Mortality Benefit of Ultrasound for Incidental Thyroid Nodules Identified With PET Imaging: A Non-Inferiority Emulated Target Trial
Conditions: Thyroid Nodule (Benign), Thyroid Nodule (Diagnosis), Thyroid Cancer
Sponsor: Brigham and Women's Hospital

Mortality Benefit of Ultrasound for Incidental Thyroid 
Nodules Identified with PET Imaging: A Non-Inferiority 
Emulated Target Trial  
Protocol Number: 2024P002073-1 
Principal Investigator: Jeffrey P. Guenette M.D. M.P.H. 
Funded by: Agency for Healthcare Research and Quality 
Version Number:  v.1.0 
20 November 2025 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
 
 
 
 
 
 

  
MGB-HSPH Clinical Trial Protocol Template – v1.0 10 Sep 2025 
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................ 1 
1 
PROTOCOL SUMMARY .............................................................................................................................. 1 
1.1 
Synopsis ............................................................................................................................................... 1 
1.2 
Target vs. Emulated Trial Table ........................................................................................................ 1 
2 
INTRODUCTION ........................................................................................................................................... 4 
2.1 
Study Rationale ................................................................................................................................... 4 
2.2 
Background .......................................................................................................................................... 4 
2.3 
Risk/Benefit Assessment ................................................................................................................... 4 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................................... 5 
4 
STUDY DESIGN ............................................................................................................................................ 5 
4.1 
Overall Design ..................................................................................................................................... 5 
4.2 
Scientific Rationale for Study Design ............................................................................................... 6 
4.3 
End of Study Definition ....................................................................................................................... 6 
5 
STUDY POPULATION .................................................................................................................................. 6 
5.1 
Inclusion Criteria ................................................................................................................................. 7 
5.2 
Exclusion Criteria ................................................................................................................................ 7 
6 
STUDY EXPOSURE ..................................................................................................................................... 7 
6.1 
Study Exposure Definition ................................................................................................................. 7 
6.2 
Measures to Minimize Bias ................................................................................................................ 7 
6.3 
Lost to Follow-Up ................................................................................................................................ 7 
7 
STUDY PROCEDURES ............................................................................................................................... 7 
8 
STATISTICAL CONSIDERATIONS .......................................................................................................... 11 
8.1 
Statistical Hypotheses ...................................................................................................................... 11 
8.2 
Sample Size Determination ............................................................................................................. 11 
8.3 
Populations for Analyses ................................................................................................................. 12 
8.4 
Statistical Analyses ........................................................................................................................... 12 
8.4.1 
General Approach ......................................................................................................... 12 
8.4.2 
Baseline Descriptive Statistics .................................................................................... 12 
8.4.3 
Analysis of the Primary Outcome Measure(s) ........................................................... 12 
8.4.4 
Analysis of the Secondary Outcome Measure(s) ..................................................... 12 
8.4.5 
Sub-Group Analyses ..................................................................................................... 13 
8.4.6 
Exploratory Analyses .................................................................................................... 13 
9 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 13 
9.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................... 13 
9.1.1 
Informed Consent Process .......................................................................................... 13 
9.1.2 
Confidentiality and Privacy ........................................................................................... 13 
9.1.3 
Key Roles and Study Governance .............................................................................. 13 
9.1.4 
Data Integrity, Handling, and Record Keeping .......................................................... 13 
9.1.5 
Protocol Deviations ....................................................................................................... 14 
9.1.6 
Publication and Data Sharing Policy .......................................................................... 14 
9.1.7 
Conflict of Interest Policy .............................................................................................. 14 
9.2 
Additional Considerations ................................................................................................................ 15 
9.3 
Protocol Amendment History ........................................................................................................... 15 
10 
REFERENCES ............................................................................................................................................. 16 
 

Mortality Benefit of Ultrasound for Incidental Thyroid Nodules Identified with PET Imaging 
Version 1.0 
Protocol 2024P002073-1 
20 November 2025 
MGB-HSPH Emulated Target Trial Protocol Template 
 
1 
STATEMENT OF COMPLIANCE 
 
The emulated target trial will be carried out in accordance with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 
21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human 
Subjects Protection and ICH GCP Training. 
 
This study has been exempted by the Mass General Brigham Institutional Review Board (IRB) for review 
and approval. The IRB protocol number is: 2024P002073.  
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Mortality Benefit of Ultrasound for Incidental Thyroid Nodules Identified 
with PET Imaging: A Non-Inferiority Emulated Target Trial  
Study Hypothesis: 
We hypothesize that all-cause mortality in patients with an incidental 
thyroid nodule on PET-CT who did not have thyroid ultrasound within 3 
months is no worse than 5% lower than those who did have ultrasound.  
Outcome Measures: 
Primary Outcome: All-cause mortality. 
Secondary Outcomes: Numbers of thyroid cancer diagnoses, thyroid 
ultrasounds, thyroid biopsies, and thyroid surgeries 
Exploratory Outcomes: Types of thyroid cancer diagnoses 
Study Population: 
All patients age 18-years and older with incidental thyroid nodule on PET-
CT performed between 1/1/2015 and 12/31/2021. 
Sites/Facilities: 
Mass General Brigham healthcare system including Massachusetts General 
Hospital, Brigham and Women’s Hospital, Mass Eye and Ear, and 
associated community sites.  
Exposure: 
Thyroid ultrasound evaluation within 3-months of PET-CT 
 
 
1.2 
TARGET VS. EMULATED TRIAL TABLE 
 
 
Target Clinical Trial 
Observational Emulation 
Design 
Non-inferiority randomized  
controlled trial 
Retrospective non-inferiority 
cohort study 
Aim 
Assess whether all-cause mortality 
in patients with an incidental 
thyroid nodule on PET-CT who did 
Same 

Mortality Benefit of Ultrasound for Incidental Thyroid Nodules Identified with PET Imaging 
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not have thyroid ultrasound within 
3 months is no worse than 5% 
lower than those who did have 
ultrasound 
Inclusion 
Thyroid nodule on PET-CT 
Age 18 or older 
Clinic note within 36-months 
before the PET-CT 
Same, with PET-CT scans between 
1/1/2015 to 12/31/2021 
Exclusion 
Thyroid ultrasound in prior 3 years 
Prior thyroid cancer diagnosis 
Same 
Treatment Strategies 
(1) Thyroid ultrasound ordered to 
be performed within 3 months 
(2) No thyroid ultrasound ordered 
(1) Thyroid ultrasound performed 
within 3 months 
(2) No thyroid ultrasound 
performed within 3 months 
Treatment Assignment  
Randomized to treatment strategy 
Non-randomized to treatment 
strategy. Randomization emulated 
via cloning patients in both arms. 
Treatment 
Implementation 
3-month grace period 
3-month grace period 
Outcome 
All-cause mortality 
Same 
Type of Outcome 
Failure time 
Same 
Follow-up Start 
PET-CT date, equivalent to 
treatment assignment 
PET-CT date, not equivalent to 
treatment assignment 
Follow-up End 
Earliest of death, 7-years from 
follow-up start, or study end 
Same 
Censoring 
Administrative censoring 
Administrative censoring 
Artificial censoring of clones 
Causal Contrast 
Intention to treat and per protocol  
Per protocol effect only 
Non-Inferiority Margin 
5% 
Same 
Statistical Analysis 
Non-inferiority intention to treat 
analysis that consists of comparing 
probability of mortality between 
treatment groups at 7 years.  
 
Non-inferiority analysis using 
clone-censor-weight strategy: 
 
1. Each subject is cloned at study 
baseline; one clone assigned to 
each treatment strategy. 

Mortality Benefit of Ultrasound for Incidental Thyroid Nodules Identified with PET Imaging 
Version 1.0 
Protocol 2024P002073-1 
20 November 2025 
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Kaplan-Meier to estimate 
probability of mortality in each arm 
Construct a 95% confidence 
interval for the absolute difference 
between the two arms, ΔRD 
Taking the type I error rate, alpha, 
to be 0.05, non-inferiority is 
concluded if the upper limit of a 
two-sided 90% = 100(1-2alpha)% 
confidence interval for ΔRDis less 
than the prespecified margin. 
 
 
 
 
2. Person-time for each clones is 
censored when a their observed 
treatment strategy is non-
adherent. That is, clones assigned 
to undergo thyroid ultrasound 
within 3 months are censored at 3 
months of follow-up if no 
ultrasound is performed. Similarly, 
clones assigned to not undergo an 
ultrasound within 3 months are 
censored at the time an 
ultrasound is performed. 
3. A pooled logistic regression 
model is fit for the (conditional) 
probability of adherence, adjusting 
for a priori specified baseline 
factors that predict adherence. 
4. A marginal structural pooled 
logistic regression model is fit to 
the mortality outcome data, as a 
function of time and treatment 
(with interaction), using inverse-
probability of censoring weights 
from step 3.  
5. Treatment-specific marginal 
probabilities of all-cause mortality 
are estimated from the fit in step 
4, from which the causal risk 
difference, ΔRD, is estimated along 
with a two-sided 90% = 100(1-
2alpha)% confidence interval 
(constructed via the bootstrap). 
6. Taking the type I error rate, 
alpha, to be 0.05, non-inferiority is 
concluded if the upper limit of a 
two-sided 90% = 100(1-2alpha)% 
confidence interval for ΔRDis less 
than the prespecified margin. 
Secondary Outcomes 
Cumulative over 7-years from PET:  
Number of thyroid cancers 
Number of thyroid ultrasounds  
Number of thyroid biopsies 
Number of thyroid surgeries 
Same 
Exploratory Analysis 
Types of thyroid cancer diagnoses 
Same 

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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Early pre-symptomatic detection of new or recurrent malignancy is frequently presumed to identify 
disease at a more treatable stage and, thus, result in better survival than detection due to symptoms.1 
However, evidence often only equivocally supports and frequently contradicts this presumption.2–7 
Furthermore, most clinical providers incorrectly estimate the harm versus benefit tradeoffs inherent in 
pre-symptomatic detection strategies.1,8–14 Based on the background information provided in Section 
2.2, we hypothesize that all-cause mortality in patients with an incidental thyroid nodule on PET-CT who 
did not have thyroid ultrasound within 3 months is no worse than 5% lower than those who did have 
ultrasound. 
 
2.2 
BACKGROUND  
 
A recent multi-decade SEER study concluded that overdiagnosis of thyroid cancer is a crucial unresolved 
public health issue.15 Overuse of thyroid ultrasound, particularly for clinically unsupported reasons, is a 
major driver of the overdiagnosis and overtreatment of small non-palpable indolent thyroid cancers.16 
Although evidence is not currently available, it is likely that ultrasound evaluation of incidental thyroid 
nodules on PET examinations fall into this overuse category, particularly given that the baseline 10-year 
mortality of patients undergoing PET examinations at our institution are in the range of 30%-50%. 
Briefly, thyroid nodules have been detected in up to 65% of people in the United States (U.S.) at autopsy 
with most autopsy series showing a prevalence of ~50%.17 However, only 1.1% of people will be 
diagnosed with thyroid cancer18–20 and only 0.4% of all cancer-related deaths are attributable to thyroid 
cancer.20 The 5-year survival for all patients with thyroid cancer is 98.6%21 and 30% of deaths are 
attributable to anaplastic thyroid carcinoma,22 which accounts for only 1% of thyroid cancers.21 
Surgical complication rates in thyroidectomy include a 12% rate of intermediate- to long-term thyroid 
surgery-specific complications including hypothyroidism, hypoparathyroidism, and hypocalcemia from 1-
month to 1-year following surgery in addition to a 6% rate of postoperative fever, hemorrhage, 
emergency intubation, tracheostomy, pneumonia, and cardiopulmonary and thrombotic complications 
within 30 days of surgery.23 
Current American College of Radiology guidelines recommend thyroid ultrasound evaluation of 
incidental nodules identified on PET with determination for biopsy based on ultrasound characteristics.24 
Based on the TI-RADS lexicon for reporting thyroid ultrasound,25 26% of thyroid nodules are 
recommended for biopsy.26  
Given the high incidence of thyroid nodules, low rates of thyroid cancer, and low associated mortality, it 
is likely that workup of incidental thyroid nodules does not impact mortality yet results in patient harm. 
We thus aim to provide evidence to help understand whether ultrasound evaluation of incidental 
thyroid nodules on PET examinations contributes to overdiagnosis and overtreatment. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
Known potential risk to subjects is limited to inadvertent breach of confidentiality due to exposure of 
identified data. This risk will be minimized by following data safety criteria outlined in Section 9. There 

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are likely no direct benefits to subjects, but it is hoped that information gathered from this study may be 
helpful to the medical care of patients in the future. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
PRIMARY PURPOSE (OBJECTIVES) 
OUTCOME MEASURES 
JUSTIFICATION FOR 
OUTCOME MEASURES 
Primary 
 
 
Estimate whether all-cause 
mortality in patients with an 
incidental thyroid nodule on PET-
CT who did not have thyroid 
ultrasound within 3 months was 
non-inferior within a 5% margin 
to those who did have 
ultrasound. 
 
 
All-cause mortality 
Determined by three thyroid 
endocrinologists and a head 
and neck surgeon to be a 
reasonable timeframe in 
which thyroid cancers have 
time to develop and 
contribute to mortality but 
not so much that it becomes 
difficult to separate thyroid 
cancer-related mortality from 
other causes. 
Secondary 
 
 
Estimate whether numbers of 
thyroid cancers, thyroid 
ultrasounds, thyroid biopsies, 
and thyroid surgeries are higher 
in patients with an incidental 
thyroid nodule on PET-CT who 
had versus did not have thyroid 
ultrasound within 3 months. 
 
Number of thyroid cancers, 
number of thyroid ultrasounds, 
number of thyroid biopsies, 
number of thyroid surgeries 
Between-group differences in 
these outcomes will help 
establish whether the 
estimated non-inferiority 
result is clinically meaningful 
and justifiable due to 
increased morbidity in those 
who under further thyroid 
nodule characterization. 
Tertiary/Exploratory  
 
 
Explore whether types of thyroid 
cancer diagnoses are different 
among patients with an 
incidental thyroid nodule on PET-
CT who had versus did not have 
thyroid ultrasound within 3 
months. 
Thyroid cancer subtypes 
It is likely that mostly 
indolent papillary thyroid 
carcinomas are identified 
when incidental thyroid 
nodules are further 
evaluated. 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
We hypothesize that all-cause mortality in patients with an incidental thyroid nodule on PET-CT who did 
not have thyroid ultrasound (the exposure) within 3 months of the PET-CT is non-inferior within a 5% 
margin to those who have thyroid ultrasound at 7-years. That is, among patients with an incidental 

Mortality Benefit of Ultrasound for Incidental Thyroid Nodules Identified with PET Imaging 
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Protocol 2024P002073-1 
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thyroid nodule on PET-CT, mortality is no more than 5% larger (in absolute difference) for those who do 
not have thyroid ultrasound compared to those who do. We will also report mortality differences at 
landmark timeframes of 1-year, 3-years, 5-years, and 10-years. 
 
Understanding an expected 30%-50% baseline 10-year mortality rate in patients who undergo PET 
imaging at our institution, a 5% non-inferiority margin was chosen based on the most conservative 
proposed margin by 2 thyroid endocrinologists (one did not respond) and a head and neck surgeon 
(other proposed margins were 7% and 10%). This margin decision was informed by typical margins of 5% 
to 10% used in non-inferiority trials of medications with outcomes involving mortality27 and by recent 
non-inferiority trials of thyroid cancer treatments.28,29 The observational nature of this non-inferiority 
study and absence of prior studies that show effect sizes for the reference make ideal margin point-
estimate and fixed-estimate calculations impossible, but our expert panel method is supported as a 
practical necessity30 to provide guidance on the fraction of the point estimate of the active comparator 
that stakeholders are willing to lose at a cost of gaining other advantages (in this case, likely fewer 
biopsies and surgeries), as in the point-estimate margin calculation method.31 Given this careful pre-
specification of our margin with this panel decision, we will follow published methodology 
recommendations30 and consider re-evaluation of the margin based on the secondary benefits seen in 
the emulated trial or we may conduct the final analysis without reference to a margin. These decisions 
will be clearly detailed in final manuscripts. 
 
To estimate group differences in mortality, we will conduct a non-inferiority emulated target trial 
utilizing clone-censor weighting to address potential immortal time bias introduced by the 3-month 
grace period. We will adjust for all variables labeled as demographic, potential confounder, or mortality 
risk adjustor in as listed in the Section 7, below. 
 
We will stratify analyses based on baseline disease severity (estimated 5-year relative survival risk) and 
disease status (progression, lymph node involvement, other sites of metastases). 
 
All subjects will be accrued from the Mass General Brigham healthcare system, which includes two 
academic medical centers, a specialty head and neck hospital, and multiple community hospitals and 
numerous community clinics. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The baseline 10-year mortality of patients undergoing PET examinations at our institution are in the 
range of 30%-50%. Our interest is in whether, following the detection of a thyroid nodule, doing nothing 
(i.e. no thyroid ultrasound) results in mortality that is no worse than 5% more than doing something (i.e. 
thyroid ultrasound). Thus we are using a non-inferiority design. Since performing an ultrasound aligns 
with ACR recommendations, we’ve designated the imaged group as the reference group.  
 
4.3 
END OF STUDY DEFINITION 
 
Mortality data collected up to October 15, 2025. Patients included in the study until they died or until 
administratively censored.  
 
5 
STUDY POPULATION 
 

Mortality Benefit of Ultrasound for Incidental Thyroid Nodules Identified with PET Imaging 
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5.1 
INCLUSION CRITERIA 
 
In order to be included in this study, an individual must meet all of the following criteria: 
1. Age >=18 
2. Thyroid nodule on PET-CT performed 1/1/2015 to 12/31/2021 
3. At least one clinical note in the EHR from the 36-month window prior to the PET 
Note, there are no restrictions on the indication for the index PET-CT. 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded: 
1. Thyroid ultrasound listed in the medical record in the prior 3 years 
2. Documented history of prior thyroid cancer diagnosis 
 
6 
STUDY EXPOSURE 
 
6.1 
STUDY EXPOSURE DEFINITION 
 
For this target trial emulation, exposure is whether a thyroid ultrasound is performed within 3 months 
of the index PET-CT. 
 
6.2 
MEASURES TO MINIMIZE BIAS 
 
Data extraction from the electronic health record data warehouse using SQL and Python scripts will 
necessarily be conducted with patient identifiers. All data will be anonymized prior to analysis and all 
blinded data utilized for analysis will be published publicly as utilized in the analysis. Study group 
assignments will be strictly performed based on whether or not thyroid ultrasound was performed 
within the 3-month period following the PET-CT; there is no subjectivity to the assignment. 
 
6.3 
LOST TO FOLLOW-UP 
 
Complete mortality data is available in the electronic health record via regular updates from electronic 
death registry systems, regardless of patients’ continued care within the study healthcare system; so 
there is no loss to follow-up for the primary outcome. The 3-month grace period between the PET 
examination and the ultrasound will be addressed with clone-censor weighting. For the secondary 
outcomes, we will consider patients who did not have any provider note for 2-years following the PET-
CT to be lost to follow-up. 
 
7 
STUDY PROCEDURES 
 
All of the following variables, except the last 12 disease status variables, will be extracted from the 
electronic health system research data warehouse using Snowflake, SQL scripts, and Python scripts. The 
extracted data will be coded as described in R. The last 12 disease status variables will be extracted and 
coded from the PET-CT reports by an instance of ChatGPT4 in Azure that is secure behind the healthcare 
system firewall. Data will be included for patients who had PET-CT examinations performed between 

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1/1/2015 and 12/31/2021, which allows a 3-year period for complete propagation of death records to 
our healthcare system’s electronic health records. All HIPAA rules and local institutional and IRB 
requirements will be followed for data collection. 
 
Exposure Variable 
Explanation 
thyroidus3mospost 
Exposure: 1 = thyroid ultrasound performed within 3-months 
following imaging examination; 0 = thyroid US not performed within 
3-months following imaging examination 
 
 
Outcome Variables 
Explanation 
mortality_binary 
Primary Outcome Binary: 1 = died within follow-up period; 0 = did 
not die within follow-up period 
follow_up_in_days 
Primary Outcome Continuous: Number of days from imaging 
examination to death, 10-years, or end of study, whichever comes 
first 
thyroid_cancer_dx_post_pet 
Secondary Outome Binary: 1 = ICD10 C73 diagnosis after PET exam; 
0 = no ICD10 C73 diagnosis 
post_pet_thyroid_excision 
 
Secondary Outcome Binary: 1 = CPT code 60100 for thyroid excision 
performed after PET exam 
thyroid_ultrasounds 
Secondary Outcome Continuous: Number of thyroid ultrasound 
exams performed after PET exam 
thyroid_biopsies 
Secondary Outcome Continuous: Number of thyroid biopsies 
performed after PET exam 
thyroid_cancer_subtype 
Exploratory Outcome: ICD10 C73 subcategory 
 
 
Inclusion/Exclusion Variables 
Explanation 
thyroid_nodule 
Inclusion Criteria: 1 = thyroid nodule reported in imaging 
examination report; 0 = thyroid nodule not reported 
priorcareinsystem 
Inclusion Criteria: 1 = clinic note within 36-months prior to PET; 0 = 
no clinic note in that timeframe 
age 
Inclusion Criteria and Demographic: age in years at time of imaging 
examination 
priorthyroidus 
Exclusion Criteria: 1 = thyroid ultrasound performed within 3-years 
prior to imaging examination;  0 = thyroid US not performed within 
3-years prior to imaging examination 
priorthyroidcancer 
Exclusion Criteria: ICD-10 C73 or ICD-9 193 before PET 
NoSustainedCare 
Exclusion Criteria: 1 = no provider note within system for 2-years 
following recommendation 
 
 
Examination Variables 
Explanation 
exam_id 
Identifier: Anonymized imaging examination ID 
patient_id 
Identifier: Anonymized patient ID 
exam_year 
Year imaging examination was performed 

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pet_cat 
Potential Confounder: PET Type - 1= "NM PET WHOLE BODY 
OUTSIDE WITH INTERPRETATION OR CONSULT"; 2="NM PET CT 
SKULL BASE TO MID THIGHS", "NM PET CT SKULL BASE TO MID 
THIGH WITH DEDICATED BRAIN", "NM PET CT SCALP TO TOES"; 
3="NM PET CT NEUROENDOCRINE TUMOR LOCALIZATION"; 4 = "NM 
PET CT PROSTATE CANCER IMAGING"; 5= "NM PET CT BONE SCAN 
SODIUM FLUORIDE" 
exam_care_level 
Potential Confounder: care level at time of examination - E = 
Emergency; I = Inpatient; O = Outpatient 
ReferringProviderDepartment 
Potential Confounder: specialty of provider who ordering imaging 
examination; specialties categorized into 6 broader groups:  surgery, 
pediatrics, emergency medicine,neurology, oncology, other 
medicine, and missing  
exam_site 
Potential Random Effect: anonymized location of scanner where 
examination performed 
 
 
Additional Patient Variables 
Explanation 
sex 
Demographic: 1 = male; 2 = female; 3 = other/unknown 
adi 
Demographic: national area deprivation index on scale 0 (low 
deprivation) to 100 (high deprivation) based on listed home address 
in 2025 
coi 
Demographic: national childhood opportunity index on scale 0 (low 
opportunity) to 100 (high opportunity) based on listed home address 
in 2025 
svi 
Demographic: social vulnerability index on scale 0 (low vulnerability) 
to 100 (high vulnerability) based on listed home address in 2025 
language 
Demographic: self-reported language 
race 
Demographic: self-reported race 
ethnicity 
Demographic: self-reported ethnicity 
smoking 
Potential Confounder: 0 = never; 1 = former; 2 = active; No_self-
report = not reported; most recently recorded prior to imaging 
alcohol 
Potential Confounder: 0 = never; 1 = occasional; 2 = heavy; most 
recently recorded prior to imaging 
social_hx_contact  
Date social history was taken  
socialhx_days_from_exam 
Days from social history to PET exam date (amount is negative if 
social history was taken after) 
obesity 
Potential Confounder: 1 = diagnosis of obesity (ICD-10 E66, ICD-9 
278.00 or 278.01) at time of imaging examination OR OR cacluated 
BMI >30 at timepoint within 1 year before and closest to imaging 
examination; 0 = no diagnosis of obesity or BMI >30 
metabolic_syndrome 
Potential Confounder: 1 = diagnosis of metabolic syndrome (ICD-10 , 
ICD-9 277.7) at time of imaging examination; 0 = no diagnosis of 
metabolic syndrome at time of imaging examination 
mi 
Mortality Risk Adjustor: Myocardial Infarction: ICD-10 I21.9; ICD-9 
410; recorded prior to date of imaging examination 

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chf 
Mortality Risk Adjustor: Congestive Heart Failure:  ICD-10 I50; ICD-9 
428; recorded prior to date of imaging examination 
pvd 
Mortality Risk Adjustor: Peripheral Vascular Disease: ICD-10 I70, I73; 
ICD-9 443, 440.2, 440.3, 440.4; recorded prior to date of imaging 
examination 
cva 
Mortality Risk Adjustor: Cerebrovascular Accident: ICD-10 I60-I63, 
G45; ICD-9 430-438; recorded prior to date of imaging examination 
dementia 
Mortality Risk Adjustor: Dementia: ICD-10 F01-F03; ICD-9 290; 
recorded prior to date of imaging examination 
cpd 
Mortality Risk Adjustor: Chronic Pulmonary Disease: ICD-10 J42-J44; 
ICD-9 491-492; recorded prior to date of imaging examination 
ctd 
Mortality Risk Adjustor: Connective Tissue Disease: ICD-10 M30-
M36; ICD-9 710; recorded prior to date of imaging examination 
pud 
Mortality Risk Adjustor: Peptic Ulcer Disease: ICD-10 K25-K28; ICD-9 
531-534; recorded prior to date of imaging examination 
ld 
Mortality Risk Adjustor: Liver Disease: ICD-10 K70-K77; ICD-9 570-
573; recorded prior to date of imaging examination 
dm 
Mortality Risk Adjustor: Diabetes Millitus: ICD-10 E8-E13; ICD-9 249-
250; recorded prior to date of imaging examination 
hemiplegia 
Mortality Risk Adjustor: Hemiplegia: ICD-10 G81; ICD-9 342; 
recorded prior to date of imaging examination 
ckd 
Mortality Risk Adjustor: Chronic Kidney Disease: ICD-10 N18; ICD-9 
585; recorded prior to date of imaging examination 
cancer 
Mortality Risk Adjustor: Cancer: ICD-10 C00-C96; ICD-9 140-209; 
recorded prior to date of imaging examination 
obesity_icd 
Mortality Risk Adjustor: Diagnosis of obesity (ICD-10 E66, ICD-9 
278.00 or 278.01) at time of imaging examination 
bmi 
Mortality Risk Adjustor: Body mass index at time of imaging 
examination 
hncancer_binary 
Mortality Risk Adjustor: Head/Neck Cancer: ICD-10 C00-C14; ICD-9 
140-149; recorded prior to date of imaging examination 
radiation_binary 
Mortality Risk Adjustor: Radiation Therapy: CPT 77401-77416, 
G6003-G6014,77385-77386,G6015-G6016 
priorneckradiation 
Mortality Risk Adjustor: Prior head/neck cancer radiation therapy 
(hncancer_binary =1 and radiation_binary =1 , then priorneck 
radiation =1;  otherwise, 0) 
Fiveyr_atPET 
Mortality Risk Adjustor: 5 year survival probability associated with 
cancer dx received before PET exam (if multiple cancers before PET, 
lowest survival probability) 
DiseaseFree 
Potential Confounder: 1 = PET-CT report indicates there is no active 
malignancy 
DiseaseProgression 
Potential Confounder: 1= PET-CT report indicates disease 
progression 
LymphNodes 
Potential Confounder: 1= PET-CT report indicates there are lymph 
node metastases 
NonNodeSites 
Potential Confounder: 1= PET-CT report indicates that there are 
axillary lymph node metastases 

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AxillaryNodes 
Potential Confounder: 1= PET-CT report indicates that there are neck 
or supraclavicular lymph node metastases 
MediastinalNodes 
Potential Confounder: 1= PET-CT report indicates that there are 
mediastinal (including paratracheal, paraesophageal, prevascular, 
subcarinal, perihilar, or hilar) lymph node metastases 
AbdominalNodes 
Potential Confounder: 1= PET-CT report indicates that there are 
abdominal (including peri-portal, celiac, mesenteric, retroperitoneal, 
iliac) lymph node metastases  
InguinalNodes 
Potential Confounder: 1= PET-CT report indicates that there are 
inguinal lymph node metastases 
NonNodeSites 
Potential Confounder: 1= PET-CT report indicates that there are 
metastases outside of the lymph nodes (liver, lungs, bones, soft 
tissue, stomach, bowel, colon, spleen, pancreas, adrenal glands, or 
other organs other than the thyroid and other than the primary site) 
Lung  
Potential Confounder: 1= PET-CT report indicate that there are likely 
metastatic lesions in the lungs 
Bone  
Potential Confounder: 1= PET-CT report indicates that there are 
likely metastatic lesions in the bones 
Liver  
Potential Confounder: 1= PET-CT report indicate that there are likely 
metastatic lesions in the liver 
 
8 
STATISTICAL CONSIDERATIONS  
 
8.1 
STATISTICAL HYPOTHESES 
 
Primary Outcome Measure 
  
Hypothesis: All-cause mortality in patients with an incidental thyroid nodule on PET-CT who did not have 
thyroid ultrasound within 3 months is no worse than 5% lower than those who did have ultrasound 
within 3 months. 
 
Null hypothesis: All-cause mortality in patients with an incidental thyroid nodule on PET-CT who did not 
have thyroid ultrasound within 3 months is more than 5% higher than those who did have ultrasound 
within 3 months. 
 
Secondary Outcome Measure(s) 
 
Hypotheses: (1) number of thyroid cancer diagnoses, (2) number of thyroid ultrasounds, (3) number of 
thyroid biopsies, and (4) number of thyroid surgeries are each higher in patients with an incidental 
thyroid nodule on PET-CT who had versus did not have thyroid ultrasound within 3 months. 
 
Null hypotheses: (1) number of thyroid cancer diagnoses, (2) number of thyroid ultrasounds, (3) number 
of thyroid biopsies, and (4) number of thyroid surgeries are each not higher in patients with an 
incidental thyroid nodule on PET-CT who had versus did not have thyroid ultrasound within 3 months. 
 
8.2 
SAMPLE SIZE DETERMINATION 
 

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Informed by a preliminary sample of 84,775 patients undergoing CT and MRI imaging in 2015 with 
baseline rates of 10-year mortality of 39.5%, covariate adjusted power was assessed via simulation. For 
each simulated dataset, we resampled sex and age from the empirical covariate distribution among the 
sample of 84,775 patients and generated a binary indicator of 5- or 10-year mortality from a logistic 
regression model whose coefficients reflected the actual strength of association between each covariate 
and mortality. A logistic regression model was then fit to each simulated data set, where the primary 
coefficient of interest reflected the log odds ratio between treatment and mortality. Covariate adjusted 
power was calculated as the fraction of simulated datasets for which the two-sided confidence interval 
for this coefficient did not contain 0.2275, the value of the log-odds ratio corresponding to a 5% non-
inferiority margin given the baseline mortality rate of 39.5%. Given that more covariates will be available 
once final analysis datasets are compiled, this method reflects a conservative estimate. Based on the 
results we anticipate having at least 75% power for a 5% non-inferiority margin. 
 
8.3 
POPULATIONS FOR ANALYSES 
 
Single dataset for per-protocol analysis including all patients who met the inclusion/exclusion criteria. 
 
8.4 
STATISTICAL ANALYSES 
 
8.4.1 GENERAL APPROACH 
 
For descriptive statistics, categorical data will be presented, stratified by observed treatment status, as 
percentages while continuous data will be presented as medians and interquartile ranges. For non-
inferiority (primary aim) inferential tests, statistical significance is defined as the estimated 7-year 
mortality two-sided confidence interval of the study group not crossing an absolute 5% lower 7-year 
mortality rate of the reference group. For superiority (secondary aims) inferential tests, statistical 
significance is defined as the estimated between-group difference two-sided confidence interval not 
crossing zero. 
 
8.4.2 BASELINE DESCRIPTIVE STATISTICS 
 
The study and reference groups will be compared on baseline characteristics, including demographics 
and disease status, using descriptive statistics without inferential statistics (there are no associated 
hypotheses). 
 
8.4.3 ANALYSIS OF THE PRIMARY OUTCOME MEASURE(S) 
 
The statistical analysis plan is outlined in detail in the Target Vs. Emulated Trial Table in Section 1.2. We 
do not anticipate substantive missing data. 
 
8.4.4 ANALYSIS OF THE SECONDARY OUTCOME MEASURE(S) 
 
No secondary endpoints are dependent on the findings from the primary endpoint. Analysis methods 
will follow the general approach for the primary outcome. Specifically, steps 1-4 of the Target Vs. 
Emulated Trial Table in Section 1.2 produce weights which reflect probability of ultrasound adherence. 
These weights will then be used to fit inverse probability weighted outcome models, which will either be 

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logistic regression or linear regression models, depending on the exact outcome data type. 
Correspondingly, results will be presented as risk differences or odds ratios with appropriate 95% 
confidence intervals. 
 
8.4.5 SUB-GROUP ANALYSES 
 
Stratified analyses will be performed based on baseline 5-year relative survival probabilities, calculated 
on the basis of the known cancer diagnoses and disease status at the time of PET. 
 
8.4.6 EXPLORATORY ANALYSES 
 
Descriptive statistics with counts and proportions of thyroid cancer subtypes in the study and reference 
groups will be performed. 
 
9 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
9.1 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
9.1.1 INFORMED CONSENT PROCESS 
 
Informed consent was waived by the institutional review board. 
 
9.1.2 CONFIDENTIALITY AND PRIVACY  
 
This study is a chart/imaging review only. There will be no interaction with the patients outside of the 
standard care being provided. Inclusion in the study will not impact or influence medical care in any 
way. Identifiable health information will be stored on a computer on the Mass General Brigham network 
with password protections enabled and anti-virus software or an encrypted laptop, with access to data 
limited to study staff. Direct identifiers, such as name and medical record number, will be removed once 
all of the data is collected and analysis performed on de-identified data. 
 
9.1.3 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
 
Name, degree, title 
Jeffrey P. Guenette M.D. M.P.H. 
Institution Name  
Brigham and Women’s Hospital 
Address 
1670 Tremont Street, 3rd Floor, 
Boston, MA 
Phone Number 
617-732-7260 
Email 
jpguenette@bwh.harvard.edu 
 
9.1.4 DATA INTEGRITY, HANDLING, AND RECORD KEEPING 
 
The principal investigator will verify that the study is conducted and data are generated, documented 
(recorded), and reported in compliance with the protocol, International Conference on Harmonisation 

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Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)).  
 
Data collection is the responsibility of the study staff under the supervision principal investigator. The 
principal investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported. 
 
Clinical data will be extracted from the electronic health records system and stored in csv files in 
restricted, password-protected, cloud folders behind the Mass General Brigham firewall.  
 
Data retention will follow Mass General Brigham and NIH guidelines. Deidentified data will be publicly 
shared on Harvard Dataverse. 
 
9.1.5 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations to the reviewing Institutional Review Board (IRB) per their policies. The site investigator is 
responsible for knowing and adhering to the reviewing IRB requirements. 
 
9.1.6 PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy. This study will be registered at ClinicalTrials.gov, 
and results information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt 
will be made to publish results in peer-reviewed journals.  Data from this study may be requested from 
other researchers by reviewing the data repository on Harvard Dataverse.  
 
9.1.7 CONFLICT OF INTEREST POLICY 
 

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Any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or 
any aspect of this study will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the design and conduct of this study.   
 
 
9.2 
ADDITIONAL CONSIDERATIONS 
 
None. 
 
9.3 
PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
11/18/25 
Initial Protocol 
Not applicable 
 
 
 
 
 
 

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