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3
Evaluation of Epidemiologic and Clinical Methods
EVALUATION OF EPIDEMIOLOGIC METHODS
The HTDS investigators examined 3,441 persons who
were born in 1940-1945 to parents living in the study areas near
Hanford. Of these, 3,190 lived in the study areas at some time from
1945 to 1957, so thyroid dose estimates for them could be derived
with the CIDER program developed by the HEDR investigators.
Dose reconstruction used the available data and accepted methods.
The study design was appropriate to address the aims of
the study. Among the possible designs, a cohort study with
accompanying thyroid screening is optimal for minimizing the
potential for bias. The investigators also chose the optimal
populations to study: children who were young at the time of the
greatest ]3~{ releases and who lived in the most highly exposed
areas. Those two choices maximized the potential of the study to
detect thyroid-disease effects. The interval between exposure and
thyroid screening was adequate to allow radiation-induced thyroid
diseases to become evident.
The epidemiologic methods were exceptionally good.
The sample was based on an almost complete census of eligible
subjects who were born in selected years and lived in what are
believed to be the high-dose regions and subjects born in the same
years who lived in regions where the doses from Hanford releases
were lower. Efforts to locate subjects and to elicit study
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participation were thorough. The investigators were able to locate
94°/0 of the targeted sample-an excellent result, considering that
40-50 years had elapsed. Since the time of exposure they
succeeded in communicating with about 98% of potential
participants by telephone and had 15°/0 refusals to participate.
Thus, their losses clue to noniocation, noncontact and refusals
totaled only about 23%. That is an excellent rate for a study that
requires people to come in for examination, especially given their
wide geographic dispersal. Furthermore, the losses to the study
were comparable among those with high and low estimated doses,
so participation rates were similar across the dose range.
There was a high level of quality control in the
epidemiologic procedures. The interviewers were carefully trained
by experienced interviewers, and detailed interview manuals were
developed. Care was taken with data entry (double entry was used
routinely), and range checks and consistency checks were
implemented to help to reveal errors in the codes entered by the
interviewers. Callbacks were used when there were clear errors or
missing data.
Care was taken to maintain "blinding" in the clinical
examination and other parts of the study where it could reasonably
be done, to ensure that selection bias, interviewer-induced response
bias, or clinical-examination bias would not creep in. For example,
the residence-milk interviews with parents or the subjects to obtain
residence and milk consumption-rate histories were conducted
before, clinical examination so that neither subjects nor
interviewers would know subjects thyroid status (except in the case
of previously diagnosed thyroid disease).
in short, the HTDS was designed with great care to
eliminate bias due to selection of subjects and due to reporting and
detection of disease. This study compares favorably with other
epidemiologic studies in these respects.
The HTDS considered an appropriate set of potential
confounding variables, including sex; age at first exposure to ]3~i
from Hanford; age at examination; history of diagnostic,
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Evaluation of Epidemiologic and Clinical Methods
51
therapeutic, and occupational radiation exposures; smoking
history; ethnicity; and estimated thyroid dose from the NTS. A few
other variables could have been considered, such as number of
childbirths (for women) and family history of thyroid disease, but
it seems improbable that these would have substantially altered the
results because it is unlikely that they would be differentially
distributed across the dose range. Another potential confounding
variable was global fallout, which is discussed in chapter 4.
MILK-CONSUMPTION ESTIMATION
The consumption of fresh milk is an essential part of
the pathway Tom release of }3~{ to thyroid dose, so information on
the amount and sources (for example, backyard cow versus
commercial dairy) of milk consumed is important in estimating the
individual doses. A questionnaire (called the CATI, for computer-
assisted telephone interview, in the HTDS Draft Final Report) was
developed to obtain information on residence history and milk
sources and amounts during 1944-1957 from the mother or a
surrogate (such as father or older sibling) who would presumably
know about a subject's dietary patterns in childhood. The
questionnaire was carefully developed and went through numerous
revisions and multiple field tests. Professionals with expertise in
questionnaire development commented on ways of eliciting
questionnaire information to maximize the completeness and
accuracy of recall. The development process was about as good as
it could be.
Although the body of the HTDS Draft Final Report
discusses how the milk-consumption questionnaire was developed
and tested and attachments at the end of the report deal with it,
there is not enough explanation of how open-ended information
was coded. In addition, more needs to be stated about how much
probing was used during the interviews, whether the booklet
devised to stimulate memories of events that occurred 40 years
earlier worked effectively and whether such memories were
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Review of the HTDS Draft Final Report
checked for reliability in a subsample (for example, by comparing
reports of the two parents).
The accuracy of such information, obtained 40-50 years
after the fact, is unknown. Food-consumption reporting that uses
questionnaire-based methods is recognized as error-prone.
Assessment (validation) of questionnaire efficacy in estimating
true dietary intake generally requires careful study as a separate
issue (Willett, 1990) before the questionnaire is used to relate food
intake to risk of disease. The HTDS investigators were not able to
evaluate the questionnaire's validity, nor did they cite any evidence
from other studies about the validity of childhood milk-
consumption reports decades after childhood. Milk consumption is
often found to be among the better-reported elements of recent diet
(for example, in the preceding year) when methods typical in
epidemiology studies are used (Salvini and others, 1989), but we
are aware of no studies that directly investigated the reliability or
validity of retrospective milk-consumption reports by surrogates.
A few studies have considered self-recall of diet after
considerable periods. Dwyer and others (1989), considering
retrospective recall of childhood (age 5-9 years) food consumption
by 72 middle-aged subjects who had originally been assessed as
children, reported a correlation of 0.3 between the retrospective
reports of whole-milk consumption and food histories taken during
childhood. It seems credible that mothers' reporting of their
children's early milk-consumption habits could be as good as the
Dwyer group's findings or possibly somewhat better, but reliance
on siblings or other relatives for information about early milk
consumption seems unlikely to be better than the self-reports
studied. Furthermore, a correlation of 0.3 does not indicate good
predictiveness of childhood eating habits.
The HTDS investigators made a strong effort to obtain
information from parents or surrogates. We would expect the
mother to be the best source of childhood milk-drinking
information. However, for 26% of the interviews, the investigators
had to rely on information from some other family member.
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Evaluation of Epidemiologic and Clinical Methods
53
Furthermore, because of parent deaths and other factors, they were
unable to obtain any interview for 38°/0 of the subjects. For the
38°/0, they obtained from the subjects themselves a residence
history and at least the sources (backyard cow, commercial dairy,
and so on) of milk drunk during 1944-1957, but not such details as
the amount consumed. Thus, they had to use default values for a
substantial fraction of the subjects, and this probably introduced
measurement error into the data analyses.
The subcommittee's evaluation of the milk-
consumption assessment is that the investigators did the best they
could under the circumstances but that the resulting data have high
intrinsic uncertainty. The effect of that uncertainty on the statistical
power of the study is discussed in chapter 6 of this report.
The HTDS report has a substantial description of the
collection of dose-related data from people but relatively little
information on how these data were used. The input to the CIDER
program is described as "scenarios", but these are not explicitly
described, nor is their construction from the data. That is separate
from how the CIDER program uses the scenarios to generate
doses. There are a number of references to the use of default values
in the CIDER program, but there is no discussion of which
parameters used default values or of the degree to which default
values changed as life circumstances changed for a given person
(for example, if a person moved from a farm to a city).
EVALUATION OF CLINICAL-DATA COLLECTION
The clinical examinations and laboratory studies used
the best modern methods of detecting and defining thyroid disease.
Subjects were given physical examinations, including thyroid
palpation by thyroid specialists, an ultrasonographic examination,
and appropriate thyroid-hormone and thyroid-antibody blood tests.
Quality control of the laboratory tests and ultrasonographic
examinations was good. The clinicians were kept blinded to
subjects' residential or milk-consumption history to avoid possible
subtle clinical biases.
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The study could have been strengthened if additional
information on the following clinical and pathologic aspects had
been gathered and presented:
Added confidence is needed in the cytopathology data.
The cytopathologic interpretation of thyroid fine-needle
aspirations (FNAs) is a key step in distinguishing benign and
malignant nodules. It would be useful to have the slides
reviewed by two or three cytopathologists who are expert in
thyroid disease and to have a consensus diagnosis when
differences in interpretation are encountered. Special attention
to the category of acellular and hypocellular aspirations that
contain colloid is needed. They were categorized as benign,
and that is not typical clinical practice. What constitutes an
adequate biopsy should be defined in terms of numbers of cells
and preparation technique.
Some subjects had nodules that were not biopsied
during the course of the study. For people with nodules greater
than ~ cm in diameter at last observation, a followup
examination including an ultrasonography to look for nodule
progression could be useful. if progression were detected, an
FNA would be useful to document the characteristics of the
lesion.
A tabular presentation of the pathways to diagnosis
would help readers to assess how the final diagnoses were
assigned. For each clinical outcome, there is more than one
way to make the assignment. For some, such as
hyperparathyroidism, this is straightforward (either high
calcium with high parathyroid hormone or a confirmed
diagnosis before the study). For others, such as thyroid cancer,
it is more complex (combinations of palpable nodule smaller
than I.5 cm, palpable nodule of at least I.5 cm, nonpalpable
nodule of at least I.5 cm, FNA, surgery, prior diagnosis, cancer
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Evaluation of Epidemiologic and Clinical Methods
55
in largest nodule, and cancer as an incidental surgery finding).
A table for each diagnosis with a list of the methods of
diagnosis and the number of each instance should be included
in the full report, and these data should be looked at for any
indication of unsuspected ascertainment bias.
. The public has expressed concern that the HTDS
analyses of the clinical data have "missed the forest for the
trees"; that is, examining the fine categories of diagnoses might
have caused the data analyst to miss trends, that occurred in
broader categories of thyroid disease. Inasmuch as autoimmune
thyroiditis, Graves disease, otherwise unexplained
hypothyroidism, and ultrasonographic texture changes all are
associated with autoimmune processes, one could score a
person with any or all of these as positive for a new global
variable of autoimmune thyroid disease (a broader category
than the one by the same name in the HTDS). Similarly, the
variable "any thyroid nodule", which was already analyzed in
the HTDS report (tables VITI-53 to VTIl-55), is a global
variable of nodular thyroid disease. Any evidence of
hyperparathyroidism or abnormal mineral metabolism could
constitute another global category of disease. These variables
would give a broad-brush view of thyroid disease in relation to
|3~{ dose, which would help to ensure that the fine diagnostic
categories used in the HTDS report did not miss possible
variations in broad categories of thyroid disease. However, a
still broader category of "any thyroid disease" is not
recommended, because combining pathophysiologically
unrelated outcomes lacks biologic plausibility.
COMPLETENESS OF ASCERTAINMENT OF THYROID DISEASE
One possible weakness in the ascertainment of pre-
existing thyroid cancers results from the HTDS investigators'
inability to locate death certificates for all the decedents. Causes of
death were not ascertained for 39 of 541 deaths. Given the small
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number of thyroid cancers in the study (only 14 had estimated
doses and could therefore be used in the dose-response analysis), a
thyroid-cancer death among the unlocated cases could affect the
results. This possibility cannot be ruled out, but it seems
improbable that there would be any thyroid-cancer deaths among
the 39 decedents for whom a death certificate or medical records
where absent. First, there were no thyroid-cancer deaths among the
502 whose cause of death was known, so finding one among the 39
seems unlikely. Second, the probability of dying from thyroid
cancer by the age of 55 is very small: the rate is about 4 per
~ 00,000 persons among both males and females, and thyroid
cancer accounts for every 1,000 deaths in the age range 0-54 years.
Even if one triples the rate to account for a possible radiation
effect, the probability is still very small that a thyroid-cancer death
would be among the 39 whose death certificates were absent.
Thyroid cancer could also be listed as a contributory condition on
the death certificate, but this is rather unlikely unless it was part of
the chain of disease leading to death, which again would have a
low probability. A consultant to our subcommittee indicated that,
of the ~ 19 thyroid-cancer cases he had seen that were diagnosed
before the age of 20 and had an average of 20 years of followup
after diagnosis, only one led to death from thyroid cancer (Ernest
Mazzafern, personal communication); this further confirms the
low likelihood of missed thyroid-cancer deaths.
Data on other thyroid diseases, but probably not thyroid
cancer, can also be lacking because medical records are missing.
The investigators reported that 37°/O of the 1,264 medical records
they sought could not be obtained and that they were not able to
obtain pathology or cytology slides for 10 of the 52 people on
whom they sought them. it would be desirable for them to indicate
for how many potential thyroid diagnoses they were unable to
obtain any medical confirmation, preferably with a breakdown by
reported type of thyroid disease.
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Evaluation of Epidemiologic ant! Clinical Methods
SUSCEPTIBILITY FACTORS FOR THYROID DISEASE
57
At the various public meetings, several people who
lived in downwind areas stated that they and their families had
experienced more-frequent thyroid diseases than would have been
expected in the population at large. They could be right, and their
disease could have been the result of unusual fallout or ingestion
patterns. However, thyroid disease does tend to run in families, and
the particular occurrences could be related to genetic factors within
the families, chance occurrences, or even mistaken diagnoses. The
findings by several research groups that many of the thyroid
cancers being found in Belarus and Ukraine, downwind of
Chernobyl, have relatively unique ptc3 mutations is one line of
evidence for genetic factors in the disease following ~3~} exposure.
An enumeration and study of such clusters could have been
undertaken but were not.
Thyroid cancer is not a common disease, and it would
be reasonable in future epidemiology surveys to identify,
document, and investigate clusters with molecular-biology probes
to characterize genetic polymorphisms that could make people
more sensitive to ionizing radiation or to look for oncogene
prevalence in affected subgroups. These methods are developing
rapidly, and will probably play a role in future environmental-
epidemiology studies.
EVALUATION OF MORTALITY DATA
As part of the study protocol, death certificates for
members of the Hanford cohort who had died were obtained. On
the basis of those early deaths, the investigators calculated a
standardized mortality ratio (SMR) for each cause of death.
Overall mortality in the Hanford cohort was 20% higher than that
in Washington state, which served as the reference population. The
increase was due largely to deaths from congenital anomalies and
"conditions in the perinatal period", although the SMR for
cardiovascular disease was also somewhat increased. in an analysis
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by geographic area, the highest SMR (close to 2.0) was observed
in Franklin County.
Some of the initial findings raise suspicion about the
contribution of radioactive releases from Hanford. The particular
vulnerability of the fetus and infant to adverse effects of radiation
is well known, and the mortality experience of this group in the
Hanford cohort was somewhat unusual. Finding the highest
mortality in the county that is closest to the Hanford site is also
suggestive.
To follow up those observations, the investigators
reanalyzed the data, breaking the total period into times before and
after the peak releases of AT (between March and November
1945) and categorizing people accordingly. In the Draft Final
Report, people are categorized by year of birth. A supplemental
table later provided to the committee by the investigators
categorized people by year of death as well. For congenital
anomalies and conditions of the perinatal penod, the year of birth
and year of death are almost always the same. Table 3.! compares
the results of the analyses by year of birth and by year of death for
the two causes of death.
Table 3. ~ Standardized Mortality Ratios for Selected Causes of
Death by Birth and Death Years
SMR (95% Confidence Interval)
. .
Year of Birth
Year of Death
Cause of
Death 1940-1944 1945-1946 1940-1944 1945+
Congenital ~ .55 ~ .3 ~ .78 ~ . ~ 9
anomalies (1.06-2.19) (0.63- 2.41) (1.15-2.63) (0.69-1.90)
Conditions
ofthe 1.73 2.86 2.~8 1.93
perinatal (~.33-2.21) (2.09-3.83) (~.68-2.78) (~.41-2.59)
period
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Evaluation of Epiclemiologic and Clinical Methods
59
In both versions of the analysis whether data are arrayed by year
of birth or year of death SMRs in the period both before the
Hanford releases (before 1945) and after 1945 are elevated. For
congential anomalies, the excess are slightly larger before 1945
than after, and the same holds true for deaths due to conditions in
the perinatal period when considered by year of death. On the basis
of the analysis, there appears to be no evidence that 13~} iS
responsible for the increased mortality from these causes in the
Hanford cohort. However, when viewed by birth year, the SMRs
for perinatal deaths do appear to be significantly higher in the
period after the beginning of Hanford releases than before. The
discrepancy between the two views of the same data is puzzling
and needs further explication. There remain additional questions
that the Hanford investigators could answer to resolve lingering
questions:
What is the distribution of types of anomalies and of
"conditions of the perinatal period" in the two periods? The
question of whether neural-tube defects are in excess around
the Hanford site has been raised by another study (Sever and
others, 1988) and the information available from the current
study should be presented. The suggestion of a possibly larger
excess in the 1945-1946 birth cohort than in the 1940-1944
birth cohort indicates that a more detailed presentation of the
data is warranted.
. To what extent is the excess mortality associated with
these two causes independent of the geographic excess in
Frar~klin County?
AMERICAN INDIAN TRIBAL ISSUES
The subcommittee had some concerns about the
extremely low number of American Indians in the study. The low
compliance or cooperation might not be completely the fault of the
.
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American Indian tribes. There are established methods for
approaching and establishing rapport and trust with ethnic
communities. The subcommittee wonders whether all these
methods were tried. Perhaps a review of the methods used would
be helpful in a future study.
A second concern is that American Indians had
additional pathways of exposure to radiation from the Hanford site.
For example, some tribes consumed much fish from the Columbia
River. The river was contaminated by various radionuclides
because it was used to coo! the eight single-pass production
reactors, in addition to the periodically increased 13~{ that would
have reached the river from rain and washoff from soil and
vegetation. However, the thyroid dose resulting from aquatic
pathways was likely to have been much smaller than that due to the
consumption of fresh milk or leafy vegetables.
Representative terms from entire chapter:
draft final
