EPA
United States
Environmental Protection
Agency
Health Effects Research
Laboratory
Research Triangle Park NC 27711
EPA-600 1-78-059
September 1978
Research and Development
Follow-up of
Patients Receiving
Diagnostic
Doses of
131 Iodine
During Childhood
3i^/l.I.t'
',s. n^i;-;;;. v '.\I._I>L~:+:CIIVS AGENCY
; /so-ii, K« J. C.-.....V
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RESEARCH REPORTING SERIES
Research reports of the Office of Research and Development, U.S. Environmental
Protection Agency, have been grouped into nine series. These nine broad cate-
gories were established to facilitate further development and application of en-
vironmental technology. Elimination of traditional grouping was consciously
planned to foster technology transfer and a maximum interface in related fields.
The nine series are:
1. Environmental Health Effects Research
2. Environmental Protection Technology
3. Ecological Research
4. Environmental Monitoring
5. Socioeconomic Environmental Studies
6. Scientific and Technical Assessment Reports (STAR)
7. Interagency Energy-Environment Research and Development
8. "Special" Reports
9. Miscellaneous Reports
This report has been assigned to the ENVIRONMENTAL HEALTH EFFECTS RE-
SEARCH series. This series describes projects and studies relating to the toler-
ances of man for unhealthful substances or conditions. This work is generally
assessed from a medical viewpoint, including physiological or psychological
studies. In addition to toxicology and other medical specialities, study areas in-
clude biomedical instrumentation and health research techniques utilizing ani-
mals but always with intended application to human health measures.
This document is available to the public through the National Technical Informa-
tion Service, Springfield, Virginia 22161.
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EPA-600/1-78-059
September 1978
FOLLOW-UP OF PATIENTS RECEIVING DIAGNOSTIC DOSES OF
131 IODINE DURING CHILDHOOD
by
Benjamin S. H. Harris, III
Martha L. Smith
Mildred I. Holt
Survey Operations Center
Statistical Sciences Group
Research Triangle Institute
P. 0. Box 12194
Research Triangle Park, North Carolina 27709
Contract Number 68-02-1213
Project Officer
William C. Nelson
Statistics and Data Management Office
Health Effects Research Laboratory
Research Triangle Park, North Carolina 27711
HEALTH EFFECTS RESEARCH LABORATORY
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
RESEARCH TRIANGLE PARK, NORTH CAROLINA 27711
:A
V
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DISCLAIMER
This report has been reviewed by the Health Effects Research Laboratory,
U.S. Environmental Protection Agency, and approved for publication. Approval
does not signify that the contents necessarily reflect the views and policies
of the U.S. Environmental Protection Agency, nor does mention of trade names
or commercial products constitute endorsement or recommendation for use.
ii
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FOREWORD
The many benefits of our modern, developing, industrial society are
accompanied by certain hazards. Careful assessment of the relative
risk of existing and new man-made environmental hazards is necessary
for the establishment of sound regulatory policy. These regulations
serve to enhance the quality of our environment in order to promote the
public health and welfare and the productive capacity of our Nation's
population.
The Health Effects Research Laboratory, Research Triangle Park,
conducts a coordinated environmental health research program in toxicology,
epidemiology, and clinical studies using human volunteer subjects.
These studies address problems in air pollution, non-ionizing
radiation, environmental carcinogenesis and the toxicology of pesticides
as well as other chemical pollutants. The Laboratory participates in
the development and revision of air quality criteria documents on
pollutants for which national ambient air quality standards exist or
are proposed, provides the data for registration of new pesticides or
proposed suspension of those already in use, conducts research on
hazardous and toxic materials, and is primarily responsible for providing
the health basis for non-ionizing radiation standards. Direct support
to the regulatory function of the Agency is provided in the form of
expert testimony and preparation of affidavits as well as expert advice
to the Administrator to assure the adequacy of health care and surveillance
of persons having suffered imminent and substantial endangerment of
their health.
This research effort was initiated with the intent of estimating the
dose response curve for the development of thyroid neoplasms in young adults
who received low diagnostic doses of Iodine 131 as children. This report
documents the data collection methodology and procedures of a follow-up
survey conducted of persons under 16 years old who received diagnostic
Iodine 131 for evaluation of thyroid function at nine clinical centers
prior to December 31, 1960.
F. G. Hueter, Ph. D.
Acting Director,
Health Effects Research Laboratory
iii
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ABSTRACT
This research effort was initiated with the overall objective of defin-
ing a dose-response curve for the development of thyroid neoplasms in young
adults who received low doses of Iodine 131 as children. In order to
accomplish this objective, a follow-up survey was conducted of persons under
the age of 16 years who received diagnostic I131 for evaluation of thyroid
function at nine participating clinical centers on or before December 31, 1960.
Certain medical, demographic, and dosimetric data were abstracted from the
records of participating clinical centers and physicians; information on
each eligible patient's health history and status was solicited from ap-
propriate respondents via mail questionnaires. Correspondence was conducted
under the letterhead of the appropriate participating clinical center.
Copies of death certificates were obtained for deceased patients.
Of 2,287 potential study subjects identified, some medical record was
reviewed and abstracted for 1,999 or some 87 percent. With study activities
incomplete, of 186 private physicians and other referral sources contacted for
supplemental data, only three or less than two percent declined to partici-
pate; of 1,362 patients who were determined eligible and entered the survey
phase, some final resolution (completed questionnaire, death certificate, or
refusal) was obtained for 1,065 or some 78 percent.
This report was submitted in fulfillment of Contract No. 68-02-1213 by
Research Triangle Institute under the sponsorship of the U. S. Environmental
Protection Agency. This report covers a period from June 8, 1973, to May 7,
1977. A related project is continuing under the sponsorship of the
U. S. Food and Drug Administration.
iv
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CONTENTS
DISCLAIMER ii
FOREWORD ill
ABSTRACT iv
FIGURES vii
TABLES ix
ACKNOWLEDGEMENTS x
SECTION 1 INTRODUCTION 1
1.1 BACKGROUND 1
1.2 OBJECTIVES 2
1.2.1 Overall Project Objectives 2
1.2.2 Research Triangle Institute (RTI) Objectives ... 2
1.2.3 Purpose of this Report 2
SECTION 2 METHODOLOGY 3
2.1 PERFORMANCE SITES . 3
2.2 DEFINITION OF STUDY GROUP 3
2.3 DATA COLLECTION 4
2.3.1 Contractual Requirements 4
2.3.2 Phase I: Enlistment of Performance Sites 5
2.3.3 Phase II 9
2.3.3.1 Hospital Data Collection 9
2.3.3.2 Referring Physicians and Facilities .... 11
2.3.4 Phase III: Survey Operations 12
2.4 DATA PROCESSING 22
2.5 REPORTS AND DATA SURRENDER 22
2.5.1 Reports 22
2.5.2 Data Surrender 22
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CONTENTS (Continued)
SECTION 3 PROJECT IMPLEMENTATION 25
3.1 INTRODUCTION 25
3.2 PILOT STUDY 25
3.3 PROBLEMS 25
3.3.1 Approval Delays 28
3.3.2 Record Systems 28
3.3.3 Respondent Reaction 29
SECTION 4 'RESULTS 30
4.1 GENERAL REMARKS 30
4.2 HOSPITAL DATA COLLECTION 30
4.3 SURVEY OPERATIONS 34
4.3.1 Referral Sources 34
4.3.2 Eligible Respondents . 37
SECTION 5 CONCLUSIONS ^ . . . . 48
REFERENCES 49
APPENDIX: TELEPHONE TRACING OPERATIONS 53
vi
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FIGURES
Number Page
1 Diagrammatic representation of implementation of the
study from contact through hospital data collection
(Phases I and II) 6
2 Diagrammatic representation of survey activities
(Phase III) 7
3 Hospital data form 8
4 Letter C, initial letter to referral sources .14
5 Letter C', revised initial letter to referral sources. 15
6 Reminder letter to referral sources 16
7 Letter A, initial letter to respondents for eligible
patients 17
8 Letter B, reminder letter to respondents for eligible
patients 18
9 Letter A', revised initial letter to eligible
respondents 19
10 Thyroid study questionnaire 20
11 Form used to monitor hospital data collection 23
12 Form used to monitor survey activities 24
13 Schedule of project timetable, activities, and
milestones 26
14 Cumulative project expenditures by month, June 1973 -
May 1977 27
15 Progress of study survey operations (in terms of
percentages of eligible respondents who returned a
completed questionnaire since the initiation of survey
operations at the site) at each of the participating
clinical centers, shown against the study performance
period 42
vii
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FIGURES (Continued)
Number
16 Progress of study survey operations (in terms of
percentages of eligible respondents who returned a
completed questionnaire since the initiation of survey
operations at the site) for each of the participating
clinical centers, plotted as though survey operations
were initiated simultaneously at all sites 44
A-l Telephone tracing control sheet 55
A-2 Unable to locate check sheet 56
viii
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TABLES
Number Page.
1 SUMMARY OF HOSPITAL DATA COLLECTION ACTIVITIES .... 31
2 SUMMARY OF HOSPITAL DATA COLLECTION RESULTS 33
3 SUMMARY OF HOSPITAL DATA COLLECTION: REASONS FOR
INELIGIBILITY 35
4 SUMMARY OF RESULTS OF CONTACTS WITH REFERRAL SOURCES . 36
5 SUMMARY OF PROJECT SURVEY OPERATIONS 39
6 SUMMARY OF MAIL SURVEY ACTIVITIES: CINCINNATI PILOT
STUDY 41
7 SUMMARY OF SURVEY ACTIVITIES: CINCINNATI PRIVATE
PATIENT STATUS AND RESPONSE RATE 46
8 SUMMARY OF TELEPHONE SURVEY ACTIVITIES: CINCINNATI . 46
9 SUMMARY OF SURVEY ACTIVITIES: ON-SITE TRACING,
CINCINNATI 47
ix
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ACKNOWLEDGEMENTS
Appreciation is hereby extended to the members of the staffs of the
various participating institutions who have contributed to the execution of
this research effort. Special appreciation is extended to Ms. Peggy M.
Hamilton, who served as Project Officer for the U. S. Environmental Protection
Agency (EPA) over the period 1973-1976, and the following Research Triangle
Institute (RTI) staff members: James D. Bates, Director of RTI's Survey
Operations Center (SOC) during the technical performance period of this
contract, whose advice and assistance as Project Supervisor were invaluable;
telephone operators Ellen M. Stuart, Cynthia A. James, and Jennifer J. Jones;
and the several secretaries and clerks who have typed and filed the project
correspondence and reports.
Particular appreciation is extended to the private physicians and inde-
pendent subcontractors at the various performance sites who have participated
in this research effort, and to the following representatives of the partici-
pating clinical centers whose cooperation and assistance were fundamental:
Dr. Eugene L. Saenger, Sylvia Noland, Margaret Shafer, Mary Louise Oberwitte,
Dorothy Woods, Lucille Longshore, and Karen Booth of the University of
Cincinnati Medical Center; Dr. Ralph G. Robinson, Herman A. Jones, Janet S.
Morrison, Betty Pitts, Delia Vaughn, Gloria Pyle, David Wells and Bill
Sanders of the University of Kansas Medical Center; Dr. Rodger W. Lambie,
Frank M. Comer, Ursula Charles, and George H. Yeckel of Menorah Medical
Center; Dr. Donald W. Brown, Stanley T. Urban, H. Wayne Sheller, Corinne
Shoener, and Manuel Jones of the University of Colorado Medical Center;
Dr. David C. Price, Daniel J. Pae, Miriam Blaustein, and Jerome M. Yalon of
the University of California Hospitals and Clinics at San Francisco; Dr.
Louis Hempelmann and Eugene Kowaluk of the University of Rochester School
of Medicine and Dentistry; Dr. Philip M. Johnson, Dr. Akira Morishima,
Dr. Edith H. Quimby, Dr. Joseph E. Snyder, Myra Enkeles, Wanda Krol, and
Doris Goddard of Columbia-Presbyterian Medical Center; Dr. Roger H. Seeker-
Walker, Jane Potter, Zatie Crawford, and Virginia Cesak of the St. Louis
University Medical Center complex; and Dr. and Mrs. Robert F, Skeels of the
Shelton Medical Clinic.
x
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SECTION 1
INTRODUCTION
1.1 BACKGROUND
Radioactive iodine 131 has been an important medical tool in the diagno-
sis of thyroid disease since the late 1940's. A series of experimental stud-
ies of animals exposed to I^l and other forms of radiation (1-7) , and epide-
miological studies of human populations exposed to x-irradiation during or
before adolescence in the course of treatment for benign head and neck
conditions (8-22), have demonstrated various levels of thyroid pathology;
Dr. L. H. Hempelmann proposed a linear dose-response relationship based on
some of these studies (13,23). There have been few studies which have
specifically investigated the effects on human thyroid tissue of 1-^1, and
those have involved persons exposed to 1^31 as a result of nuclear explosions
in Japan, the south Pacific, and the southwestern United States (24-28), and
persons with diseased glands (29-35). At least one study (35) of the effects
of I1^! on the thyroid gland observed that there -Is a relatively higher risk
of developing malignant and benign neoplasms in patients treated with j^32
below the age of 20 than in older age groups (36). Based upon this scattered
and inconclusive information, it would appear that a specific study of the
long-term effects of exposure to low levels of I^l SUch as those utilized
in diagnostic procedures would be worthwhile.
The radiosensitivity of the growing thyroid of children is of special
interest because of the potential exposure of large segments of the popula-
tion to radioactive iodine and other radionuclides dispersed into the
environment from the potential malfunction of nuclear power plants and fall-
out from nuclear testing. Children who received diagnostic doses of I-^l
comprise a unique human population, one of the few irradiated human popu-
lations available for study that could provide insight into the problems of
evaluating established national environmental and emission standards for
radioactive materials, specifically radioactive iodine. The large range of
doses involved and the long latent periods which have elapsed provide an
opportunity to establish the shape of a dose-response curve for the devel-
opment of thyroid neoplasms in young adults exposed to I^l radiation as
children and thereby enable the determination or description of the rele-
vant sectors of the dose-response curve for this radioactive substance. In
view of the current unrest over the levels of safety represented by the
legally acceptable limits for exposure of the population at large, and the
importance of the practical decisions affecting the availability of nuclear
power, study of this population can provide one basis for evaluating estab-
lished national environmental and emission standards for radioactivity.
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1.2 OBJECTIVES
1.2.1 Overall Project Objectives
The purpose of this research effort was to conduct a follow-back study
of persons who received diagnostic doses of I-"I during childhood in
an effort to define a dose-response curve for the development of thyroid
neoplasms in young adults following I-^l exposure. It was anticipated that
this effort would result in the identification of a relevant sector of the
dose-response curve and aid in the establishment of the long range effects
of exposure to 1^31.
1.2.2 Research Triangle Institute (RTI) Objectives
The purpose of RTl's involvement in this research effort was to collect
health history information on persons who received I"l prior to 1961 in a
form that would enable the sponsor, the Health Effects Research Laboratory
(HERL) of the U. S. Environmental Protection Agency (EPA), to define the
aforementioned dose-response curve. RTl's role in this research effort was
to furnish the necessary personnel, materials, services, equipment, and
facilities, except as specified, and otherwise do all things necessary for,
or incident to, the collection of data for the study from and through
participating clinical centers. RTI was to collect necessary study data,
act as a central agency for the collection of the data, and be sure that
data were comparable within and between clinical centers and collected
according to protocol. RTI was to abstract pertinent and necessary medical
and demographic information from the records of participating clinical
centers and physicians; solicit information on each eligible patient's
health history from appropriate respondents primarily via mail questionnaires;
and submit data to the Project Officer or his designee as collected.
1.2.3 Purpose of this Report
This report is the final report on RTI project activities conducted
under Contract Number 68-02-1213 over the period 8 June 1973 - 7 May 1977.
However, an RTI contract with the Bureau'of Radiological Health (BRH) of the
Food and Drug Administration (FDA) is continuing and expanding the study.
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SECTION 2
METHODOLOGY
2.1 PERFORMANCE SITES
1 "^1
The study was to involve some 3,000 patients who received IJ-->J- for
diagnostic purposes over the period 1946 through 1960. The clinical centers
and sites involved in this research effort were specified by EPA and were
as follow:
Cincinnati General Hospital (CGH) , Cincinnati, Ohio;
University of Kansas Medical Center (KUMC) , Kansas City, Kansas;
University of Colorado Medical Center (UCMC) , Denver, Colorado;
University of California Hospitals and Clinics at San Francisco,
California (UCSF) ;
Menorah Medical Center (MMC) , Kansas City, Missouri;
Strong Memorial Hospital (SMH) , Rochester, New York;
Shelton Medical Clinic (SMC), Los Angeles, California;
Saint Louis University Medical Center (SLU) , St. Louis, Missouri; and
Columbia-Presbyterian Medical Center (CPMC) , New York, New York.
2.2 DEFINITION OF STUDY GROUP
Lists of patients identified as have received I"! for diagnostic
purposes at the various clinical centers during the study period, with
appropriate identifying information, were to have been provided RTI by EPA
(37). The persons under study were selected from those patients identified,
based upon the following study criteria:
1. Received I for the first time before January 1, 1961;
2. Were less than 16 years of age at the time of first
administration of 1^1;
3. Did not have a diagnosed thyroid lesion (malignant or benign) at
the time of the diagnostic test;
4. Had not received goitrogen therapy or radioactive iodine for
hyper thyroid ism; and
5. Were not diagnosed as being hyperthyroid or athyrotic at the
time of the test.
The objective was to obtain a study population who received diagnostic
j!31 before age 16 and prior to 1961, and who were free of thyroid lesions
and not hyperthyroid or athyrotic. Restricting this study to those persons
who received radioactive iodine prior to 1961 provided a sufficiently long
3
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latent period for the development of thyroid lesions, and by relating the
dose level received, a dose-response curve could theoretically be deter-
mined. These data will also allow the evaluation of the Relative Biological
Effectiveness (RBE) of l!31.
The study was designed originally to test Hempelmann's hypothesis that
the dose-response for radiation-induced benign tumors is 38-52/rad/10°/yr
for 25 years (23); therefore, there was considered to be no specific need
for a control group. Dr. Hempelmann has established that the normal
prevalence of palpable thyroid lesions in a group of young adults (average
age 22.5 years} is one percent at a maximum (23).
2.3 DATA COLLECTION
2.3.1 Contractual Requirements
Exhibit A - Scope of Work of Contract No. 68-02-1213 (37) specified
the following data collection requirements of the contractor (RTI):
The contractor shall collect data for a study designed to define a
dose-response curve for the development of thyroid neoplasms in young
adults who were given diagnostic doses of 131l as children. The contractor
shall abstract information from the records of physicians and medical centers
and shall obtain questionnaires soliciting information in patients ' illnesses
history.
In collecting the data required, the Contractor shall use the
procedures indicated and such other procedures as necessary:
1. The Contractor shall contact the medical centers to make
arrangements for the collection of data from the hospital-
records and contacting patients through the hospital. Items
of consideration being:
(a) procedures for handling hospital records
(b) utilization of hospital and contractor personnel
(c) method and amount of payment for services
2. The contractor shall provide for a review of medical records
of each person on the list to determine his eligibility for
inclusion in the study, following protocol guidelines.
S. For accepted patients:
(a) Abstract data from medical records including:
Birthdate, sex, race, date of exposure to (and dose '
of) Diagnostic 131-I administered, uptake, size of gland,
reason for test, final diagnosis, and name and address
of parent or guardian and/or other location information.
(b) Mail cover letter and questionnaire to each parent or
guardian on letterhead of the medical center involved.
4. For rejected patients, the reason for rejection shall be shown.
5. The Contractor shall make every effort to locate all patients
accepted for the study. This may require more than one mailing
and the use of other follow-up and location procedures.
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6. Death Certificates or the data therefrom shall be obtained where
the patient is deceased.
7. The Contractor will turn all data over to the Human Studies
Laboratory3 Environmental Protection Agency, Research Triangle
Park; North Carolina as it is collected.
Based upon the above listed contractual requirements and other guide-
lines provided by EPA (23), RTI developed the procedures presented in
following sections for implementation of the study under contract to EPA.
Figures 1 and 2 are flow charts which present the procedural steps
graphically. At each performance site, the study has been implemented in
three basic phases, Phase I consisting of initial contact and arrangements
for cooperation and participation; Phase II consisting of the Hospital Data
Collection (HDC) - that is, medical record abstraction; and Phase III con-
sisting of survey operations. Figure 1 presents the implementation of the
study from initiation through HDC (Phases I and II), while figure 2 presents
survey and follow-up procedures (Phase III).
2.3.2 Phase I; Enlistment of Performance Sites
Although the contract stated that the contractor shall contact the
medical centers to make arrangements for the collection of data from the
hospital records and contacting patients through the hospital (37), the
EPA Project Officer actually made initial contact with each clinical center,
as shown in figure 1, in order to review the overall project plan with
appropriate clinical center representative(s) and obtain preliminary or
tentative permission to work through the clinical center during the study
and use clinical center records. The EPA representative then designated
particular appropriate clinical center representative(s) as contacts for the
RTI data collection staff. Following this preliminary EPA contact, the RTI
Project Leader visited the proposed performance site to review the detailed
study protocol and procedures with appropriate clinical center representatives
and make any necessary modifications according to the particular procedures
of the clinical center/performance site.
Once the site representative(s) agreed to cooperate and participate in
the study, arrangements were made to obtain,the review medical records;
obtain clinical center letterhead stationery and envelopes; arrange for the
signature of the appropriate and responsible clinical center representative
to affix to study correspondence for the site; make arrangements for mail
pickup and delivery; agree on reimbursement for clinical center costs
incurred in involvement in the study; and enlist an on-site representative
to reduce the necessity and expense of RTI staff travel where possible.
Originally RTI intended to use a Post Office Box to handle all project
mail; however, due to the unavailability of Post Office boxes, as well as
the possibility of confusion engendered by a Post Office address different
from the letterhead address^it was decided that the participating clinical
centers would serve as the mail repository where volume permitted; at those
sites, project mail was coded in the return address with specific identifying
letters to facilitate recognition and sorting of project mail from other mail
received at or returned to the site.
5
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Figure
Diagrammatic representation of implementation of the
study from contact through hospital data collection
(Phases I and II).
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Figure 2. Diagrammatic representation of survey activities (Phase III)
7
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Originally, it was also planned that the site would open project mail
and copy completed questionnaires for their files; however, in order to reduce
the number of people handling project mail, and the amount of project work
required of clinical center staff, project mail was returned to RTI where
copies were made and provided the site, along with copies of related
correspondence and appropriate identifying information. Some level of on-site
assistance was enlisted at all sites.
2.3.3 Phase II
2.3.3.1 Hospital Data Collection
At each performance site, the medical records staff were requested to
provide the medical records for the patients on the lists of individuals to
be studied, in accordance with the various clinical center regulations.
Staff of the various clinical centers' medical records departments physically
performed the record search and retrieval.
Once the medical records were pulled by clinical center staff, they were
reviewed by the RTI Project Leader in order to obtain and verify certain
necessary medical and demographic information determining the eligibility of
each patient according to previously outlined guidelines (see section 2.2).
Each patient for whom a clinical center record was located or a private
physician record anticipated was assigned a two-part, seven-digit study number:
the first four digits designated the clinical center and were unique for the
clinical center, having been assigned by EPA; the last three digits designated
a patient within the clinical center and were assigned by RTI consecutively
from 001 up. Patients were identified by the'study number entered on the
Hospital Data Form (HDF); this form, which was designed, prepared, and
supplied by EPA, is reproduced as figure 3. Even though space was proveded on
the HDF, the patient's name did not appear on that form, which was submitted
to EPA, for reasons of confidentiality.
The records of each person whose name was provided were reviewed to
determine the patient's eligibility for inclusion in the survey phase of the
study. For inclusion in the survey phase, patients had to meet each of the
criteria cited in section 2.2. Every name provided RTI was to be either
accepted for the survey phase of the study (meets all of the criteria), or
rejected (failure to meet one or more of the criteria), and the reason(s)
for rejection noted on the HDF prepared for each patient. At the outset of
the project, the plan was to hold in abeyance patients in the study population
whom EPA indicated as having a final diagnosis of hyperthyroidism, thyroiditis
and/or thyroid neoplasia, and some of those who did not have clinical center
record numbers. However, in view of the limited number of total patients
in this study, the EPA Project Officer and the RTI Project Leader decided to
include in the study some of those patients held in abeyance in the event that
a record might be located or that the diagnosis recorded on the EPA. card might
be incorrect.
For those individuals meeting the requirements for inclusion in the study
survey sample, pertinent medical data necessary to define the dose-response
curve, as well as information pertaining to the location of the patient's
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family or guardian, was abstracted from medical records (see figure 1) .
The pertinent demographic and medical data entered on the HDF (figure 3)
included the following information:
(1) Birthdate,
(2) Sex,
(3) Race,
(4) Date(s) of administration of diagnostic I ,
(5) Dose(s) of diagnostic I administered (in microcuries) ,
(6) Uptake with time (24 hour if available) ,
(7) Estimated size of gland,
(8) Pre-test diagnosis (or reason for referral) , and
(9) Final diagnosis.
Pieces of data were found to be missing from the medical records and/or
radioisotope (RAI) laboratory files of patients whose records were reviewed
during the Pilot Study at CGH; this matter was discussed with the Project
Officer with the decision that RTI was to proceed with the best available
data, using information from the EPA cards -if other bits of information from
the EPA cards could be verified from available records.
Information collected/abstracted pertaining to the location of the
patient's family or guardian included the following:
(1) Patient's name and names of parents, spouse, and any
other relatives or friends provided in the medical records;
(2) The most recent and any other addresses provided for
the above individuals;
(3) Information on the employment, education, and/or institution-
alization of the above individuals; and
(4) Any other pertinent information available, such as Social
Security numbers and indicated interest/ involvement of social
service agencies, physicians, and other medical care
institutions.
Where possible, all information was dated in order to make it most relevant.
Locator information was entered on a separate 5 by 8 inch index card, along
with the patient's study number and birthdate; these cards were retained at
RTI for tracing purposes.
The EPA Project Officer and the RTI Project Leader agreed that a death
certificate or the information therefrom was adequate without soliciting
interim medical history from the parents or guardian of the patient, provided
the patient died within three years of receiving the isotope for the first
time. Furthermore, with regard to patients who had expired, it was decided
in discussion with the Project Officer that a copy of the death certificate
would not be sought if a copy of the death certificate was available for
review in the patient's medical record; in many of these cases, an autopsy
was also performed at the clinical center, so that a detailed pathology
report, in many cases including a report of microscopic examination of the
thyroid gland, was available. In actual practice, however, a death certifi-
cate copy was requested in most instances.
10
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The components of the various participating clinical centers involved
in this phase of the study were primarily the RAI Laboratories or Nuclear
Medicine Departments and the Medical Records Departments. Several of the
sites had maintained files of old RAI reports separate from the medical
records, but the medical record was the most complete and consistent source
of the medical and demographic data necessary for the execution of this
study. Old l!31 uptake reports provided valuable information on patients
with no other clinical center records and/or data missing from other medical
records.
Part of the necessary study information was abstracted from medical
records and part from the questionnaire sent to the appropriate respondent,
usually the parent. The date(s) of administration of I13^-, the dose(s) of
1131 administered and the percent uptake and time were usually available
from the RAI report, although one or more of these elements may have been
missing from the RAI report and was sought in the doctor's orders, nurses'
notes, progress notes, discharge summary, or a subsequent letter to a
referring physician (RMD). The birthdate, sex, and race appeared at any one
of several points in the medical records, such as the admission sheet or
various physicians' workups, The estimated size of the thyroid gland and
the reason for the test, or pre-test diagnosis, occasionally appeared as
part of the RAI report but more likely came from the physical examination
and impression of the attending physician's workup on admission or preceding
clinic visit. The best sources for the final diagnosis were the diagnosis
sheet at the front of the medical record, where one was available, the
discharge summary, diagnosis on a subsequent clinic visit, or again a letter
to an RMD. Location information occurred throughout the medical record,
including the admission sheet, insurance forms, and correspondence; social
service workups were particularly helpful where they were available.
The majority of medical record abstraction for this study was performed
by the RTI Project Leader.
2.3.3.2 Referring Physicians and Facilities
At each performance site, the medical records of some patients recorded
as having received diagnostic 1-^-31 at the clinical center were inadequate
for the purposes of the study. Where medical and/or demographic data from
the medical records were inadequate for the purposes of the study, but the
name of the RMD was provided in available records, every attempt was made
to locate that RMD. Sources consulted included the Directory of Medical
Specialists (38) , the Alphabetical Physician Reference listing (39) , telephone
directories and directory assistance for the last known address, local medical
societies, and state licensing agencies, Cooperation was excellent. RTI
originally intended not to contact RMD's outside of the respective
metropolitan areas, but subsequently decided to do so in the event that the
patient's office records might still be in the respective metropolitan
area, or the RMD might be able to provide the necessary information by mail
or telephone.
For all performance sites except SMC, where contact with referring
physicians was not necessary, and CPMC Csee below), a letter (called letter
11
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C in figure 1) such as that shown in figure 4 was sent to the appropriate
EMD or other referral facility, explaining the project and requesting per-
mission for the RTI Project Leader to review the patient's office records
in an effort to obtain necessary medical and/or demographic data on the
patient. Where private physicians or other referral facilities agreed to
participate in the study and provide access to patient records, arrange-
ments were made to access necessary medical, demographic and locator
information. Due to the large number of RMDs for CPMC with only one patient
each dispersed over four states (CT, NJ, NY and PA), RTI is attempting to
obtain missing data via mail using a modification of the letter presented
in figure 4. This modification is presented in figure 5.
Discussions between RTI and EPA technical representatives determined
that potential study patients for whom no medical record or RAI file could
be located, and study patients who were apparently eligible but for whom no
final diagnosis or RMD was forthcoming from the HDC, would be held apart
from the study. However, where a patient had no medical record or RAI file,
but the RMD was indicated on the EPA card, the RMD was contacted regarding
patient data.
The review of medical records of study patients in private physicians'
offices was a most profitable procedure from a data standpoint, although
communications with RMDs and other referral sources presented some problems.
At three sites where the participating clinical center served as a referral
center for laboratory services for other primary medical care facilities in
the community, arrangements were made for RTI staff to access patient
records at the other institution(s). In many instances only the RMD's last
name was recorded in a patient's medical records requiring that several
physicians with the same last name be written or called regarding the same
patient(s) , after eliminating unlikely (due to age, etc.) prospects by
referring to physician directories (38,39).
RTI did not anticipate nonresponse from referral sources. Therefore,
EPA and RTI technical representatives decided to pursue referring physicians/
facilities who did not respond to initial correspondence (letter C) with
reminder letters, such as that reproduced as figure 6, or by telephone.
2.3.4 Phase III; Survey Operations
In most instances, the review of the medical records provided a last
known mailing address for the appropriate respondent for each patient accepted
into the survey phase of the study; this address was underscored on the
locator card. As indicated previously, RTI obtained clinical center letter-
head stationery for use in preparing project correspondence.
There were two basic letters mailed to eligible respondents on clinical
center letterhead stationery over the signature of the appropriate clinical
center representative. The first letter, letter A, an example of which is
reproduced as figure 7, was the initial cover letter included with the
questionnaire and sent to all eligible respondents; the second letter, letter
B, an example of which is reproduced as figure 8, was sent to all eligible
respondents whose questionnaires or initial correspondence was not returned
12
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within a reasonable period following the first mailing. In actual practice,
two letter A's were employed during the course of the study. The letter
shown in figure 7 was used predominantly for the first four participating
clinical centers (CGH, UCMC, UCSF, and KUMC); this letter was expanded to the
form shown in figure 9 for the remaining sites (see section 3.3.3). Various
participating clinical centers made minor wording changes; in addition,
transmittal and reminder letters were modified as appropriate for various
respondents that is, whether the respondent was the patient, a parent, a
sibling, a guardian, etc. All study correspondence was prepared for mailing
on automatic word-processing equipment at RTI by members of the RTI staff.
The questionnaire, reproduced as figure 10, was designed, prepared and
supplied by EPA.
Letter A was addressed to the last known address of the patient's parent
or other responsible guardian, then returned to the appropriate clinical
center to be signed by the appropriate representative and mailed from the
site, or the signature affixed at RTI and then returned to the site for
mailing, the envelopes having been previously stamped at RTI (see figure 2).
A questionnaire and letter A were mailed from the site to the last address
known for each eligible respondent. There were three basic possible results
to this initial mailing: questionnaires completed and returned; unopened
packets returned by the U.S. Postal Service as not deliverable; and packets
not returned at all (see figure 2). Letters to RMDs were handled in virtu-
ally the same manner.
The basic purpose of letter A was to request that the respondent(s)
complete the questionnaire (figure 10), thereby providing a brief medical
history for the patient. At the end of the questionnaire, a release state-
ment to be signed by the appropriate person authorized further examination
of medical records of the named patient, if required (see figure 10). This
authorization applied to EPA personnel and did not imply that RTI staff are/
were responsible for examining medical records other than as required in the
initial determination of eligibility for the survey phase of the study and
the collection of basic demographic, medical, and locator data at that time.
In actual practice, however, RTI has written where authorized to physicians,
clinics, hospitals and laboratories to complete or verify information
provided by respondents regarding hospitalizations, thyroid function tests,
and thyroid medication, and to obtain pathology reports for throat, neck, or
thyroid surgery.
Each mailout packet included a postage-paid preaddressed return envelope
for returning the completed questionnaire. RTI made arrangements for the
collection of project mail at each performance site and its return to RTI for
sorting, recording, and appropriate action. RTI staff visited the perfor-
mance sites as appropriate during the course of the study.
Once a completed questionnaire was returned, the original was submitted
to EPA along with the corresponding HDF, and a copy returned to the site for
the patient's records at the clinical center. In the event of a death, a
copy of the death certificate was requested from the appropriate state or
local office and dispensed in the same manner.
13
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Dear Dr. :
This hospital ia presently involved in a study to determine if people
suspected of thyroid disease in early life do or do not develop thyroid
disease or other illnesses in later years. In reviewing our files and
medical records, we have encountered the name of one of your private patients
who was referred to this hospital for diagnostic procedures, but for whom
there is no medical record maintained at this hospital, the name of that
patient is given below:
(Patient's name)
We are writing at this time to request permission for Mr. Benjamin S. H.
Harris, III, a representative of the Research Triangle Institute in Research
Triangle Park, North Carolina, who is working with this hospital and the
Environmental Protection Agency, under whose auspices this research effort is
being undertaken, to visit your offices and review the medical record of
the patient listed above in order to ascertain his eligibility for inclusion
in the study sample and, if eligible, to abstract certain basic medical and
demographic information in order to solicit information from the parents of
this patient regarding the patient's medical history and current health
status. For your information, a copy of the protocol and procedures for
implementing the study is enclosed.
We would greatly appreciate your cooperation in this research effort.
Yours very truly,
Figure 4. Letter C, initial letter to referral sources,
14
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Dear Dr. :
This hospital is presently involved in a national study to determine
if people suspected of thyroid disease in early life do or do not develop
thyroid disease or other illnesses in later years. In reviewing our files
and medical records, we have encountered the names of several private
patients who were referred to this hospital for diagnostic procedures, but
for whom medical records are inadequate for purposes of the study. Further-
more, in several instances, we only have the referring physician's last name
We are writing at this time to inquire as to whether or not one or more of
the patients in question were referred by you, and, if so, to request certain
information necessary for our research effort but missing from the medical
records and radioisotope laboratory files here.
In reviewing our files and medical records, we encountered the name of
one (Patmt a none), who was referred by you to this hospital for care in
(year), at which time he received radioactive iodine for suspected thyroid
disease. However, there is no definitive final diagnosis recorded relative
to the (year) uptake test. Do you by any chance have any information in
your records on (Patient's name} regarding a definitive final diagnosis
relative to a (year) uptake test? A stamped, self-addressed return envelope
is enclosed for your convenience. Please address your response to that
address.
We would greatly appreciate any information which you could provide
on this matter.
Yours very truly,
Figure 5. Letter Cf, revised initial letter to referral sources,
15
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Dear Dr. :
You may recall that this hospital recently asked foe your participation
and assistance in a study to determine if people suspected of thyroid disease
in early life do or do not develop thyroid disease or other illnesses in
later years. In a previous letter, a copy of which is attached, we re-
quested permission for Mr. Benjamin S. H. Harris, III, a representative
of the Research Triangle Institute in Research Triangle Park, North Carolina,
who is working with this hospital and the Environmental Protection Agency,
under whose auspices this research effort is being undertaken, to visit -
your offices and review the records of certain of your private patients
who were referred to this hospital for diagnostic procedures, but for whom
there is no medical record maintained at this hospital. The purpose of
Mr. Harris' visit would be to ascertain the eligibility of your patient(s)
for inclusion in our study sample, and, if eligible, to abstract certain
basic medical and demographic information in order to solicit information
from the parents of the patient(s) regarding the patient's medical history
and current health status. For your information, a copy of the protocol
and procedures for implementing the study was enclosed.
As of this date, we have received no reply from you. As our study
sample is somewhat circumscribed, each response and Information on each
patient in the study sample is of considerable importance to us. Your
participation and cooperation in this research effort would be greatly
appreciated.
Thank you for your consideration. We look forward to hearing from
you in the very near future.
Yours very truly,
Figure 6. Reminder letter to referral sources.
16
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Dear :
In (year), your child, (Patient's name), was given a test in this
hospital for suspected thyroid disease. This hospital is presently involved
in a study to determine if people suspected of thyroid disease in early
life do or do not develop more illnesses or develop thyroid disease in
later years. In order to make this determination, it is important that we
receive information concerning your child.
Please answer the questions on the enclosed questionnaire and return
it in the self-addressed envelope. Give the best information you can, even
though you may not know the exact answers to some of the questions. All
answers will be held in strict confidence and all information will be used
only for statistical purposes. Your participation in this research effort
is, of course, voluntary, but your cooperation would be greatly appreciated.
Yours very truly,
Figure 7. Letter A, initial letter to respondents for eligible patients.
17
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Dear :
You may recall that this hospital recently asked for your participation
in a national-study to determine if people suspected of thyroid disease in
early life do or do not develop more illnesses or develop thyroid disease
in later years. We requested that you complete a brief questionnaire re-
garding the health of (Patient's name) for this purpose. As of this date,
your reply has not been received.
The questionnaire was mailed only to a select group of people; since
you are one of the select few and your response is of importance to us,
we are taking the liberty of mailing you another copy of the questionnaire.
Won't you please take a few minutes to answer the questions and return the
completed questionnaire to us? Again, we want to assure you that your re-
ply will be held in strictest confidence and used for research purposes
only.
If you have mailed the completed questionnaire to us during the last
few days, please disregard this reminder. However, if more than a few
days have elapsed since you returned the questionnaire, we would greatly
appreciate your completing this additional questionnaire, as your response
has apparently been lost in the mail.
Thank you for your cooperation.
Sincerely,
Figure 8. Letter B, reminder letter to respondents for eligible patients.
18
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Dear :
In (^ear), your child, (Patient's ^jcme), was given a test in this hospi-
tal that is often given to detect conditions that might be due to thyroid
malfunctions. This test is relatively routine for a number of conditions,
and was probably one of many tests your child received at the time. The
fact that your child had a "thyroid test" at some time does not mean your
child has thyroid disease.
We are presently involved in a study to determine if people suspected
of thyroid-related illnesses in early life do or do not develop more ill-
nesses or develop thyroid disease in later years. As part of this study
we are reviewing the records of all young people who had a thyroid test in
this Center, whether or not the gland was found to be normal at the time
of the test. In order to make our determinations in this study it is
important that we receive information concerning your child.
Please answer the questions on the enclosed questionnaire and return
it in the self-addressed envelope. Give the best information you can, even
though you may not know the exact answers to some of the questions. All
answers will be held in strict confidence and all information will be used
only for statistical purposes.
Due to the passage to time, some of the patients in our study are
adults or have passed away. If your child is of age, you might wish to have
him or her complete the questionnaire and/or sign the authorization. If
your child resides at a different address we will gladly forward the
questionnaire if you will provide us with the correct address. In the
event that your child has passed away, we would greatly appreciate your
completing the questionnaire covering the time up to passing and indicate
date and place of death on the questionnaire.
Your participation in this research effort is voluntary, but your
cooperation would be greatly appreciated.
If you have any questions or problems with the study or questionnaire,
please note such on the back of this letter or questionnaire and return in
the enclosed self-addressed envelope. Each inquiry will be handled promptly
and on an individual basis.
Thank you for your cooperation.
Yours very truly,
Figure 9. Letter A', revised initial letter to eligible respondents
19
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THYROID STUDY QUESTIONNAIRE
Stud-/ ,Vo Sirthdate
O»M i'MOvtO
OMi «U1 S7300«
iComplatt of correc; Sirtnaats
if in error.)
1. What do you consider tie currant status of the nealth of this child? P'ease ;heck one.
~ Good ~ Fair ' Poor
If you do not consider this person m good health, state briefly his or her health problem
2. Has this ctiild had any illnesses o'her than the usual childhood diseases' If yes. list illnesses
and year of onset of that illness.
Illness, year of onset Illness, year of onset
3. Has this child been hospitalized since he or she was tested in this center7 If yes. hst placs.
time and reason for nospitaiization.
Hospital name City, state Year of nospitahzation fleascn for nospitaiira:.on
4. Has this person been tested for tnyroid disease since he or she was seen in th°s cantsT"7 If ^as. lis
place and time of test.
Place of test Year of test
5. Is this person presently on or has he or she ever seen on th>roid medication7 If ves. pisase stats
kind of medication
Cosage__ Date of medication 'ram to
i year/ '/ear:
Thank you very much for this information. Ycur cooperation m this effort is greatly needea anc ascrec:atsd.
If you have answered yes to questions 3 and 4 please sign the autnoniaticn beio.v
AUTHORIZATION
For purposes of this madical survey. I ajthcriTe the personnel conducting this survey to examine ;he ,-nsdicai
records of my child in Soth private pn/sic;ar.s afficas and in rospitais if necessary.
Signature:
Addrosa:
Figure 10. Thyroid study questionnaire.
20
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It was anticipated that the addresses of respondents obtained from
medical records may not have been updated for several years and therefore
a number of the initial (and even subsequent) mailouts (letters and question-
naires) would be returned to the site by the Postal Service as not deliver-
able, indicating incorrect addresses, addresses unknown, moved-not forward-
able, etc. Any packets thus returned unopened were returned to RTI where
tracing procedures were utilized in order to locate respondents (see figure
2). RTI attempted to contact the patient, relatives, employers, schools,
etc., and employ such resources as telephone and city directories, service
agencies, marriage and voter registration, drivers license files, and other
sources in order to locate potential respondents. The order in which these
sources were utilized varied from individual to individual, depending in
part on what and how much information was available in/from the medical
records. Once a respondent was located, the questionnaire and letter A were
sent to the correct address. Telephone tracing operations guidelines
developed by RTI staff and utilized in the tracing operations are presented
in an appendix. Every effort 'has been made to locate and obtain a response
for eaah eligible patient.
For those respondents to whom the initial letter and questionnaire were
assumed to have been delivered (not returned by the Postal Service), but from
whom no response was received within a reasonable time after mailing, usually
about four weeks, letter B (figure 8) was mailed on clinical center letter-
head stationery again signed by the appropriate clinical center representa-
tive. Letter B was intended to urge the respondent to complete the question-
naire and return it to the site as soon as possible. Following this second
mailing, expected responses were similar to those encountered after the first
mailing; again following a reasonable period of time, usually about four weeks,
nonrespondents were contacted by RTI by telephone, or personal visit if
necessary, in order to resolve the case. The respondent was given the option
to provide the information over the telephone if absolutely necessary.
Similarly, when questionnaires were returned incomplete, every effort was
made to complete these by telephone. Again, in the event of a patient's
death, an attempt was made to obtain a copy of the death certificate from
the appropriate office; these have been submitted as appropriate to EPA.
In many cases, multiple mailings for the same patient were required,
because respondents lived out of the study area(s) and/or without telephone
service or by going through the following process:
21
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Letter An
i 1
No Response -Letter B,
I
Returned by Postal Service Tracing
Location --Letter A0
I 2
No Response -Letter B,
I '
No Response
i
New Address- Prompting
No Response Letter A~
Letter B-
2.4 DATA PROCESSING
All data processing for this research effort was handled manually util-
izing the two log sheet forms reproduced as figures 11 and 12. As study
numbers were assigned, the patient was listed by name on the short form
(figure 11) along with an indication as to whether the patient had an RAI
file and/or a clinical center record, an HDF was completed, and the patient
was eligible or ineligible for the survey phase; the clinical center medical
record number, if one existed; and reasons for ineligibility or other
pertinent remarks. A study number was assigned when an RAI file or a clinical
center medical record was located, or when a letter was sent to an RMD. The
long form (figure 12) recorded the various survey steps and the date and
result of each step by study number. In essence, the short form summarized
HDC (Phase II) , while the long form monitored survey operations (Phase III) .
2.5 REPORTS AND DATA SURRENDER
2.5.1. Reports
Technical Progress Reports outlining, and in many cases detailing, pro-
ject progress, problems, and plans were submitted to the EPA Project Officer
by RTI on a monthly basis from July 1973 through May 1977; copies were also
provided to participating clinical centers. A detailed report of study
activities at/ through the CGH pilot site through January 31, 1975 was pro-
vided the EPA Project Officer on March 4, 1975; an interim report of study
activities at/through all performance sites through February 28, 1975 was
provided the EPA Project Officer on May 2, 1975. Dialogue between RTI and
EPA technical representatives was continuous and excellent throughout the
project performance.
2.5.2 Data Surrender
HDFs of ineligible patients; completed questionnaires and corresponding
HDFs; and other information on patients lost to the study, deceased, and re-
fusals were transmitted to the EPA Project Officer of his designee as re-
ceived and/or as appropriate endpoints were reached (see figures 1 and 2) .
22
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2
-------
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SI
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Figure 12. Form used to monitor survey activities,
24
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SECTION 3
PROJECT IMPLEMENTATION
3.1 INTRODUCTION
This section will discuss the implementation of the project at the
various performance sites, citing the time frame(s) and specific steps taken
to realize the methodology at the various sites. For the most part, the
project was implemented using the previously described methodology at the
various performance sites as planned.
Figure 13 presents graphically the schedule of project implementation
at the various performance sites, from contract initiation in June 1973
through the termination of the technical performance period in May 1977. As
indicated in section 2.3.1, the study was implemented at each performance
site in three basic phases, Phase I consisting of initial contact and
arrangements for cooperation and participation, Phase II consisting of medical
record abstraction, and Phase III consisting of survey operations.
Figure 14 presents graphically projected and actual cumulative project
expenditures by month, from project initiation in June 1973 until contract
termination in May 1977. Project expenditures can be related to project
activities by comparing figures 13 and 14.
3.2 PILOT STUDY
As intimated in previous sections, CGH was the specified pilot site for
this research effort. Virtually all project procedures and activities were
tested at CGH before implementation at other sites. Modifications were
minimal.
The pilot study did result in the refinement and detailed documentation
of study procedures. EPA had provided a general study protocol (23) and RTI
had proposed certain general procedures to implement that protocol which
outlined the methodology presented in section 2 of this report. In August
1973, RTI developed a detailed description of the procedures which would be
utilized to implement the study and execute the EPA protocol, including the
draft questionnaire and transmittal letter designed and revised by HERL/EPA.
3.3 PROBLEMS
Significant problems during the conduct of this research effort were
few; non were insurmountable. Problems were related primarily to delays in
25
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cd
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gaining approval at some clinical centers, variations in recordkeeping
systems, and respondent overreaction.
3.3.1 Approval Delays
As reflected in figure 13, approval delays were particularly marked at
two performance sites where 4 and 11 months respectively elapsed between the
first RTI contact and initiation of HDC. These delays were promulgated by
requirements at the individual clinical centers that the study be reviewed
by an internal committee. At the other sites, approval was virtually
immediate. The presence during initial discussions of representatives of all
involved clinical center disciplines - administration, nuclear medicine, and
medical records - seemed expeditious.
The delays did require extensions in the technical performance period
of the contract. In spite of these delays, however, RTI attempted to make
the most effective and efficient use of project time and funds in the mean-
time so that the study could proceed with all deliberate speed once activities
reached an appropriate point. The various delays undoubtedly resulted in
more precise data collection instruments and a more efficient outline of
procedures for implementing the study by both EPA and RTI.
3.3.2 Record Systems
The variability in record systems between participating clinical centers
was marked. The passage of time had resulted in the loss of a number of
records. The RAI laboratories and RMDs had taken advantage of a statute
which only requires them to retain records for five years. Of the nine
participating clinical centers, only two had complete RAI laboratory files
and three had no RAI files at all other than what existed in the patient's
medical record.
At all nine participating clinical centers, there were some patients
for whom no medical record could be located even though these patients
ostensibly had record numbers. At one clinical center, of 21 patients for
whom there was no medical record number provided by EPA or the RAI laboratory
files, none of these patients apparently had a clinical center medical record,
even though one of the patients was known to have d-Led at the elinlcal center
according to the death certificate.
Of the female patients for whom no medical record could be located, RTI
speculated that records on many of these patients were not located due to
last names changed through marriage and not all facilities maintaining re-
cords cross-referenced by maiden and married names. RTI attempted to deter-
mine the names of at least some of these patients through marriage records,
but this process met with limited success; for example, marriage records in
Denver cannot be located without the approximate date of the marriage.
The record problem at the clinical centers was complicated somewhat by
problems with misspelled patient names and other errors on the cards and
lists provided by EPA. In several cases, RTI staff documented that the error
was transcribed from a typographical error in the RAI files, but where RAI files
28
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did not exist, the EPA information was frequently the only guide. For
example, on one list prepared and supplied by EPA, one patient was listed
under two first names, only one of which was correct, and another was
listed under two last names, neither of which was correct; in both cases,
the two listings represented separate isotope administrations for the
same patient.
3.3.3 Respondent Reaction
In early November 1974, one of the clinical center physicians whose
signature was affixed to study correspondence indicated that he no longer
wished to have his signature so affixed.due to problems which he was en-
countering mostly in the form of telephone calls from curious and concerned
respondents. After discussions with RTI and EPA technical representatives,
the physician agreed to the continued use of his signature, but requested
that RTI implement a revised letter A for the clinical center's private
patient population. Prompted by comments received in writing from Dr.
Robinson of KUMC and verbally from Drs. Saenger of CGH and Price of UCSF,
and experience gained in the survey operations, the EPA Project Officer and
the RTI Project Leader had already discussed revisions in the initial trans-
mittal letter which would facilitate survey operations at future performance
sites. As stated by Dr. Robinson, the public...is grossly uninformed
generally about medical practices3 and...undue concern has been generated in
some of the families because of the survey. In addition, RTI and EPA
technical representatives felt that followup with respondents could be
reduced. As a result, a revised letter A was developed for future initial
correspondence; an example of the revised letter A is reproduced as figure
9. The revised letter required approximately twice the time to play back
on automatic word processing equipment than the initial letter used for the
first four performance sites; on the other hand, the revised letter required
two pages and since the second page did not change from respondent to
respondent, it could be printed, including the signature, thereby eliminating
the time required to affix the signature.
During the course of this study, two television programs produced some
reaction from respondents and/or participating clinical centers. In early
1975, an episode of the television series Marcus Welbys M.D. involved a re-
search firm conducting a survey of individuals who had received radioactive
iodine for thyroid disorders. The RTI telephone tracing operators reported
some comment by persons contacted in the course of tracing and prompting
operations immediately following the episode, but there was no written re-
ference to the Marcus Welby episode by a respondent. In early 1977, 60
Minutes aired a segment dealing with the effects of therapeutic application
of radioactive iodine. The participating clinical centers were deluged with
calls from persons who received therapeutic and diagnostic doses of 1^31. in
some instances, the patient lists for this study were the most readily avail-
able source of quickly identifying those persons who had received diagnostic
doses. These episodes may have had some immeasureable effect on the study
response rate.
29
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SECTION 4
RESULTS
4.1 GENERAL REMARKS
This section presents a summary of results of study activities as re-
lated to HOC and survey operations. As reflected in figure 13, all procedural
study steps were completed or were in some stage of implementation at/through
all nine clinical centers participating in this research effort as of the con-
tract termination date, May 7, 1977. As shown in figure 13, study activities
at the CGH pilot site and UCMC were terminated in November 1975, while study
activities at the other seven clinical centers continued. RTI continued to
attempt to resolve unresolved cases as possible and appropriate within the
limits of cost-effectiveness as long as funds were available in order to at-
tempt to obtain a response for every eligible study subject.
At the time of contract termination in May 1977, study activities were
virtually complete for all sites except SLU and CPMC, where Phase III survey
activities were not initiated until 1976 (see figure 13). In the tabulations
in subsequent sections, data will be presented for the participating clinical
centers in three groups - the CGH pilot site alone; UCMC, KUMC, MMC, SMC, SMH,
and UCSF grouped together as Group I since study activities at those six
participating clinical centers were virtually complete at the time of contract
termination in May 1977; and SLU and CPMC grouped together as Group II where
study activities were still ongoing at the time of contract termination in
May 1977. Although the contract terminated on May 7, 1977, tabulations for
this report were not prepared until August to permit outstanding mail to
reach RTI from the various performance sites.
4.2 HOSPITAL DATA COLLECTION
As shown in table 1, which summarizes medical record abstraction, RTI
was provided with 2,287 potential study patient names for the nine partici-
pating clinical centers, for whom some medical record (clinical center record,
RAI file, and/or RMD office record) was reviewed and abstracted for 1,999 or
some 87 percent. Of those potential patients for whom some medical record
was reviewed and abstracted, 1,085 or some 54 percent had a central clinical
center medical record only, 305 or some 15 percent had an RAI file only, and
538 or some 27 percent had both a central clinical center medical record and
RAI file. In addition, 71 patients or some 4 percent of the potential study
population for whom some medical record was abstracted had an RMD office re-
cord only (see table 1 and section 4.3.1 below). These figures do not in-
clude clinical center records reviewed for incorrect patients with similar
30
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names and ages as potential study patients, or reflect patients having clini-
cal center records and RMD office records reviewed and abstracted or an esti-
mate of the variability in record volume and time required to review and
abstract.
As shown in table 1, clinical center medical records have been avail-
able on 1,623 patients or some 71 percent of the potential population, with a
range of 23-94 percent among the nine performance sites, while RAI files have
been available on 843 patients, or some 37 percent of the potential popula-
tion, with the range among the nine clinical centers being 0-97 percent.
Table 2 presents a summary of the results of medical records abstraction
at the nine clinical centers which participated in this research effort. As
shown in table 2, of the 2,287 potential study population patients whose names
were provided to RTI, 1,362 or some 60 percent were determined to be eligi-
ble for inclusion in the survey sample (see section 4.3.2 below); 309 or
some 14 percent were determined to be ineligible for inclusion in the survey
sample based on study guidelines; 29 or some one percent were determined
from HDC to have expired within three years of the first administration
of the isotope, thereby obviating further followup beyond procurement of a
copy of the death certificate or the data therefrom; 554 or some 24 percent
of the potential total have apparently been lost to the study due to insuf-
ficient medical data available in/from medical records or the refusal of a
private physician to provide missing data (see section 4.3.1); and the status
of 33 or some one percent were undetermined as of the date of the tabulation
(August 1977).
In order to include a study patient in the survey sample, it was essenti-
al that at least one item of the RAI data be verified (at the very least, it
was necessary to verify that the medical record in hand was indeed that of
the patient in question), and that there be some resolution of a final diag-
nosis for at least one of the isotope administrations. As indicated in pre-
vious sections, RTI initiated additional efforts to locate records for
patients lost to the survey phase due to insufficient medical data through
marriage records, provided appropriate information could be located. For
the Interim Report in February 1975, a cursory review of the 335 patients
lost to the study due to insufficient medical data at the five performance
sites covered by that report (CGH, UCMC, UCSF, KUMC, MMC) revealed that some
57 percent were female and some 42 percent were male. At Cincinnati, marri-
age records were searched as far back as 1946 for 16 study patients (male and
female) who were apparently lost to the study due to insufficient medical
data or failure to locate through mail, telephone, and other on-site tracing
activities. Information gleaned from the marriage records search provided
possible leads on four patients, some 25 percent of those for whom informa-
tion was sought. Subsequently, marriage records were searched only for fe-
male patients.
As shown in table 2 and cited in a preceding paragraph, 309 patients
or some 14 percent of the total potential patient population were deter-
mined upon review of their medical records to be ineligible for inclusion
in the survey sample - that is, they failed to satisfy one or more of the
criteria for inclusion cited in section 2.2 of this report. The ineligible
32
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TABLE 2. SUMMARY OF HOSPITAL DATA COLLECTION RESULTS
Result
Total poten-
tial patient
population
Lost to
studye
Expired
within 3
years
Ineligible
for
survey*
Eligible
for J:
surveyr
Status
unde-
termined!
Patient population by clinical center(s)
CGH pilot study
Number
144
6
3
29
106
_
Percent
100.0
4.2
2.1
20.1
73.6
_
Group I facilities*
Number
1,533
407
12
236
878
Percent
100.0
26.5
0.8
15.4
57.3
Group II :
Number
610
141
14
44
378
33
'acilities**
Percent
100.0
23.1
2.3
7.2
62.0
5.4
Total
all sites
Number
2,287
554
29
309
1,362
33
Percent
100.0
24.2
1.3
13.5
59.6
1.4
* UCMC, fCDMC, UCSF, MMC, SMH, SMC; study activities virtually complete.
** SLU and CPMC; study activities incomplete.
6 Due to insufficient data in medical records.
TT Due to having received isotope for the first time after 12/31/60, age 16 or over, or
diagnosis of hyperthyroidism, toxic or nodular goiter, athyreosis, thyroiditis, or
thyroid neoplasm; see table 3.
4i
+ All these patients were involved in the survey phase; see table 5.
§ The ultimate status of these patients depends on the results of responses from non-
respondent RMDs and further searches for medical records.
33
-------
patients for the nine performance sites are broken down according to reasons
for ineligibility in table 3. As shown in table 3, the most common reason
for ineligibility was having received the isotope for the first time after
December 31, 1960; 174 or some 56 percent of the ineligible patients fell
into that category. Thirteen patients were excluded from the survey sample
for having been over 16 years of age at the time of first isotope administra-
tion; 87 patients were ineligible due to a final diagnosis of hyperthyroidism
or toxic or nodular goiter, 14 due to a final diagnosis of athyreosis, 14 due
to a final diagnosis of thyroiditis, and 27 due to a final diagnosis of thy-
roid neoplasia; and five received l!31 for reasons other than thyroid uptakes
(see table 3). Several patients have been ineligible for more than one rea-
son; therefore, the breakdown of ineligibles in table 3 totals more than 309,
or 100 percent. For example, a patient may have received the isotope for the
first time after 12/31/60 and also been diagnosed as hyperthyroid.
4.3 SURVEY OPERATIONS
4.3.1. Referral Sources
As mentioned in preceding sections, referral sources were contacted in an
attempt to complete medical data on patients for whom clinical center records
were inadequate for the purposes of the study. In most instances, the data
item(s) sought were dosimetric data and/or the .final diagnosis. Table 4
summarizes the results of contacts with referral sources through each and all
performance sites. In table 4, physic-ions (or referral sources) refers to
the number of RMD's or other referral sources in each category; primary RMD
refers to the referring physician or facility cited in the clinical center
record and/or EPA card, and secondary care sources refers to physicians or
facilities to whom the primary RMD referred the study as currently caring for
the patient(s) in question or holding the necessary records. The numerous
physicians who were contacted in the course of tracing operations are not
considered here.
As shown in table 4, RTI contacted 170 primary referral sources through
eight of the participating clinical centers (no RMDs were contacted for data
through SMC, but then SMC is a private group medical practice and not an in-
patient facility), as a result of information in the clinical center records
and/or on the EPA cards, in attempts to complete necessary medical data on
patients for whom records maintained at the various participating clinical
centers were inadequate for the purposes for the study - that is, to deter-
mine eligibility and include the person in the survey sample. As indicated
in table 4, there were four basic responses by referral sources - they could
agree to participate in the study, in which case they may or may not have
had records on all the patients in question; they could refer the study to
another source of care; records on the patient(s) may have been lost or
destroyed; or the physician or facility could decline to participate in the
study. In addition, the RMD could have expired with the disposition of the
records unknown, or be a nonrespondent. An RMD could be a nonrespondent one
of three ways: as indicated in a preceding section, in many cases only the
RMD's last name was provided in the patient's medical record or on the EPA
card, resulting in several possible physicians with the same last name being
contacted regarding data on the same patient(s); if the requisite data were
34
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35
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TABLE 4. SUMMARY OF RESULTS OF CONTACTS WITH REFERRAL SOURCES
Result
Primary referral
sources, total
Agreed to
participate
Referred to se-
condary source
No records
Declined to
participate
RMD deceased
No response
or lost
Secondary care
sources , to tal
Agreed to
participate
Referred to
another HD
No records
Performance site
CGH pilot study
Number
7
4
1
1
1
3
-
I9
2
Percent
100.0
57.1
14.3
14.3
14.3
100.0
33.3
66.7
Group I facilities*
Number
72
34
11
18
3
6
6
6
Percent
100.0
47.2
15.3
25.0
4.2
8.3
100.0
100.0
Group II facilities**
Number
91
11
7
20
2
51+
7
1
6
Percent
100.0
12.1
7.7
22.0
2.2
56.0
100.0
14.3
85.7
Total
all sites
Number
170
49
19
39
3
9
51
16
7
1
8
Percent
100.0
28.8
11.2
22.9
1.8
5.3
30.0
100.0
43.8
6.2
50.0
* UCMC, UCSF, KUMC, MMC, and SMH; study activities virtually complete. No referral sources were
contacted for SMC and no secondary sources were contacted for UCMC or UCSF.
** SLU and CPMC; study activities incomplete.
6 Referred to MD already in survey.
r 46 of these are CPMC physicians to whom letters were sent just after contract termination; the
remaining five are SLU physicians of whom two were lost - unable to locate and three were phy-
sician with the same last name as another contacted who had records on the patient and were
therefore not pursued.
36
-------
obtained, outstanding or nonrespondent physicians for the patient(s) were not
pursued further. A few physicians could not be located despite extensive
tracing activities, and many of the CPMC physicians have not been pursued yet
beyond the initial letter.
As shown in table 4, 49 of the 170 primary referral sources contacted
(or some 29 percent) agreed to participate in the study; 19 or some 11 per-
cent referred the study to secondary sources; 39 or some 23 percent indicated
a lack of records; 9 RMDs had expired, representing some five percent; and no
response had been received from 51 referral sources at the time of this tabu-
lation. Most of these nonrespondents represented RMDs for CPMC for whom let-
ters went out after the contract terminated. Of the 16 secondary care sources
contacted, one referred the study to one of the other secondary sources; eight
indicated a lack of records; and seven agreed to participate in the study.
Three referral sources representing less than two percent of the total
referral sources contacted refused to participate in the study by refusing to
provide information from or access to patients' records; one refusal was from
a juvenile court referral center while another was from a physician with
terminal cancer. One referring physician provided the necessary medical and
demographic data to complete the HDF, but requested that the study not contact
the patient or his family. One RMD agreed to participate in the study but
required patient authorization to release information from office records;
RTI is seeking the required authorization.
4.3.2 Eligible Respondents
Table 5 presents a summarization of project survey operations for the
nine participating clinical centers, including the status of all eligible
respondents as of August 1977. In table 5, the Group I facilities are fur-
ther subdivided into two subgroups in that the short version of the initial
transmittal letter A (figure 7) was used predominantly at UCMC, UCSF and
KUMC, while the longer version of the initial transmittal letter A (figure
9) was used predominantly at MMC, SMH and SMC. In terms of overall response
rate, as reflected in the total cases resolved shown in table 5, the dif-
ference in the letters does not appear to have had a significant impact.
As shown in table 5, of the 1,362 patients eligible for the survey phase
of this study, 1,065 cases or some 78 percent were successfully resolved as
of August 1977 - completed questionnaires were obtained on 1,010 patients or
some 74 percent of the eligible survey population; 17 patients representing
some one percent of the eligible survey population were determined from
survey activities to have died within three years of the initial isotope ad-
ministration and a copy of the death certificate obtained; and 38 respondents
representing less than three percent of the eligible survey population re-
fused to participate in the study. Many respondents provided considerable
information beyond that requested by the questionnaire; some even went so
far as to write separate letters or notes.
Of the 297 cases unresolved as of August 1977, as shown in table 5, 176
or some 59 percent are from CPMC where the survey phase of the study was not
initiated until November 1976 (see figure 13). Of the 297 unresolved cases
37
-------
shown in table 5, 216 or some 73 percent reflect active correspondence or
tracing activities; only 81 cases or some 27 percent had been relegated to
some inactive category such as nonrespondent or unable to locate. Of the
total patient population eligible for the survey phase, these 81 cases
represent only six percent.
As an example of the study mail survey activities, table 6 summarizes
such activities at the CGH pilot site as of September 1975, two months before
study activities were suspended at CGH. In table 6, letter A refers to the
initial letter A sent to eligible respondents (see figure 1); An refers to
letter A's sent to eligible respondents whose letter A was returned by the
U. S. Postal Service as not deliverable and who were then traced and located,
or some subsequent letter A in accordance with some response to a letter A
or B or a tracing or prompting call (see figure 2); B^ refers to letter B
sent to eligible respondents whose letter A was not returned by the Postal
Service and from whom no response was received (see figure 2); B refers
to subsequent reminder letter(s).
As shown in table 6, all 106 eligible CGH respondents (see tables 2 and
5) were sent letter A to the last address available from clinical center and/
or RMD records. From this initial mailing, 18 or some 17 percent of the
eligible respondents returned a completed questionnaire, one respondent (less
than one percent of the eligible respondents) provided information short of
a completed questionnaire, 48 or some 45 percent of the initial letter A's
were returned by the Postal Service as not deliverable, and 39 or some 37
percent of the initial letters remained outstanding. As a result of supple-
mental information regarding the location of eligible respondents obtained by
mail and/or telephone and/or on-site tracing (see below), 59 eligible respon-
dents were sent a second letter A (letter A_ - see table 6), of whom 23 or
some 39 percent returned a completed questionnaire and two or some three per-
cent responded in some other fashion; three or some five percent of these
second letter A's were returned by the Postal Service as not deliverable, and
31 or some 53 percent remained outstanding. A third letter A (letter A_) was
sent to 17 eligible respondents, while one case required a fourth letter A
(letter A.); results of these mailings are shown in table 6.
As further shown in table 6, 65 eligible respondents were sent an ini-
tial reminder letter (letter B ), in response to which 24 respondents or some
37 percent of the total returned a questionnaire, one or some two percent re-
fused to participate in the study, and two or some three percent provided
some other response; only six or some nine percent of these initial reminder
letters were returned by the Postal Service as not deliverable, while 32 or
some 49 percent remained outstanding. A second reminder letter (letter B~)
was sent to 28 eligible respondents, of whom 12 or some 43 percent returned
a questionnaire, and three or some 11 percent refused to participate in the
study; one of these second reminder letters, or some four percent of the
total sent, was returned by the Postal Service as not deliverable, and 12 or
some 43 percent remained outstanding. Eleven respondents required a third
reminder letter (letter B_), nine a fourth reminder letter (letter B,) , and
two a fifth reminder letter (letter B,.) ; results of these mailing are shown
in table 6. Two respondents each returned two questionnaires.
38
-------
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As might be expected, the best response rates were in response to
letters A .. and reminder letters B; letters An resulted in the most re-
turned as not deliverable, but were necessary in order to establish a
baseline based upon the-last known address; letter A and reminder letters
B accounted for the most letters presumed or verified delivered with no re-
sponse; and reminder letters ultimately resulted in the most refusals. The
CGH pilot study required approximately three letters per respondent. The fig-
ures in table 6 do not fully reflect correspondence conducted in the course
of tracing activities.
Figure 15 presents graphically the progress of study survey operations at
each of the nine participating clinical centers in terms of percentage of el-
igible respondents who returned a completed questionnaire since the initiation
of survey operations at the site, shown against the study performance period.
Figure 15 may be compared with figures 13 and 14 to determine the relation-
ships and overlaps of survey operations with other project activities and
phases. The decrease in the response rates for KUMC and MMC in January 1975
represented the entrance of additional eligible respondents into the survey
phase. Figure 16 presents graphically those same rates shown in figure 15 at
which the study survey operations progressed, in terms of percentages of eli-
gible respondents from whom a completed questionnaire was Teoei,ved3 but plot-
ted as though the survey phase were initiated simultaneously at all sites.
Despite variations in the timing of various survey activities at the different
sites, the response curves in figure 16 are quite similar, with less than five
percentage points separating the response rates for all sites except SLU and
CPMC during the fourteenth month of activity.
Those study patients who entered the survey phase only after the ac-
quisition of certain medical data from private physicians formed a special
subpopulation, although for MMC the 330 patients who entered the survey phase
after the acquisition of such data from RMD's represented some 82 percent of
the MMC survey patient population; furthermore, those 330 MMC private patients
represented more than the combined eligible survey patient populations for
CGH, UCMC, and UCSF. The private patients also presented other variables;
in many cases, additional demographic information, including addresses more
current than those in clinical center records, were obtained. For MMC pri-
vate patients, the revised longer letter A (figure 9) was used and one
group of MMC private patient letter A's were inadvertantly mailed from RTI
rather than Kansas City and demonstrated a shorter turnaround time from mail
to return. Table 7 presents the response rates and status for the CGH pri-
vate patients as an example.
As shown in table 8, which summarizes study telephone survey activities
for the CGH pilot study, 15 eligible respondents were prompted at least once
following nonresponse to letter B's while 71 eligible respondents were re-
ferred to RTI telephone tracing operators for location following the return
of correspondence by the Postal Service. Although ten of the prompted re-
spondents are shown in table 8 as ultimately submitting a completed question-
naire, several of these were actually completed by personal visit or tele-
phone, following nonresponse to the prompting call(s). Of those 15 respon-
dents prompted, two or some 13 percent were determined to have expired with-
in three years of the first isotope administration and a copy of the death
40
-------
1
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TABLE 7. SUMMARY OF SURVEY ACTIVITIES: CINCINNATI PRIVATE
PATIENT STATUS AND RESPONSE RATE
Status
Total patients
Questionnaire received
Refused to participate
Lost-unable to locate
Number
15
12
2
1
Percent
100.0
80.0
13.3
6.7
TABLE 8. SUMMARY OF TELEPHONE SURVEY ACTIVITIES: CINCINNATI
Result
Total respondents referred
Questionnaire obtained
or respondent located
Expired within 3 years
Refused to participate
Other response
Respondents not located
Prompting
Number
15
10
2
2
1
Percent
100.0
66.7
13.3
13.3
6.7
Tracing
Number
71
62
1
8
Percent
100.0
87.3
1.4
11.3
46
-------
certificate obtained, two of some 13 percent refused to participate in the
study, and one or some seven percent provided information which resulted in
additional correspondence. Of the 71 respondents referred to the telephone
tracing operators for location, 62 or some 87 percent were ultimately located
by some combination of telephone, mail, and/or personal followup on-site,
while extensive tracing activities failed to locate eight respondents/pati-
ents, or some 11 percent of the total referred to tracing. As shown in table
8, one respondent refused to participate in the study during the course of
telephone tracing contact, less than two percent of the total referred.
Tracing activities were most effective among the CGH study patient population,
some 89 percent of those respondents referred to tracing having ultimately
been located. Just as some respondents required more than one reminder let-
ter, several required more than one prompting call and/or were traced more
than once, but these are not double-counted in table 8.
As indicated in figure 13, on-site tracing activities were instituted at
all sites except the two New York sites to retrieve questionnaires from re-
spondents who had not returned them and make one last effort on-site to lo-
cate respondents who had not been located by telephone and mail tracing acti-
vities. Table 9 presents a summarization of on-site tracing activities for
the CGH pilot study, indicating the disposition of all cases so .traced. As
shown in table 9, of the 25 respondents and/or patients who were traced on-
site, completed questionnaires were obtained from 16 or 64 percent by admini-
stering the questionnaire in person or by phone, or mail followup to the
personal visit; one patient was determined to have died within three years of
initial isotope administration and a copy of the death certificate obtained;
and on-site tracing and subsequent mail and telephone followup were unable to
locate eight respondents. As shown in table 9, tracing at Cincinnati result-
ed ultimately in the successful resolution of 68 percent of the cases traced
on-site; however, in most instances, successful on-site tracing required
visits to more than one address in greater Cincinnati or more than one visit
to the most current address.
TABLE 9. SUMMARY OF SURVEY ACTIVITIES; ON-SITE TRACING, CINCINNATI
Status/Disposition
Total cases traced
Questionnaire received
Expired within 3 years
Refused to participate
Lost-unable to locate
Number
25
16
1
8
Percent
100.0
64.0
4.0
32.0
47
-------
SECTION 5
CONCLUSIONS
The purpose of this study was to locate and obtain pertinent medical
information on approximately 2,300 patients who as children received l!31
for diagnostic purposes over the period 1946 - 1960 at nine clinical centers.
Of 2,287 potential study subjects identified, some medical record was reviewed
and abstracted for 1,999 or some 87 percent. With study activities incomplete,
of 186 private physicians and other referral sources contacted for supplemental
data, only three or less than two percent declined to participate; of 1.362
patients who were determined eligible and entered the survey phase, some final
resolution (completed questionnaire, death certificate, or refusal) was
obtained for 1,065 or some 78 percent.
A pilot study was conducted, the primary objective of which was to test,
and refine as necessary, the data collection scheme for this project, a goal
which was achieved relatively early. Furthermore, the pilot site experience
contributed greatly to project implementation at the other sites. In particu-
lar, the pilot site experience accelerated project approval and implementation
at the other performance sites by involving representatives of all concerned
disciplines at each site thereby abbreviating Phase I at seven of the eight
subsequent sites (see figure 13), and in part accelerated and facilitated HDC
and survey operations at the other sites. At least some of this acceleration
was due to improved efficiency resulting from the pilot study experience.
RTI's original techncal proposal (40) stated that RTI will -instigate a
series of tracing procedures designed to locate 90 percent of the families
of the patients in the study population, and, based upon previous experience
cited by [EPA] staff3 RTI anticipates a very high response by patients who
are located in this study. For the two clinical center patient populations
for whom study activities were suspended in November 1975 (CGH and UCMC), RTI
located respondents for over 90 percent of the patients who were eligible for
inclusion in the survey phase of the study, and obtained a response (completed
questionnaire, refusal, or evidence that the patient died within three years
of receiving the isotope for the first time) from over 99 percent of those
located. For the seven sites (CGH, UCMC, UCSF, KUMC, MMC, SMH and SMC) where
study activities were completed or virtually complete, the response rate in
August 1977 in terms of completed questionnaires was some 85 percent while
the percentage of resolved cases in terms of completed questionnaires, death
certificates, and refusals was some 90 percent.
The successful acquisition of these data provide a unique opportunity to
assess the chronic effect of low dose 1-^1 exposures.
48
-------
REFERENCES
1. Bustad, L.K., Marks, S., George, L.A., and Seigneur, L.J. Thyroid adeno-
mas in sheep administered Iodine-131 daily. Nature, 179:677, 1957.
2. Doniach, I. Experimental induction of tumours of the thyroid by radia-
tion. British Medical Bulletin, 14(2):181-183, 1958.
3. Frantz, V.K., Kligerman, M.M., Harland, W.A., Phillips, M.E., and
Quimby, E.H. A comparison of the carcinogenic effect of internal and
external irradiation on the thyroid gland of the male Long-Evans rat.
Endocrinology, 61:574-581, 1957.
4. Goldberg, R.C., and Chaikoff, I.L. Development of thyroid neoplasms in
the rat following a single injection of radioactive iodine. Proceedings
of the Society for Experimental Biology and Medicine, 76:563-566, 1951.
5. Lindsay, S., Potter, G.D., and Chaikoff, I.L. Radioiodine-induced
thyroid carcinomas in female rats: Induction by low doses of radio-
iodine. Archives of Pathology, 75:8-12, 1963.
6. Maloof, F., Dobyns, B.M., and Vickery, A.L. The effects of various
doses of radioactive iodine on the function and structure of the thyroid
of the rat. Endocrinology, 50:612-638, 1952.
7. Walinder, G., and Sjoden, A.M. Late effects of irradiation on the
thyroid gland in mice. III. Comparison between irradiation of foetuses
and adults. Acta Radiologia, 12:201-208, 1973.
8. Clark, D.E. Association of irradiation with cancer of the thyroid in
children and adolescents. Journal of the American Medical Association,
159(10):1007-1009, 1955.
9. DeGroot, L., and Paloyan, E. Thyroid carcinoma and radiation: A
Chicago endemic. Journal of the American Medical Association,
225(5):487-491, 1973.
10. Duffy, B.J., and Fitzgerald, P.J. Cancer of the thyroid in children:
A report of 28 cases. Journal of Clinical Endocrinology, 10:1296-1308,
1950.
11. Hagler, S., Rosenblum, P., and Rosenblum, A. Carcinoma of the thyroid
in children and young adults: latrogenic relation to previous irra-
diation. Pediatrics, 38(1):77-81, 1966.
49
-------
12. Hanford, J.M., Quimby, E.H., and Frantz, V.K. Cancer arising many years
after radiation therapy: Incidence after irradiation of benign lesions
in the neck. Journal of the American Medical Association, 181(5):404-
410, 1962.
13. Hempelmann, L.H. Risk of thyroid neoplasms after irradiation in child-
hood. Science, 160:159-163, 1968.
14. Hempelmann, L.H., Pifer, J.W., Burke, G.J., Terry, R., and Ames, W.R.
Neoplasms in persons treated with x rays in infancy for thymic enlarge-
ment. A report of the third follow-up survey. Journal of the National
Cancer Institute, 38(3):317-341, 1967.
15. Janower, M.L., and Meittinen, O.S. Neoplasms after childhood irradia-
tion of the thymus gland. Journal of the American Medical Association,
215(5):753-756, 1971.
16. Latourette, H.B., and Hodges, F.J. Incidence of neoplasia after irra-
diation of thymic region. American Journal of Roentgenology, Radium
Therapy and Nuclear Medicine, 82(4):667-677, 1959.
17. Modan, B., Mart, H.; Baidatz, D., Steinitz, R., and Levin, S.G. Radia-
tion-induced head and neck tumours. Lancet:277-279, 1974.
18. Newman, C.G.H. Long-term follow-up of 32 patients irradiated for thymic
enlargement in infancy. British Medical Journal, 1:34-36, 1960.
19. Pifer, J.W. , Hempelmann, L.H., Dodge, H.J., and Hodges, F.J. Neoplasms
in the Ann Arbor series of thymus-irradiated children: A second survey.
American Journal of Roentgenology, Radium Therapy and Nuclear Medicine,
103(1):13-18, 1968.
20. Pifer, J.W., Toyooka, E.T., Murray, R.W., Ames, W.R., and Hempelmann,
L.H. Neoplasms in children treated with x rays for thymic enlargment.
I. Neoplasms and mortality. Journal of the National Cancer Institute,
31(6):1333-1356, 1963.
21. Saenger, E.L., Silverman, F.N., Sterling, T.D., and Turner, M.E.
Neoplasia following therapeutic irradiation for benign conditions in
childhood. Radiology, 74(6):889-904, 1960.
\
22. Simpson, C.L., Hempelmann, L.H., and Fuller, L.M. Neoplasia in children
treated with x rays in infancy for thymic enlargement. Radiology,
64:840-845, 1955.
131
23. Protocol: Risk of thyroid neoplasms after receiving doses of I dur-
ing childhood. Research Triangle Park, NC: Environmental Protection
Agency, 1973.
24. Conard, R.A., Dobyns, B.M., and Sutow, W.W. Thyroid neoplasia as late
effect of exposure to radioactive iodine in fallout. Journal of the
American Medical Association, 214(2):316-324, 1970.
50
-------
25. Conard, R.A., Rail, J.E., and Sutow, W.W. Thyroid nodules as a late
sequela of radioactive fallout in a Marshall Island population exposed
in 1954. New England Journal of Medicine, 274(25):1391-1399, 1966.
26. Sampson, R.J., Oka, H., Key, C.R., Buncher, C.R., and lijima, S.
Metastases from occult thyroid carcinoma: An autopsy study from
Hiroshima and Nagasaki, Japan. Cancer, 25(4):803-811, 1970.
27. Weiss, E.S., Rallison, M.L., London, W.T., and Thompson, G.D.C. Thyroid
nodularity in southwestern Utah school children exposed to fallout rad-
iation. American Journal of Public Health and the Nations Health,
61(2):241-249, 1971.
28. Wood, J.W., Tamagaki, H., Neriishi, S., Sato, T., Sheldon, W.F., Archer,
P.G., Hamilton, H.B., and Johnson, K.G. Thyroid carcinoma in atomic
bomb survivors, Hiroshima and Nagasaki. American Journal of Epide-
miology, 89(1):4-14, 1969.
29. Baker, H.W. Anaplastic thyroid cancer twelve years after radioiodine
therapy. Cancer, 23(4):885-890, 1969.
30. Dobyns, B.M., Sheline, G.E., Workman, J.B., Tompkins, E.A., McConahey,
W.M., and Becker, D.V. Malignant and benign neoplasms of the thyroid
in patients treated for hyperthyroidism: A report of the cooperative
thyrotoxicosis therapy follow-up study. Journal of Clinical Endocrino-
logy and Metabolism, 38(6):976-998, 1974.
31. Karlan, M.S., Pollock, W.F., and Snyder, W.H. Carcinoma of the thyroid
following treatment of hyperthyroidism with radioactive iodine. Cal-
ifornia Medicine, 101(3):196-199, 1964.
32. Kreps, E.M., Kreps, S.M., and Kreps, S.I. Treatment of hyperthyroidism
with sodium iodide I 131: Carcinoma of the thyroid after 20 years.
Journal of the American Medical Association, 226(7):774-775, 1973.
33. McDougall, L.R., Kennedy J.S., and Thomson, J.A. Thyroid carcinoma
following Iodine-131 therapy. Report of a case and review of the
literature. Journal of Clinical Endocrinology, 33:287-292, 1971.
34. Sheline, G.E., Lindsay, S., McCormack, K.R., and Galante, M. Thyroid
nodules occurring late after treatment of thyrotoxicosis with radio-
iodine. Journal of Clinical Endocrinology, 22:8-18, 1962.
131
35. Staffurth, J.S. Thyroid cancer after I therapy for thyrotoxicosis.
British Journal of Radiology, 39(462):471-473, 1966.
36. Hoffman, D.A. A research protocol for a study of persons investigated
for endocrine disorders during childhood. Bureau of Radiological
Health, Division of Biological Effects, Epidemiologic Studies Branch.
37. Follow-up of patients receiving diagnostic doses of 131 Iodine during
childhood. Contract No. 68-02-1213, June 8, 1973.
51
-------
38. Directory of Medical Specialists, 1975-1976 (17th Edition). Chicago:
Marquis Who's Who, 1975.
39. 1976 U.S. Alphabetical Physician Reference Listing. Fisher-Stevens,
1976.
40. Project proposal: Follow-up of patients receiving diagnostic doses
of 131'iodine during childhood (RTI No. 25-73-24-01 in response to
RFP No. DU-73-B431). Research Triangle Park, NC: Research Triangle
Institute, April 1973.
52
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APPENDIX
TELEPHONE TRACING OPERATIONS
I. Background Information
RTI is under contract to the Environmental Protection Agency (EPA) to
collect data about patients who received diagnostic doses of Iodine 131
during their childhood. From several medical centers in the U. S., records
have been abstracted to select a sample of patients who received ll31 during
the period January 1, 1946 - December 31, 1960; all patients selected were
younger than 16 years of age at the time of the procedure.
The objective of the research effort is to provide data for the defini-
tion of a dose-response curve for the development of thyroid neoplasms in
the patients exposed to 1131 radiation. Data are being collected via short
questionnaires directed to the patients' parents.
II. Tracing Objective and Procedures
The objective of telephone tracing for this project is to obtain a
current mailing address for the parents of a specific patient so that the
Thyroid Study Questionnaire can be mailed to them.
For each tracing case, the operator will be provided with a data card
on the patient, which gives the following information:
- study number (a seven digit number)
- patient's name
patient's birthdate
- parents' name
- all known previous addresses
- various types of information such as employment data for
parents, evidence of involvement with public agencies
(welfare, housing, etc.), and other data that might aid
in locating the parents.
In addition, the envelope in which the initial correspondence was
mailed will be attached to the patient data card.
Several problems are obvious from the onset of tracing: the patient may
be as old as 43 or as young as 13; the address(es) shown on the patient data
card may be out-of-date; the patient's parents (or guardian) may be dead,
in which case you must attempt to secure a current mailing address for the
patient.
53
-------
Specific procedures for tracing are as follow:
1. Study the patient data card; have names of patient and parents
firmly in mind; compute the patient's age from his birthdate
so that you can evaluate his "usefulness" for tracing (i.e., is
he old enough to have a phone listed in his own name, etc.).
2. Begin tracing by consulting Directory Assistance (DA) in the town
where the patient/parents last lived; in cases of unusual last
names or in small towns, secure listings for persons with same
surname. Area phone books will be available for your useconsult
them, where applicable.
3. In cases where telephone numbers are shown on the patient data
card, call the most current one. If the number is no longer
assigned to the patient/parents, try to find out how long the
party with whom you are speaking has had the number.
4. City Directory Service is available through many public libraries.
These listings also cover many smaller suburban areas. Be
specific in the items for which you are requesting information.
5. In cases where employment data for patient/parent is less than
five years old, call the last known employer.
6. In some cases, the names of physicians who have treated the
patient are given on the patient data card. We may contact
these offices for addresses if all other sources fail.
7. Where patients/parents may have been clients of public agencies
(welfare, housing, etc.), attempt to secure any address data
the agency may have on file. These sources, however, may not
be productive since many of their records are confidential.
As in all tracing cases, document fully your efforts and your
findings on the Control Sheet (figure A-l). Make certain the operator
name, hospital and patient number have been entered on the Control Sheet.
Indicate if the case was completed by marking the yes/no box. If the
case is pending, write "pending" in this box.
The source of address should be specified, especially in the "other"
category.
Parent/patient names should be shown on the Control Sheet as they
are on the patient data card. Do not substitute initials for names.
Include in the updated address the proper ZIP Code. Do not abbreviate
any element of the address.
In general, complete all areas of the Control Sheet before returning
it to Lil Smith.
Before a patient is considered "unable to locate," glean the patient
data card for pertinent information and leads. Other sources should be
pursued as indicated. All should be exhausted before pronouncing the
patient lost. When it has been determined that the patient cannot be lo-
cated, complete the Unable To Locate Check Sheet (figure A-2) and attach
it to the Control Sheet.
54
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TELEPHONE TRACING
PROJECT 25U-374
Call 1
Call 2
Call 3
Call 4
Call 5
Call 6
Call 7
Call 8
Call 9
Call 10
Case Comp
1 1 Yes
Source of
I"""1 Pati
1 1 Othe
Date
Time
To
CASE NUMBER:
OPERATOR:
Result
leted?
r~i NO
address data
enc 1 1 Parent
r
Parent Name:
Sc. Address:
City, State, Zip:
Phone Number
Reason for unable to locate:
Mail Questionnaire to:
i 1 Parent i J Patient
Pntienc Name:
St. Address:
City, St.iti.-, ;:tp:
Comments:
Approved
Date:
by:
Figure A-l. Telephone tracing control sheet.
55
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CHECK SHEET UNABLE TO CONTACT
SOURCES CONTACTED/USED
Locator Card
City Directory
Chamber of Commerce
Board of Election
DMV
Figure A-2. Unable to locate check sheet.
56
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III. Script Outline
In this study, there are strict requirements regarding how we represent
ourselves to individuals and organizations by phone. There are to be no
exceptions to these requirements. Specifically, RTI and EPA are not to be
mentioned in conjunction with this study; all references to sponsorship of
the study are to be made as though the M.D. at the specific hospital were
the project sponsor. For example, when you are talking to a patient or his
parents from the Cincinnati population, you would introduce yourself as
follows:
"Hello. My name is Sue Smith and I am working with Dr. Eugene
Saenger of Cincinnati General Hospital."
Do not indicate that you are calling from RTI or from North Carolina.
If you are queried about who you are and who you represent, repeat that you
are working with Dr. Saenger of Cincinnati General Hospital.
In general, do not get involved with medical terms which you cannot
explain. Your description of the study should be brief and concise, based
on the suggested narrative below:
"Your son/daughter (Patient's name) was tested at (appropriate partici-
pating clinical center) for suspected thyroid disease. The hospital is
presently conducting a study to determine if people suspected of having
thyroid disease in childhood are inclined to have more illnesses or
tend to develop thyroid disease in later years. Your son/daughter was
chosen from a number of patients. We have tried to mail you a brief
questionnaire concerning your son/daughter's general health, but the
questionnaire was returned to us by the Postal Service. Could I have
your current mailing address so that we can mail you another question-
naire?"
"Thank you very much. You will be getting the questionnaire within
a few days. We would appreciate your filling it out and returning it
as soon as possible. Thank you again."
If a parent or patient asks detailed questions, do not attempt to answer
them. Instead, refer them to Ben Harris. If someone wants to know how the
information will be used, explain that this is a statistical study and that
all information obtained will be held in strict confidence. Furthermore, we
are following up all persons who had the test, whether or not the test was
abnormal.
IV. General Information
All calls are to be dailed direct station-to-station. Do not, under any
circumstances, leave a message for a patient/parent to call back collect here.
We will initiate all calls.
When you complete a case, give it to Lil Smith for review and approval.
Questions concerning tracing procedures or conversations with patient/parent
should be referred to Lil Smith or Ben Harris.
57
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
1. REPORT NO.
EPA-600/1-78-059
2.
3. RECIPIENT'S ACCESSION-NO.
4. TITLE AND SUBTITLE
Follow-up of Patients Receiving Diagnostic Doses of
131 Iodine During Childhood
5. REPORT DATE
September 1978
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
Benjamin S. H. Harris,
Mildred I. Holt
III, Martha L. Smith,
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Research Triangle Institute
P. 0. Box 12194
Research Triangle Park, N. C. 27709
10. PROGRAM ELEMENT NO.
1FA628
11. CONTRACT/GRANT NO.
' Contract No. 68-02-1213
12. SPONSORING AGENCY NAME AND ADDRESS
Health Effects Research Laboratory RTP,NC
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
13. TYPE OF REPORT AND PERIOD COVERED
Final report covering 6/73-5/7
14. SPONSORING AGENCY CODE
EPA 600/11
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report documents the data collection methodology and procedures of a
follow-up survey conducted of persons under 16 years old who received diagnostic
Iodine 131 for evaluation of thyroid function at nine clinical centers prior to
December 31, 1960. The intent of this data collection effort is to estimate
the dose response curve for the development of thyroid neoplasms in young;adults
who received low diagnostic doses of Iodine 131 as children.
Of 2,287 potential study subjects identified, some medical record was
reviewed and abstracted for 1,999 or some 87 percent. With study activities
incomplete, of 186 private physicians and other referral sources contacted for
supplemental data, only three or less than two percent declined to participate;
of 1,362 patients who were determined eligible and entered the survey phase,
some final resolution (completed questionnaire, death certificate, or refusal)
was obtained for 1,065 or some 78 percent.
The statistical analysis of these data will be performed under a related
project sponsored by the U. S. Food and Drug Administration.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS
c. COSATI Field/Group
thyroid
iodine
diagnostic dose
fo Flow-up
Follow-up study
18. DISTRIBUTION STATEMENT
Release to Public
19. SECURITY CLASS (ThisReport)
unclassified
21. NO. OF PAGES
68
20. SECURITY CLASS (Thispage)
unclassified
22. PRICE
EPA Form 222JM (9-73)
58
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