/range checks

Quality control measures apply to monitoring the following components of
the TEDDY Study:

1.  The performance of HLA screening laboratories with respect to the
    accuracy of identifying the eligible study population.

2.  Compliance with protocol defined data collection and data collection
    schedules.

3.  Tracking specimen shipping, receipt and laboratory throughput.

4.  Data completeness and validity, including data entry error rates and
    assay precision and reproducibility.

5.  Laboratory internal quality control procedures and the assessment of
    measurement errors using split samples.

6.  External laboratory quality control procedures through the exchange
    of masked samples with another laboratory.

The monitoring of data quality begins with the identification of the
study target population through HLA screening. It also includes the
collection, handling, processing, and analysis of subsequent biological
and environmental specimens. And it includes measures to ensure
consistency in collection and recording of observational data from
interviews and data collection instruments.

For some measures, quality assurance procedures consist of laboratory
protocols involving the exchange of samples for parallel independent
testing, performance in an external quality control program, or the
internal data confirmation of assay results. For other measures, quality
assurance procedures consist of records review and observation of staff
by supervisors and/or site visitors to verify protocol completeness, and
adherence, as well as within and between staff differences.

# OVERVIEW OF QUALITY CONTROL

## Clinical Center Responsibilities

Clinical centers are responsible for implementing the TEDDY protocol and
in order to fulfill this task to recruit and train study staff. Every
clinical center is expected to have a Study Coordinator who is a member
of Study Coordinators Committee, together with selected other center
representatives as needed on the Committee. This involves participating
in telephone conference calls and in-person meetings as scheduled. It is
through this committee that clinical centers have a forum for monitoring
study-wide activities, bringing matters of interest to study-wide
attention and resolution according to the study protocol.

All clinical center study staff participate in TEDDY training
initiatives. To that end, TEDDY has conducted centralized multi-day
training meetings which are posted on the TEDDY website. Both video
tapes and PowerPoint presentations from training sessions are available
on the TEDDY website. English-speaking TEDDY staff who have not attended
the in-person training are expected to view the material over the web to
be certified to participate in the study. Non-English speaking staff
must complete language-specific training sessions that contain the same
training dimensions as the English-language materials.

In addition all staff must complete the required minimum practice
sessions conducted locally for all aspects of the protocol that applies
to that position's job description. Additional information about
training requirements is found in the section "Centralized Training" of
this document.

Each center is also responsible for obtaining IRB approval from all
necessary institutions to conduct the TEDDY Study and to keep the DCC
and Steering Committee appraised of any concerns or issues that are
presented locally. As noted below it is the responsibility to keep all
documents including IRB approvals and informed consents on file with the
DCC.

## Data Coordinating Center Responsibilities

The TEDDY Coordinating Center (DCC) has primary responsibility for
monitoring and ensuring the overall quality of study data. Specific
responsibilities of the Coordinating Center in developing and carrying
out quality control measures are listed below:

1.  Organize and conduct centralized staff training sessions, in concert
    with the appropriate TEDDY Study committees to teach standardized
    data collection protocols.

2.  Organize and conduct data monitoring activities for all TEDDY
    reference labs and clinical site HLA screening laboratories in
    concert with the TEDDY genetics, laboratory and immunology
    committees.

3.  Review and establish procedures for clinical centers to meet
    performance standards as recommended by the appropriate TEDDY
    committees.

4.  Develop a system for monitoring study recruitment and communicate
    with the Study Coordinators regarding recruitment progress and
    related issues.

5.  Develop a system for promptly processing and analyzing incoming data
    and generating quality control reports for distribution to clinical
    centers, and TEDDY committees.

6.  Identify problems and notify Clinical Centers of the quality of
    performance of network and clinic personnel throughout the entire
    data collection period.

7.  Identify problems and notify the Laboratory Committee of the quality
    of performance of TEDDY laboratories throughout the entire data
    collection period.

8.  Develop and maintain a system for tracking TEDDY specimens from
    collection at the clinics to receipt at the reference laboratories
    and the TEDDY repository.

9.  Report pertinent information to the QA/QC Committee and the Steering
    Committee.

10. Maintain historical data that describes the quality and performance
    of the entire TEDDY study.

11. Produce and maintain the study documents related to quality
    control: (1) to be presented to the QA/QC Committee and Steering
    Committee; and (2) to the TEDDY External Advisory Board.

## Quality Control/ Quality Assurance Committee

The TEDDY QA/QC Committee has overall responsibility for the oversight
of QC policies and procedures. This committee will rely on the
scientific expertise of the appropriate TEDDY committees in carrying out
this responsibility. The QC Committee will develop appropriate reports
and documentation for circulation to the Steering Committee and the
External Advisory Board.

#  PROCEDURES & PERFOMANCE STANDARDS

## Human Subjects Research

As TEDDY is a study that is international in scope, requirements may
vary for institutional review and ethics boards, and they may also vary
for subjects' confidentiality and privacy criteria. All Institutional
Review Board (IRB) Approval Letters and approved Consent Forms are kept
on file at both the DCC and the Clinical Centers. All IRB annual
reports, IRB re-approval letters, and updated consent forms (with date
clearly marked) are kept on file at the Clinical Centers and the DCC.

The QA/QC Quality Control Committee will monitor TEDDY enrollment forms
to ensure that the appropriate boxes are checked to verify signed
informed consent is obtained for every study participant prior to the
collection of blood samples for HLA screening at all sites. US sites
conform to local IRB requirements regarding the signing of HIPAA forms
by participant families prior to TEDDY screening and/or enrollment.

At the Clinical Centers, personal data (names, addresses, contact
persons, etc) for TEDDY study participants are kept in local tracking
databases and on hard-copy forms designed by each center. This
information is used primarily for scheduling and results notification
purposes, and is reviewed at each visit to maintain accuracy. It is also
essential information for establishing and maintaining a connection to
the family. Participant files are kept under lock and key in study
record storage rooms.

The DCC does not receive any personal information on study participants.
All information obtained for this study is identified by the unique
study number, and is not linked with the participant's name to files
that are transmitted to the DCC. Data from TEDDY examinations and
procedures is sent to the DCC to be entered into a database used for
statistical analysis. The DCC is provided only with information that
identifies the general geographic location of each subject, such as
Colorado, Finland, or Germany, for example. No further identifying
factors are available to staff at the DCC.

Additionally, Certificates of Confidentiality have been required by the
U.S. Department of Health and Human Services to allow TEDDY
investigators to protect and maintain the privacy of TEDDY study
records. The Certificate of Confidentiality is designed to guard against
disclosure of information that potentially might affect a subject's
insurability or employability.

To ensure diversity in the study population, distributions of gender,
race, and ethnic group for each participating country is monitored and
reported annually to the TEDDY Steering Committee. If the study
population does not reflect recruitment targets, the TEDDY Steering
Committee will take corrective actions.

Additional information regarding the guidelines for Human Subject
Research is found in Chapter 4 of the TEDDY Manual of Operations.

## Centralized Training

Centralized training occurs as needed in order for TEDDY personnel to
acquire specific study procedures and skills in a standardized manner.
The goals of each training session include 1) familiarization with the
details of the study protocol including hypotheses, rationale and
requirements for each component of the data collection, 2) review and
practice of procedures, and sharing of experiences to develop best
methods that work across all the clinical sites.

Video tapes and PowerPoint presentations have been produced for each
centralized training session. These training materials are available on
the TEDDY website. New personnel who join the study will be required to
view/review these resources before being certified for data collection
tasks, and to participate in follow up training as needed.

## Manuals and Form Development

With guidance from the TEDDY Steering Committee, a Manual of Operations
(MOO) has been developed. Primary responsibility for its content and
ongoing review is assigned to the DCC and the Coordinators Committee.
The MOO describes, in detail, procedures for all measures and
interactions that comprise the TEDDY Study.

Model informed consents, HIPAA authorizations, scripts, and letters of
notifying subjects of results have been developed and are available in
the MOO. All MOO sections and consent forms, including the site-specific
MOO appendices, are to be provided to the DCC in English.

## Certification for Data Collection

General certification to collect study data requires participation
and/or viewing of all centralized training activities, completing the
minimum practice/local training sessions for each task and being
approved by local study coordinators to collect TEDDY data. Other
general certification requirements vary by clinical center and country.
In general, each clinical center needs to be in compliance with
institutional certification requirements for such areas as: IRB, HIPAA,
blood borne pathogens handling, and competency in phlebotomy involving
newborns and infants. Additional specific certification requirements for
portions of the protocol are noted below in the appropriate section of
this document.

## Validity and Reliability Measures

Reliability and validity of data are of paramount importance in the
TEDDY study. As part of the centralized and local training, the emphasis
is placed on the pivotal role played by study staff in assuring data
reliability and validity. Accordingly, the DCC generates reports that
serve to monitor metrics of data validity and reliability; reports will
include individual, group, and site-wide assessments, and will be
enhanced by local reports at the clinical sites. Together, these
monitoring systems constitute important vehicles for positive and
constructive feedback for individual and total center performance, with
both individual and team responsibility and accountability, and most
importantly, assurance of valid and reliable outcomes evaluation.

# Quality Control Procedures

## General Monitoring Procedures

### Observation

The Quality Control process for data collection uses observational
techniques to monitor study performance and procedures, with appropriate
documentation. Observation permits the supervisor and/or site visitor to
verify protocol completeness, adherence, within and between staff
differences, and general protocol compliance.

Several methods of observation may be used including direct observation
(e.g. in exam room, on phone), video taped practice sessions, and
audio-taped practice or live (with subject permission) sessions. These
generally are applied to the portions of the data collection protocol
that include subject interaction such as recruitment procedures, results
notification, and interviewing. Local and centralized observation
schedules will be developed for selected portions of the data collection
protocol and will account for the different languages used at the TEDDY
sites. Any checklists developed for such sessions will serve as logs and
documentation provided to the DCC and QA/QC Committee as these protocols
are developed.

Performance and/or procedural issues identified during quality assurance
monitoring will be reviewed by the TEDDY QA/QC Committee as well as
local study staff in order to target areas where development of
additional study-wide training may be needed. Ongoing training helps to
ensure that minimal deficiencies are reported in subsequent quality
assurance monitors.

### Site Visits

Site visit teams will include personnel from the DCC and TEDDY clinical
centers and may include members of relevant standing committees, most
especially the QA/QC Committee. The first site visit is scheduled to
occur six to nine months after the last TEDDY clinical center begins to
see participants in the follow-up study. A site visit protocol for TEDDY
contracted laboratories will be assessed. Need for annual site visits
will be determined over time.

The goals of the site visit are:

-   To observe TEDDY study staff under normal operating, real life
    conditions to assess understanding and adherence of the protocol

-   To increase and facilitate communication between the DCC, QA/QC
    Committee, study investigators, and clinical personnel

-   To demonstrate and document the study's performance regarding data
    quality

Components of the clinical protocol that are proposed to for site visit
observation include observation of:

-   HLA Screening sample collection and processing

-   HLA "positive" patient screening results notification and follow-up
    recruitment phone calls

-   All interview, physical exam, and laboratory portions of all visits
    being conducted (e.g. a 3 month, 6 month and 9 month visit should be
    observed)

-   Data entry/edit procedures.

Additionally, there will be reviews of:

-   Logs and form storage

-   Study documentation

-   Communication routines with other centers and laboratories.

Following each site visit, a formal report is to be written and
distributed to the Steering Committee, the QA/QC Committee, NIDDK, and
each clinical center. The QA/QC Committee will have the responsibility
to review the site visit reports, and make recommendations for the
follow-up and correction required, together with the timeline for these
activities to the individual site. Study coordinators at the affected
sites will respond in writing to the QA/QC Committee regarding
resolution and response to the recommendations made, recognizing that
*time is of the essence* in remedying deficiencies in order to assure
study integrity.

The QA/QC Committee will also review each report with an eye to identify
issues which may require further centralized training on a study-wide
basis. When study-wide training issues are identified, the QA/QC
Committee along with the DCC will assign training schedules and
development of Powerpoint presentations, videos or other appropriate
collateral materials to facilitate training.

## Communication with Participants

The TEDDY Study includes ongoing communications to/from participant
families about what the clinic visits are like and what families might
expect over the years of the study. Many of these communications occur
face-to-face within the setting of a clinic visit, but several points of
communication with participants are outside the visit portions of the
screening and follow-up data collection protocol. These include the
following communications:

-   Letters and/or phone calls related to recruitment of eligible
    subjects into the follow-up portion of the study

-   Letters and phone calls notifying participants about screening
    results

-   Phone calls and follow-up mailings for scheduling of initial and
    subsequent visits

-   Ongoing notification in letters and/or phone calls about results of
    autoantibody and glucose monitoring tests.

### Model Scripts

Full model scripts and letters have been developed for all interactions
and can be found in the sections 6, 7, 12, and 13 of the MOO. Each
clinical center may tailor the models to accommodate the requirements of
their respective IRBs and operational circumstances. All site-specific
letters and other written communications are provided in appendices of
the appropriate MOO sections.

The model letters and scripts are used as the basis for training and
observation at the centralized training sessions. Training of all
personnel who will be interacting with the participants in these
encounters recruitment staff emphasizes sensitivity and good listening
skills when approaching candidate families and discussing TEDDY with
them. One level of quality control for interview and script skills
occurs during annual site visits to TEDDY Clinical Centers; interviewers
are observed and rated, as described in Appendix C of this document.

### Documentation of Communications

After eligible families enroll in the TEDDY follow-up study, all
communications with subjects required by the protocol are documented in
the local study records. Clinical centers have developed local tracking
mechanisms for recording and tracking the contacts made for recruitment
into the follow-up TEDDY study and subsequent scheduling activities.

### Communications for Recruitment

Eligible families must be recruited and children must have their first
TEDDY visit by the age of four months. Recruitment of families may
require many attempts at contacting and scheduling before a subject is
enrolled/visit completed or recruitment refused/visit not completed.
This process may be complicated by study personnel having limited or
inaccurate contact information. When telephone contact is not
successful, alternate sources of contact will be pursued, such as
Internet white pages, alternate contact persons, and finally a letter.

Local centers will document in their tracking databases all contact and
scheduling attempts and their outcome. The final outcome (visit
completed, refused, ineligible) is documented on the enrollment form,
which is routinely reviewed by the DCC for compliance with the four
month limit and completeness. It is from this form that queries and
reports on enrollment and response rates are generated.

### Communications for Results Notification and Study Details

All TEDDY staff members engaged in direct contact with families must be
trained and practiced in results notification and details of the TEDDY
follow-up study before contacting participants. Elements of the training
are the same across the life of the study and include:

-   Successful completion of Humans Subjects Protections Training course

-   Reading the Manual of Operations and the Protocol related to all
    types of results notification and follow-up procedures

-   Training in how to communicate results to families, explaining the
    meaning of the results, educating parents about diabetes, reviewing
    the study and its purpose, inviting parents to ask questions and
    being prepared with answers to the Frequently Asked Questions (FAQ)
    list.

-   A minimum of two observation sessions of certified personnel
    communicating each kind of result (HLA eligible, Antibody positive
    results)

-   A minimum of two practice sessions with experienced personnel role
    playing the participant receiving the results. After such practice
    and with the determination of at least one certified TEDDY study
    member, a new staff person may begin participant communications. The
    first two sessions must be observed by the trainer. With the
    successful completion of these interactions, a new staff person
    would be certified for each of these subject communications.

Before being approved to begin reporting positive antibody results, all
new staff must listen/observe at least two interactions when positive
results are given to the family. When participants are tested for islet
autoantibodies (GAD65, ICA512/IA-2, and IAA), notification of test
results should take place prior to or at the next scheduled clinic
visit, with negative results being reported in a letter and positive
results being reported first in a phone conversation and with a
subsequent letter. Results should be given within six weeks, but no
later than twelve weeks after the blood sample was drawn. Standard
scripts and letters have been developed for these communications, and
are available in the Manual of Operations.

## Questionnaire and Interview Data

### Overview of Procedures

There are two ways that participants supply data to TEDDY research teams
\-- 1) written data recorded in various self-administered instruments
that are later reviewed with study personnel at the clinic visit, and 2)
verbal data supplied during the clinic interviews or through prompted
conversations that expand the written portions of information recorded
in self-administered instruments.

There are three types of self-administered instruments in the TEDDY
study:

-   Food records which describe 3-day diet histories for the TEDDY child
    (3-day food diaries are detailed in Section D on page
    [13](#dietary-data) of this document)

-   The TEDDY Book which is a diary parents use to record important
    information as it occurs

-   Various questionnaire forms, including:

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-   First Questionnaire - Mother

-   First Questionnaire - Father

-   First Questionnaire - Primary Care Taker

-   6 Month Questionnaire

-   Family History Questionnaire

-   9 Month Questionnaire

-   15 Month Annual Parent Questionnaire

-   27 Month Annual Parent Questionnaire

-   Ongoing TEDDY Book Extraction at each clinic visit

Data are also input by clinical staff onto a form for the 3 Month
Interview that comprises the first TEDDY clinic visit. Forms are
completed by clinical staff during the interview and they are later
extracted to the TEDDY website. All forms are reviewed at the time of
the visit for completeness and clarity of recording, and coding of
required fields. Data from questionnaires and other forms that are
completed by participants and clinical staff are then scanned into the
local computer, and later transmitted to the TEDDY website using the
"Data Upload' utility.

Additionally, information from the TEDDY Book is registered on TEDDY
Extraction Forms by clinic staff, with appropriate data entry codes. The
Extraction Form is scanned and 1) sent by Internet or 2) sent online to
the DCC, using the "Data Upload" utility on the TEDDY Website, as
described in Section 17 of the Manual of Operations. Following
submission to the DCC, the data from questionnaires and the TEDDY Book
are available for online viewing at the TEDDY website.

All TEDDY staff members engaged in data collection must be trained and
practiced in all elements to be certified to engage in these activities.
Elements of the training are the same across the life of the study and
include:

-   Successful completion of Humans Subjects Protections Training
    course.

-   Successful completion of the centralized training or review of video
    tapes and presentations under the direction of a certified trainer.

-   Reading the Manual of Operations and the Protocol related to all
    visits.

-   A minimum of two practice sessions with experienced personnel role
    playing the participant. After such practice and with the
    determination by a certified TEDDY staff member, the new staff
    person is certified for data collection.

-   Training and testing of coding accuracy will be developed to insure
    cross-site comparability of coding.

### Onsite Quality Assurance

All participant self-administered questionnaires are reviewed during the
clinic visit in order to assure:

-   The questionnaire is completed in black pen

-   Any questions are answered that the respondent may have about how to
    answer the items or complete the form

-   The date is entered on the form the European format (day/month/year)
    and all other dates are entered in the same format

-   No items are omitted by accident or expressly; however, if a
    respondent purposefully refuses to complete an item when questioned
    about it, the reviewer will so note on the questionnaire.

-   The respondent's answers are clearly visible and readable

-   If the respondent changes one or more answers:

    -   the first, "incorrect" response is erased completely

    -   or a large X should be drawn across the incorrect response.

-   The respondent has not filled in boxes designed for staff coding

Quality monitoring of the self-administered questionnaires is done
through ongoing review of forms, regular meetings of clinical staff and
investigators to review protocol questions and issues of clarification,
and regular meetings/conference calls with the Study Coordinator
Committee to review issues of study-wide importance.

Interviewers will also make periodic audio tapes of participant
interviews and these tapes will be forwarded for review to the Quality
Control and Psychosocial Committees, or to a designated, qualified,
neutral outside reviewer to assess within and between center
standardization of clinic visit interviews and questionnaire review
procedures. Consent forms are to be developed for families to enable
taping of the review sessions. A checklist for measures to be evaluated
in the site visits is found in Appendix C of this document. An
additional level of quality control exists with the annual site visits
to TEDDY sites, during which interview processes will be observed and
rated.

A checklist for site quality control visits is found in Appendix B of
this document.

### DCC Quality Assurance

Each Clinical Center is required to submit a 5% random sample of form
sets to the DCC on a quarterly basis for a manual quality control
review. A list of randomly generated ID numbers for each clinic is
supplied by the DCC. The manual review of forms by staff of the DCC will
entail a page-by-page review of the following items:

-   form completion

-   affixed TEDDY ID and quality control labels, when applicable

-   interviewer IDs

-   skip patterns observed

-   ethnicity and study coding; and

-   overall form consistency and preparedness for data entry.

A report of errors and/or recommendations for improvement will be sent
to the Clinical Center and the Director of the DCC following each
review.

There are quality assurance measures performed at the DCC for each type
of data entry available to Clinical Centers, to capture data errors. For
automated forms (paper forms which are scanned and electronically read),
verification of the form data is done at the DCC after the form has been
submitted, before the data is automatically inserted into the TEDDY
database. This allows for system read errors to be corrected. This
automated data entry improves upon traditional data transcription errors
because the form that was completed is scanned directly into the TEDDY
system, and no transcription actually takes place.

Also available to Clinical Centers is direct data entry via the TEDDY
web-based study management application. The web forms have both
client-side and server-side data integrity checks to ensure that data
being entered is within proper boundaries. Examples of these data
integrity checks include range checking, data type checking, required
field checks and database relational integrity checks.

Another data quality assurance measure is the generation of monthly
compliance reports for each Clinical Center. These reports are used to
assess the completeness, accuracy and timeliness of data entry.
Information generated by these reports includes \-- the percentage of
forms that are considered complete, the percentage of forms that are
completed by their due date, and a list of forms that are overdue. TEDDY
is targeted to achieve levels of 95% each for compliance, timeliness and
accuracy. If a particular level falls below 95%, the result is reported
the appropriate Clinical Center(s) and the Steering Committee. Each
Clinical Center is then required to take commensurate remedial action.

### Immunization Records

Parent reported data is verified in random samples by independent
analysis of hospital or clinical records of immunizations within the
limits requirements for confidentiality in all countries and
specifically HIPAA in the USA.

### Family History Data

Recent studies on the way parents report data on their family history
has shown that self reported pedigrees are accurate. The DCC will not
monitor.

## Dietary Data

### Overview of Procedures

Field staff collecting dietary data include study nurses (in Sweden).
Study nurses and physicians (in Finland), dietary interviewers (in the
US), and nutritionists (in Germany). Their duties are as follows:

-   They conduct 24-hour food recall interviews (3-month TEDDY visit
    only)

-   They collect 3-day food records that have been completed by
    participant families

-   They conduct interviews with families to probe for and confirm
    dietary intakes shown in the 3-day food records

-   They or nutritionists (in Sweden and Finland) enter 24-hour recall
    and 3-day food record data into one of the four database systems
    assigned for nutrition data collection

A site lead nutrition person is either a nutritionist or a person
trained in coding and quality control, located at each site and
responsible for coordinating the food coding, data entry and onsite
quality control.

Food analysis databases in use for TEDDY are:

-   Germany: LEBTAB, owned by Forschungsinstitut für Kinderernähring
    (Research Institute for Child Nutrition) (FKE)

-   Sweden: Food database owned by the Swedish National Food
    Administration

-   Finland: FINELI, owned by the National Public Health Institute

-   United States: NDS-R, owned by the University of Minnesota, School
    of Public Health, and licensed to the TEDDY sites in the USA.

### Training & Certification

Field personnel are trained and certified in TEDDY-specific methods and
procedures before they begin to interview participants for the 24-hour
food recalls and 3-day food records. Training is multi-disciplinary in
content and includes, 1) training in research and interview methods for
obtaining the 24-h food recalls and 3-day food records from
participants, 2) subject expertise in the common food supply and dietary
supplements in use by the country in question with emphasis on infant
and toddler foods, as well as yields after preparation, recipe models,
cookbooks, and nutrient composition tables, 3) skill in the estimation
of portion sizes, and 4) training and certification in the use of
database software, codes, and rules for data entry (e.g. simulation of
recipes and possible modifications of recipes).

The training in interview methods for the 24-hour recall and 3-day food
record collection is intended to ensure consistency in interview scripts
and prompts, and minimize the tendency for recall bias. An unconscious
wish to portray their child as eating a healthy diet could be associated
with a tendency to overestimate or underestimate intakes by infants and
toddlers. The training for TEDDY is intended to ensure that interview
personnel establish an objective, non-judgmental atmosphere to minimize
the tendency for this social desirability bias that is commonly reported
in studies of diet.

Training materials for field personnel include a Manual of Operation and
additional materials about infant diet and feeding habits beginning at
the age of three months, information about formulas, vitamins, beverages
and medications, and check-lists of different food items, visual
materials to estimate portion size, and product brochures for foods and
dietary supplements. Different methods of estimating portion sizes and
different household measures are provided in order to accommodate
differences in how TEDDY participants might record and report their
dietary information (e.g. household measures depict tablespoon,
deciliter etc., and picture booklets depict weight lists of different
sized food items, such as 1-inch cubes, 30-cm circles, etc.).

Different processes for training and certification are provided \-- one
process is used for TEDDY sites in the USA, whereas each TEDDY site in
Europe uses a slightly different process. The differences are necessary
accommodate software and database differences among the countries, as
well as culture and language-specific differences in interview methods.
Quality control for all sites will include an analysis of the extent
forms and interviews are fully completed.

In the European TEDDY sites, a certificate is granted to field staff
after completion of the tasks described below.

> CERTIFICATE OF 24 HOUR RECALL AND FOOD RECORD: NURSES AND PHYSICIANS

-   Three 24-hour recall exercise cases and two real ones satisfactorily
    completed

-   Three 3-day food record exercise cases and two real ones
    satisfactorily completed

-   Four to six annual training sessions (updating, more age groups)

> CERTIFICATE FOR 24 HOUR RECALL AND FOOD RECORD: NUTRITIONISTS

-   The same as for nurses and physicians

-   Three data entry exercises and one test case satisfactorily
    completed

-   Commitment to participate in regular discussion of nutrition topics
    and data entry

At TEDDY sites in the USA, "dietary interviewers" are defined as
research personnel who have been trained and certified by the University
of Minnesota Nutrition Coordinating Center (NCC) to use Nutrition Data
System for Research (NDS-R) dietary data collection software to collect
24-hour dietary recalls and the food records from the participants.
Dietary interviewers and lead nutrition persons attend a two-day
training workshop at NCC to become familiar with NDS-R program features,
understand the NDS-R database structure, gain skill at data entry,
editing and data management, increase or enhance their dietary
interviewing skills and to learn their responsibilities for the
TEDDY-specific dietary assessment protocol.

The NCC grants a certificate to field staff after completion of the
tasks described below.

> CERTIFICATE FOR 24 HOUR RECALL AND FOOD RECORD FOR DIETARY
> INTERVIEWERS

-   Attendance at two-day training workshop

-   Completion of a scripted baseline recall with NCC staff

-   Collection of 10 unscripted recalls and food records from
    study-similar subjects (such as infants age 3-24 months) (3 recalls
    and 7 food records)

-   Completion of a scripted follow-up recall with NCC staff

> CERTIFICATE FOR 24 HOUR RECALL AND FOOD RECORD FOR SITE LEAD NUTRITION
> PERSONS

-   Attendance at two-day training workshop

-   Completion of a scripted baseline recall with NCC staff

-   Collection of 10 unscripted recalls and food records from
    study-similar subjects (such as infants age 3-24 months) (3 recalls
    and 7 food records)

-   Completion of a scripted follow-up recall with NCC staff

-   Commitment to participate in regular discussion about nutritional
    topics and data entry

### Onsite Quality Assurance

Dietary data collection (food records), checking, entering and coding
processes is standardized in the TEDDY countries. 100% of the food
records will be entered promptly for quality control purposes. Onsite
quality assurance is coordinated by lead nutrition persons who review
the overall quality of the dietary data collected in the field by the
dietary interviewers in their charge. On-site quality control procedures
will include these steps:

-   At the European TEDDY sites, between 5% and 10% of the data (for
    each age group) is to be double entered and checked for consistency.

-   There is a review (and corrections as necessary) of each dietary
    recall and food record by interviewer within 1-2 days of the input
    of each dietary record.

-   There is to be a review of each dietary recall and food record by
    site lead nutrition person within 1-2 weeks, of the input of each
    dietary record, with feedback provided to the respective dietary
    interviewer.

-   Quality control observations of each dietary interviewer are to be
    conducted by the site lead nutrition person on four occasions while
    they are interviewing a Primary Caretaker each year. These
    observations are intended to provide feedback on the quality of
    their interviewing style.

At this time there is no research to indicate whether dietary interviews
performed by nutritionists and those performed by nurses and other
non-nutrition personnel will yield like results. This question among
others will be addressed for quality assurance purposes.

Interviewers will make periodic audio tapes of participant interviews
and these tapes will be forwarded for review to the Quality Control and
Diet Committees, or to a designated, qualified, neutral outside reviewer
to assess within and between center standardization of clinic visit
interviews and questionnaire review procedures. Consent forms are to be
developed for families to enable taping of the diet review sessions. A
checklist for measures to be evaluated is to be found in Appendix C of
this document. An additional level of quality control exists with the
annual site visits to TEDDY sites, during which dietary interview
processes will be observed and rated.

### DCC Quality Assurance

The Clinical Centers transfer dietary data to the DCC on a monthly basis
and the lead nutrition person at the DCC is responsible for external
quality assurance. Data transfer from the Clinical Centers to the DCC
occurs after quality onsite assurance activities have been completed.
The site lead nutrition person combines the food diaries and recalls
into a computer file which is database-specific, and submits the data to
DCC. Upon receipt, the DCC confirms the successful transmission of the
electronic file, and via e-mail notifies the person sending the data
from each site accordingly.

The DCC reviews the monthly data from each site, with particular
attention to those records which reflect dietary intake that is in the
top 5% and bottom 5% of estimated energy requirements as projected by
the Institute of Medicine (IOM). (*Institute of Medicine. Food and
Nutrition Board. Dietary Reference Intakes: Energy, Carbohydrate, Fiber,
Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids, National
Academy Press, Washington, DC 2002*) The rationale for this analysis is
that reported energy intake (EI) may be expressed as a ratio of
estimated energy requirements (EER). Values of EI: EER falling below the
95% confidence limit of agreement in these two measures signify the
presence of underreporting, and those falling above the 95% confidence
limit signify overreporting. A formula for calculating the lower 95%
confidence limit to assess external validation was proposed by Goldberg
(the Goldberg cutoff) and it has been used by numerous authors to
analyze dietary data. (*Goldberg GR et al., Critical evaluation of
energy intake data using fundamental principles of energy physiology.
Eur J Clin Nutr 1991:45:569-581*)

Questionable foods, unreasonable amounts, or questionable total energy
intakes are called to the attention of the site lead nutritionists, with
a DCC recommendation regarding editing when it is thought that the
dietary interviewer made an inappropriate choice during data entry.
Sites are contacted on a monthly basis regarding any questionable items
noted during the DCC quality control review. The queries serve to
resolve the immediate questions and to alert the interviewers to the
types of issues that are questioned and require confirmation and
documentation.

In addition, the DCC will analyze internal consistency by reviewing
questions that should yield the same answer, such as the analysis of
participants' responses to questions about vitamin/mineral supplements,
which is reported both in the TEDDY book and in the 3-day dietary
recalls.

### Nutritional Biomarkers

Biomarkers of nutritional status are being collected in TEDDY in
association with outcomes analysis. But biomarkers can also provide
laboratory measures of the validity of dietary intake that is reported
in food recalls and diaries for nutrients of interest. Nutrients of
interest in TEDDY that are the best candidates for validity study
include:

-   Plasma alpha and gamma-tocopherols (biomarker of vitamin E intake)

-   Erythrocyte fatty acid membrane composition (biomarker of omega-3
    fatty acid intake)

-   Plasma ascorbic acid

It is important to consider how a biomarker is affected by laboratory
procedures, so samples used for analysis of nutritional biomarkers will
use laboratory quality control procedures that are outlined in Chapter
14 of the Manual of Operations.

## Physical Examinations 

Chapter 13 of the Manual of Operations contains standard equipment and
procedures for clinical measurements during each physical examination of
TEDDY children. Standards include weighing and measuring, random glucose
measures, oral glucose tolerance testing, and others. The Physical
Examination form is completed by medical staff and later
extracted/uploaded to the TEDDY website. The performance of exam teams
is monitored during observations of by personnel conducting TEDDY site
visits.

## Specimen Collection and Disposition

### Overview of Procedures

Clinical and laboratory staff collect and handle blood, stool and
toenail samples from TEDDY participants. To the extent possible,
specimens are collected, processed, and stored in such a manner as to be
compatible with both immediate and future testing requirements. Each
clinical and laboratory procedure has standards for operations and
performance monitoring which are documented below, and also in Chapter
14 of the Manual of Operations. An additional level of quality control
occurs during annual site visits to TEDDY Clinical Centers; laboratory
procedures are observed and rated, as described in Appendix C of this
document.

There is a quality control mechanism built into data management programs
associated with laboratory specimens. Electronic forms in the "Sample
Shipment System" of the TEDDY website and database are used to identify,
describe, and organize each sample. Data entered into the electronic
forms are captured and submitted to the DCC and to relevant
laboratories, shipping vendors, and clinics, as is detailed in Sections
2 through 7 below.

In brief, staff at each laboratory or clinic log onto the "Sample
Shipment System," and make a menu selection to create a shipping list
for the particular type of specimen and lab assay desired (e.g.,
genotyping, autoantibody, etc.) After the list is created, the user
clicks a *Save Shipment* button on the computer screen. The data is
uploaded to the TEDDY database, and an MS Excel worksheet is created
containing information for the specimens. An automated process transmits
a "Notification of Shipment" email to the DCC and to the receiving
laboratory to alert a pending shipment. In cases where an Excel
worksheet is created, the worksheet is transmitted as an attachment in
the email. The DCC staff verifies that data entry of the forms (or MS
Excel spreadsheet) is complete and accurate. The DCC will record missing
information as a quality control measure and include the information in
an exception report if corrective action is not feasible.

When the samples arrive at their destination, laboratory staff will
verify the contents of the shipment against the information in the data
form or MS Excel worksheet. If there are deficient specimens, an
exception list is generated; laboratory staff marks the MS Excel
worksheet with a code that specifies the reason for the deficiency.
(Deficiencies include, among others, "*sample arrived thawed*," "*vial
was damaged*," or "*low volume*"). If there are no deficient samples,
the worksheet is forwarded from the laboratory via email to the DCC with
appropriate notations. If there are deficiencies, a copy of the marked
MS Excel file is sent to the DCC with a confirmatory email.

On a quarterly basis, the DCC generates exception reports that tabulate
the number and origin of deficient samples and reasons for deficiency.
Investigations to determine root causes and take corrective action occur
as necessary. All data and computer files received by the DCC are
archived on file servers according to data management standards and
practices.

### HLA Genotyping

All HLA screening laboratories have been certified by submitting an
analysis of 50 masked samples sent from the Newborn Screening
Proficiency Testing program at the Centers for Disease Control and
Prevention in 2004. A standard of 98% accuracy was the minimum
performance level. All HLA screening laboratories successfully completed
this task. To continue to screen, each center must pass annual
Proficiency Testing by the same mechanism.

Another measure of quality control is provided by the TEDDY Central
Genotyping Laboratory located at Children\'s Hospital Oakland Research
Institute in California, which confirms eligibility on 100% of positive
samples and a small percentage of negative samples, sent in quarterly
batches. To qualify as competent, the Clinical Center must demonstrate a
98% or greater accuracy compared to the Central Lab and continue
screening during the interval between CDC proficiency tests.

Internal quality control at the TEDDY Central Genotyping Laboratory
includes the following operating procedures:

-   The performance of immobilized HLA strips is evaluated for
    specificity and functionality by hybridizing to a panel of
    standardized control cell lines (\~10-12 DNAs). Only strip batches
    that have passed QC are used by the research group.

-   Positive and negative controls are included in sample preparation to
    monitor possible contamination during sample extraction.

-   Calibration of PCR thermal cyclers is done twice a year. A set of
    positive and negative controls is included to monitor PCR
    amplification efficiency.

-   During TEDDY genotype assignment, a proprietary software program is
    used to automate allele calls, but manual confirmation of each
    assignment is required. There is a macro to check DRB1-DQB1
    haplotypes and "flag" samples with unusual haplotypes which are
    reanalyzed. Strips with faint positive signals are also retyped.

-   One set of DNA samples is taken from each row on a PCR tray. Each of
    these samples are reamplified, retyped, and checked for its
    reproducibility.

At the DCC, a third level of quality control is conducted. The reported
genotypes are compared to the protocol-defined eligible list.
Discrepancies are noted and clarification is required before a reported
HLA is determined to be eligible.

### Shipping Confirmation

Clinical Centers automatically forward a copy of their shipment data to
the DCC as part of the computer programming built into the "Sample
Shipment System." There is an exception procedure for shipments that are
sent but not received. If the receiving laboratory does not have the
specimens within two weeks of the "Notification of Shipment" email, the
DCC enables a tracking system with the shipper to trace the shipment
from the Clinical Center.

### Autoantibody Laboratories

The two TEDDY autoantibody laboratories (University of Colorado, Denver
CO USA; Southmead Hospital, Bristol UK) is expected to be responsible
for its internal quality control program, to include daily testing of
quality control preparations, blind replicates, participation in the
DASP proficiency program, and repeat testing, and to make those results
available to the QA/QC Committee.

Prior to initiation of the TEDDY study, the laboratories evaluate a set
of masked samples for GAD65 and IA-2/ICA512 autoantibodies. These
findings were reported to the DCC to establish the comparability between
the laboratories.

Analysis of quality control data is by standard methods that include the
use of Shewart plots and monthly means. Data for QC preparations are
sent to the DCC on a monthly basis. Under coordination of the DCC, each
laboratory also receives and tests blinded samples and split samples,
and a panel of QC samples bi-monthly. These are generated at the
clinical centers under direction of the DCC. Discrepancies are
identified and if necessary action taken to adjust thresholds for
positivity if systematic differences are found, or to determine causes
of discrepancies if sporadic discrepancies are found.

During the course of the study, any sample found to be positive for one
or more autoantibodies must be confirmed by the other laboratory.
Additionally, 5% of negative samples randomly selected by the DCC are
tested by the second central laboratory. This serves as a quality
control check of the laboratory procedures as well as the entire
collection and distribution system. Procedurally, the first laboratory
notifies the DCC of their results. The DCC instructs the TEDDY
Repository to ship matching sample (two aliquots are made at the time of
blood draw for autoantibodies). One sample is sent directly to the
autoantibody laboratory and the other to the repository.

The second laboratory, (masked to which samples were reported to be
positive or negative) performs the routine assays and report them to the
DCC. Using these results, the determination is made as to whether the
sample is confirmed autoantibody positive or negative for reporting to
the clinical center. In addition, the data serves as a validation and
performance evaluation of the laboratory.

The QC committee will construct appropriate actions involving additional
sample testing in the advent of a disagreement between the laboratories
or a rate of disagreement that is deemed to be above acceptable. Any
changes in operating procedures, assay constructs, etc. need to be
reviewed and approved by the DC committee before they are to be
implemented for the processing of TEDDY samples. All TEDDY samples
remaining in the autoantibody laboratories remain the property of the
TEDDY study and their disposition needs approval from the QC Committee.

There are two types of mathematical analysis to assess the quality of
the reports from the autoantibody laboratories. First, univariate
analyses are conducted on monthly data results uploaded to the DCC.
Within each laboratory, comparisons of data results over time are
recorded. Based on these analyses, summary statistics (e.g., means,
variances) and out-of-range values are obtained and, if necessary,
investigated further. In addition to graphical inspection of the data,
reliability is assessed using correlation coefficients and the McNemar's
test is used to assess whether the amount of disagreement between the
labs in terms of the sample outcomes is statistically different.
Autoantibody binding levels are entered in Q-Q plots to monitor the
distribution of binding levels and the deviation of biding levels from a
log normal distribution. The Coefficient of Variation (CV) is calculated
for each pair of samples. The average CV, as well as standard deviation,
minimum and maximum, is tabulated for each sample type. If there is
evidence of unreliability, a statistically significant amount of
disagreement, or a high average CV then the laboratory is contacted and
queried for an explanation.

Additional detail regarding external and internal quality control
procedures is found in each laboratory-specific Manual of Operations.

### Stool Samples

In the USA, monthly stool samples are mailed from the homes of
participants to the NIDDK Repository, using pre-printed US Post Office
Express Mail mailing labels provided by the Clinical Center. Shipping
instructions for parents are listed in the "Poop Sample Collection
Instructions (USA Version)" located in the Manual of Operations.

At European sites, monthly stool samples are returned by mail to
Clinical Centers from the homes of participants. Shipping instructions
for parents are listed in the "Poop Sample Collection Instructions
(European Version)" located in the Manual of Operations. European
clinical centers package stool samples into boxes, and send the boxes,
through World Courier, in bulk shipments once a month on dry ice to the
NIDDK Repository.

European Clinical Center staff completes a form for each specimen using
the "European Stool Sample Shipment" utility of the TEDDY website and
database. In brief, each sample is collected in tubes with etched
barcodes. The barcode is scanned into the TEDDY database and additional
information is completed to identify the date of collection and the box
number used in bulk shipment. Clinical Centers automatically forward a
copy of their shipment data to the DCC as part of the computer
programming built into the "Sample Shipment System."

Quality Control includes DCC monitoring of sample date to dates of
preparation at Clinical Centers and shipment to the NIDDK Repository.
Completion and missing information on sample forms is also recorded. The
NIDDK Repository inspects and scores each shipment and reports results
via email as described in Section 1 above.

## Infectious Agent Quality Control

All laboratories will participate in the European Union "Quality Control
for Molecular Diagnostics" (QCMD; *http://www.qcmd.org*) quality control
program for the TEDDY agents for which they will test, insofar as QC
panels are available through the QCMD program. Proficiency panel scores
and internal quality control data is provided to the TEDDY steering
committee.

Cross-contamination between biological samples is possible during
processing in clinical centers and at the repository. Highly infective
doses of some viruses in clinical samples may contaminate negative
samples which are processed at the same time or in the same batch. Risk
of cross-contamination will be monitored by processing and testing
selected water samples on a monthly basis. Sterile water will be placed
in ten aliquots (150 µl each) in the same location where clinical
samples are processed. The water samples will be sent to the repository
for testing along with the associated blood/stool samples. In addition,
the repository makes same kind of aliquots if processing stool samples
e.g. from shipped wipers.

Five aliquots of these water samples will be analyzed for the presence
of enterovirus and rotavirus by PCR every three months to monitor the
risk of cross-contaminations. The rest of the samples will be kept in
the freezer for possible later use in QC procedures. In case that a
contamination is observed, the sample processing chain will be checked
and additional water samples will be processed and analyzed to eliminate
the source of contamination.

To monitor the preservation of viruses in clinical samples during long
term storage in the repository, additional stool and plasma samples
known to be positive for infectious agents, such as enterovirus or
rotavirus, will be stored separately in aliquots at the repositories.
The titre of virus present in a given sample will be measured by
real-time PCR and infectivity titration immediately upon receipt, and
then once every three years to monitor possible changes in infectivity
during long-term cryostorage. Investigations suggest that viral survival
is greater at low temperatures than at ambient temperatures, and many
cryopreserved viruses have survived for decades at --70°C without the
need for special preservation.[^1] But it should be noted that data for
long-term viral survival are not widely available from other studies
with human samples and cryostorage preservation data should be very
useful in the ancillary studies and analyses of TEDDY samples. This is
particularly important for low viral titers.

# DATA MANAGEMENT

The Data Coordinating Center (DCC) for the TEDDY Study located at the
University of South Florida will have a key role in the operational
conduct of the study and for data analysis in accordance with the
policies set forth in the study protocol and the procedures specified in
the study Manual of Operations. The TEDDY Data Coordinating Center QC
function will have as its primary responsibility the surveillance of
data collection to assure adequate adherence to the protocol, the
processing and analysis of all data from the study, and the preparation
of interim technical and statistical reports for review by internal and
external study committees.

A comprehensive series of written and tabular technical and statistical
reports describing the progress of the study is prepared for review by
the QA/QC Committee and the TEDDY Steering Committee. Preparation of
these reports is a collaborative effort involving the Steering
Committee, its subcommittees, the Clinical Centers, Core Laboratories,
and the DCC. However, the DCC is the focal point for this activity
including, but not limited to, tabulation of data, and preparation and
distribution of drafts of study progress.

Additionally, the TEDDY DCC provides biostatistical and methodological
expertise and advice to the Steering Committee, Study Centers, and Core
Laboratories, in the consideration of revisions to the Protocol, Manual
of Operations and study forms and in development of procedures to
implement these revisions.

Specifically, the DCC is responsible for the following activities and
provide such other services that may reasonably be required by evolving
demands of the study:

1.  Study Wide Communications, Dissemination of Study Materials, and
    Related Activities including:

    a.  coordination of the drafting and dissemination of revisions of
        study forms or other study documents as necessary;

    b.  development of revised or new procedural aspects in cooperation
        with the TEDDY study group (e.g., quality control procedures,
        data collection/ transmission schedules and procedures), and
        development of procedures to implement these plans;

    c.  conducting training sessions as needed for clinical center
        personnel in methods of data collection and transmission to the
        TEDDY Data Coordinating Center;

    d.  responding promptly to telephone or written inquiries regarding
        the protocol or data management practices; Operations, or forms
        from study investigators, clinic personnel, etc.;

2.  Data Management and Records Maintenance including:

    a.  design and implementation of computerized systems for inventory,
        data storage, and retrieval;

    b.  maintenance of centralized files of study documents;

    c.  receipt and storage of all data transmitted by the participating
        clinical centers; Online, Internet-based methods to be the
        primary means for data transmission; centers, core labs, etc.;

    d.  protection against loss of materials by providing back-up of all
        electronic copies of study forms and other important documents,
        storing one copy outside the DCC, and archiving data tapes;

    e.  development, design, and pre testing of new or revised study
        forms;

    f.  identification of problems encountered in data collection and
        development of proposals for remedial changes in study
        procedures;

    g.  review and processing of all data transmitted online or on
        standard forms including prompt editing; for completeness,
        accuracy, consistency, out of range values, and overall quality;

    h.  preparation of periodic reports to participating sites on
        outstanding, incomplete, and delinquent data or other missing
        information; and prompt processing of corrections generated as
        responses to the above checks and edits;

    i.  transfer of information on paper forms to a machine readable
        format compatible with online data submission methods,
        development of a computerized data storage system for these
        data, and maintenance of this computerized data storage system
        in response to protocol changes as well as hardware and software
        changes;

    j.  maintenance and further development of hardware and software
        systems and related procedures for receiving, processing,
        editing, analyzing, and storing study data including a
        management information system and such other filing systems that
        can be used in meeting reporting requirements;

    k.  establishment and maintenance of systems for computer to
        computer transmission of data from the central laboratories,
        other central support units, and clinical centers where
        feasible.

3.  Clinical Center and Core Laboratory Monitoring including:

    a.  monitoring all clinical centers and core laboratories for
        adherence to the study protocol, etc.;

    b.  conducting periodic site visits as may be required;

    c.  implementing and maintaining requirements for standardization of
        observations, objective application of definitions, and other
        measures of quality control; identifying problems in adhering to
        the details of the protocol and helping to solve these problems
        promptly;

    d.  developing and implementing procedures to monitor specified
        parameters of clinical status of patients and to promptly notify
        clinics when therapeutic intervention is required according to
        the Protocol.

4.  Data Analyses consisting of written reports, tables and graphs,
    including but not limited to the following:

    a.  descriptive analyses of all patients eligible for participation,
        including individuals who declined to participate, dropouts,
        losses to follow-up, etc.;

    b.  examination of the data base to determine the types of analyses
        needed to provide relevant information to monitor operational
        aspects of the study and to assess adverse and/or beneficial
        treatment effects, etc.;

    c.  detailed analyses of accumulated data to monitor the progress of
        the study and to detect adverse and/or beneficial treatment
        effects;

    d.  preparation of a proposed schedule of analyses required for
        reporting study results or other reports of interest to the
        scientific community;

    e.  generation of other analyses relating to specific questions not
        now anticipated which may arise during the course of the study;

    f.  development of new or modified methods of analysis which meet
        the specific needs of the study; design of supplementary
        methodological studies required for the proper conduct and
        analysis of the main study.

    g.  preparation of periodic reports to participating sites on
        outstanding, incomplete, and delinquent data or other missing
        information; and prompt processing of corrections generated as
        responses to the above checks and edits.

The TEDDY Data Coordinating Center shall implement methods to evaluate
its management procedures and to assess the cost efficiency of various
procedures for data handling and analysis. The TEDDY Data Coordinating
Center staff shall also implement methods to evaluate the quality
control procedures used for various aspects of the study. The TEDDY Data
Coordinating Center staff shall provide quarterly reports to the QA/QC
Committee for review and reporting to individual Clinical Centers and
the TEDDY Study Steering Committee.

#   {#section .unnumbered}

#   {#section-1 .unnumbered}

# APPENDIX A: SITE VISIT AGENDAS {#appendix-a-site-visit-agendas .unnumbered}

## Clinical Center Site Visits {#clinical-center-site-visits .unnumbered}

The following are areas for quality control review of TEDDY Clinical
Centers. Quality reviews are targeted to be conducted on an annual
basis.

### Observation of HLA Screening Sample Collection

Will include items TBD in accordance with laboratory standards.

### Review of Recruitment

Measures to be evaluated include:

-   Goals

-   Changes to projections

-   Recruitment strategies and materials

-   Refusal records

### Review of Data Entry/Edits

Measures to be evaluated include:

-   Missing data

-   Errors

-   Data entry flow and timing from collection to entry

### Review of Logs

The review of logs will include:

-   Daily Freezer Temperature Log

-   Discarded ID Log

-   Participant and QC Selection Log/ Adequacy of QC Sampling

-   Data Editing Log

-   Other Clinical Center Logs (e.g., Staff IDs, Clinic IDs, etc)

### Storage of Forms

Form review includes:

-   Data Collection Forms from Clinics

-   Shipping Forms from Laboratories

-   Layered Portion of Informed Consent Forms from Clinics

-   IRB Approvals/Informed Consents

### Study Documents

Study documents to be reviewed include:

-   Manual of Operations

-   Protocol

### Miscellaneous

Site visits will also include evaluation of the following procedures and
items:

-   Communication with Laboratories

-   Communication with Coordinating Center

-   Reimbursement/ Invoicing

-   Adverse Events

# APPENDIX B: SITE VISIT CHECK SHEETS {#appendix-b-site-visit-check-sheets .unnumbered}

## BLOOD COLLECTION CHECK SHEET (UNDER REVIEW) {#blood-collection-check-sheet-under-review .unnumbered}

**CLINIC ID DATE \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ OBSERVER(S)
TECHNICIAN ID\_\_\_\_\_\_\_\_\_**

COMMENTS:

S = Satisfactory

U = Unsatisfactory

A. Equipment, environment 

1.  Isolated room, professional environment. 

2.  Equipment, forms, supplies adequate 

> (needles, vacutainers, bandaids, alcohol swabs, gauze, tourniquet, ice
> bath, ammonia, inhalants, butterfly needles, butterfly adapter,
> syringes)

B. Procedure 

1.  Label checked. 

2.  Participant prepared, procedure explained. 

3.  Bleeding disorders queried and recorded. 

4.  Needle, adapter, vacutainer prepared. 

5.  Tourniquet applied properly. 

6.  Vein palpated, cleansed, and dried. 

7.  Venipuncture technique. 

8.  Tubes filled in proper order and inverted. 

9.  Tourniquet released as soon as flow starts in last tube. 

10. Total tourniquet time within 2 minute limit. 

11. Vacutainers filled. 

12. Stasis obtained. 

13. Needle disposed properly. 

14. Tubes labeled properly. 

15. Form completed accurately. 

16. Other 

COMMENTS:

S = Satisfactory

U = Unsatisfactory

## BLOOD HANDLING, STORAGE, SHIPPING CHECK SHEET (UNDER REVIEW) {#blood-handling-storage-shipping-check-sheet-under-review .unnumbered}

CLINIC ID DATE\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ OBSERVER(S)
TECHNICIAN ID\_\_\_\_\_\_\_\_\_\_\_\_\_

COMMENTS:

S = Satisfactory

U = Unsatisfactory

A. Equipment

> 1\. Equipment, supplies adequate. 
>
> 2\. Equipment working correctly. 
>
> 3\. Daily record of refrigerator, freezer, and room temperatures
> up-to-date. 
>
> 4\. Biohazard labels available. 
>
> 5\. Other 

B. Procedure

1.  Tubes labeled accurately. 

2.  Tubes:

> Red top tube to rack at room temperature 30-60 minutes. 
>
> Purple top tube to ice water 30-60 minutes. 
>
> Green/yellow top tube(s) at room temperature until shipped (daily). 
>
> Centrifuge balanced. 

3.  Centrifuge operation. 

4.  Aliquot equipment ready, vials labeled/organized, biohazard labels
    available. 

5.  Proper specimen volumes in respective vials. 

6.  Vial filling priority observed. 

7.  Sealing of vials. 

8.  Sample purple top tube saved for shipment; purple top tube
    re-labeled, if needed 

9.  Completion of blood collection form. 

10. Freezer organization and storage. 

11. Time constraints seen in procedure (90 min max from drawing to
    freezing). 

12. Other 

C. Shipping

1.  Knowledge of shipping schedule for the laboratory. 

2.  Dry ice available. 

3.  Shipping supplies adequate (for daily ambient and monthly frozen
    shipments). 

4.  Specimens for labs packed properly (for daily ambient and monthly
    frozen shipments); adherence to IATA regulations. 

5.  Serum and plasma specimens remain frozen while being packed. 

6.  Shipping forms complete properly. 

> 7\. Other 

COMMENTS:

S = Satisfactory

U = Unsatisfactory

## INTERVIEWING CHECK SHEET {#interviewing-check-sheet .unnumbered}

CLINIC ID \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ DATE
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

OBSERVER(S) \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ INTERVIEWER ID
\_\_\_\_\_\_\_\_\_\_\_

RATING

Circle one:

1 = Yes (satisfactory) 2 = No (unsatisfactory)

Type of Interview:
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\
(*Recruitment, results notification, etc.*)

I. Communication Skills Maintained:

> A. Adequate eye contact with participant 1 2
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> B. Neutral attitude 1 2 \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> C. Non-judgmental voice tone and manner 1 2
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> D. Good rapport with participant 1 2 \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> E. Professional, confident, competent manner 1 2
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

II\. Interviewing Techniques

> A. Good pacing and tempo; maintained pace while allowing the
> participant time to\
> answer 1 2\_\_\_\_\_\_\_\_\_\_\_

B. Probes

> 1\. Appropriate use of repetition and neutral probes 1 2
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> 2\. Appropriate verification of responses 1 2
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

C. Phrasing and pronunciation

> 1\. Clear, easily understood phrasing of sentences 1 2
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> 2\. Proper pronunciation of medical terminology 1 2
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

III\. Interviewing Procedures

> A. Recorded responses correctly 1 2 \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> B. Made notations in margin as appropriate 1 2
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> C. Skip patterns followed correctly 1 2
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> D. Other interviewer instructions followed correctly:
>
> 1\. Interviewer instruction not read aloud 1 2
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> 2\. Response categories read correctly, where appropriate 1 2
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> 3\. Cue cards used appropriately 1 2 \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> 4\. When two alternate phrasings have been provided, the appropriate
> one is\
> chosen 1 **2 \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\
> **

IV\. COMMENTS:
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\
(*Use reverse side of page for additional comments if necessary*)\
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

[^1]: Gould EA. Methods for long-term virus preservation. Molecular
    Biotechnology, 1999;13(1): 57--66