Determining the Validity of ThinkSono Guidance for Ultrasound Image Acquisition and Remote Detection
Phase: NA
Conditions: Deep Vein Thrombosis, Deep Vein Thrombosis, Pulmonary Embolus
Sponsor: ThinkSono, Ltd.

Determining the Validity of ThinkSono Guidance for 
Ultrasound Image Acquisition and Remote Diagnosis 
(DVT GUARD)  
 
A multi-center, prospective, double-blinded, pivotal study evaluating artificial intelligence 
driven automatic detection of proximal deep vein thrombosis.  
NCT Number: NCT06652568 
Document date: 12/01/2025 
 
 
 
Sponsor: 
ThinkSono, Ltd. 
Company Number 10470929 
33 Flowers Avenue 
HA4 8GA 
United Kingdom 
 
 

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STUDY PROTOCOL  
Note 
This protocol is intended as an illustrative example of the protocols utilized at sites participating in 
the DVT GUARD study. Elements of this protocol are customized to each participating site as 
required. All critical elements of study protocols are conserved across sites. Protocols utilized in the 
study may differ from this example in content and verbiage.  
Statement of Compliance  
This study will be conducted in accordance with the Code of Federal Regulations on the Protection 
of Human Subjects (45 CFR Part 46), any other applicable US government research regulations, and 
institutional research policies and procedures. The Principal Investigator will assure that no deviation 
from, or changes to the protocol will take place without prior agreement from the sponsor and 
documented approval from the Institutional Review Board (IRB), except where necessary to 
eliminate an immediate hazard(s) to the trial participants. All personnel involved in the conduct of 
this study have completed the required trainings.  
 

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1. 
Introduction 
1.1    
Purpose of the Study  
The purpose of this study is to confirm the safety and efficacy of the ThinkSono Guidance System as 
per the intended use defined as:  
ThinkSono Guidance is a guidance, data acquisition, and communication tool that guides non-
ultrasound-trained healthcare staff to collect point of care compression ultrasound data in the 
proximal deep venous system of the lower extremity for interpretation by qualified clinicians.   
1.2   
Background  
Deep vein thrombosis (DVT) is well recognized to cause significant morbidity and mortality both at 
the time of diagnosis and post-diagnosis. Between 30-50% of patients diagnosed with DVT will go 
on to develop post-thrombotic syndrome which has a significant impact on patients' long-term 
quality of life.1,2 Patients with DVT are also at risk of fatal pulmonary embolism (PE), with rates 
estimated to be 0.4% (95% Confidence Interval; 0.2-0.6%) during the initial anticoagulation period 
and 0.3/100 patient-years after treatment.3  
With an estimated incidence of 1- 2 per 1,000 people, over to 300,000 people in the United States 
(USA) will be diagnosed with venous thromboembolism (VTE) per annum and two-thirds of these 
will be DVT.4 However, positive cases only represent 12-25% of the total number of patients who 
present with suspected DVT.5 In other words, between 75-88% of suspected DVT cases, when fully 
investigated, are negative. Estimates have placed the yearly cost of VTE to the USA healthcare 
system as up to $10 billion.6  
It is notoriously difficult to diagnose a DVT by clinical evaluation alone. The standard approach to 
making a diagnosis of proximal DVT currently involves an algorithm combining pre-test probability 
assessment, such as using a Wells score, and compression ultrasonography. Handheld ultrasound 
(US) probes have recently become available and enabled 'app-based' compression ultrasonography to 
be performed without the need for bulky cart or laptop-based ultrasound machines. These new 
machines have a small form factor, meaning only the ultrasound probe is required for diagnostic 
purposes in conjunction with a smartphone or tablet.  
Although the new handheld probes are smaller and are better suited for point of care diagnosis, they 
still require an experienced trained clinician or sonographer to perform the compression ultrasound 
exam. This means that these devices can only be used wherever sonographers/trained clinicians are 
located, which is most often hospital radiology departments. However, due to recent advances in 
"machine learning", software is now available for these 'app-based' probes to assist non-radiology 
healthcare professionals (e.g. nurses, non-radiologist physicians, general practitioners and other 
allied healthcare professionals), as well as caregivers and family members, to perform a compression 
ultrasound exam with minimal or no prior training.  

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The ThinkSono Guidance System is a guidance software expected to help non-specialist healthcare 
professionals produce compression ultrasound image data that meet or exceed the minimal image 
quality criteria for a remote diagnosis by an expert physician (e.g. radiologist).   
This will be based on the American College of Emergency Physicians (ACEP) ultrasound image 
quality scores, where a score of 3 or more is considered adequate for diagnostic quality.   
The ThinkSono Guidance System is not FDA approved; however, in the context of this research 
study, it meets the definition of a non-significant risk (NSR) device in accordance with 21 CFR 
812.3(m) because:  
1. It is not an implant; 
2. It is not purported or represented to be for a use in supporting or sustaining human life; 
3. It is not for a use of substantial importance in diagnosing, curing, mitigating, or treating 
disease, or otherwise preventing impairment of human health in a way that presents a 
potential for serious risk to the health, safety, or welfare of a subject; and 
4. It does not present a potential for serious risk to the health, safety, or welfare of a subject. 
2. 
Study Design 
This is a multi-site non-randomized, double-blinded, prospective cohort pivotal study.  
Double blinding will be done by the ThinkSono software itself because it will not be giving any 
indication of diagnosis or image quality to the operator.  The comparison scan will be done by a 
qualified imaging specialist as per standard of care, but they will also not know the results of the 
ThinkSono scan. There will also be "remote qualified clinicians" reviewing the ThinkSono data who 
will not know the results of the local imaging studies at sites.   
Below is a diagram of the blinding:  
 

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3. 
Subject Population 
3.1  
Number of Subjects, Specimens, and Records   
The study population consists of patients in inpatient vascular labs, emergency departments, 
medical/surgical wards, outpatient offices, or intensive care units requiring a lower extremity venous 
duplex ultrasound scan. These patients will receive a full duplex scan by a trained technologist as per 
the standard of care at sites, and ThinkSono Guidance will be used as an adjunctive test.   
3.2   
Sample Size  
The sample size will be calculated and adjusted for each site to ensure adequate power within local 
site constraints. This study is powered at 80% with a two-sided 95% confidence interval assuming a 
75% point estimate of adequate image quality to ensure the lower bound of the CI is ≥ 60%.  
3.3   
Inclusion Criteria  
Any patient for whom a compression ultrasound scan of the lower extremity is clinically indicated 
will be eligible for enrollment in this study. This means the following:  
1. The participant is willing to provide written informed consent to participate in this research. 
2. The participant is over the age of 18 
3. The participant has signs/symptoms suggestive of a deep venous thrombosis (DVT) 
4. The diagnostic DVT algorithm indicates that an ultrasound is needed 
3.4  
Exclusion Criteria  
1. Patient consent not given or retracted during the study. 
2. Patients who undergo a local imaging scan and initiation of new treatment for DVT (e.g.) 
lytic agents, therapeutic anticoagulation, or intervention after the local imaging scan) before 
a ThinkSono scan can be performed. 
To address this, the ThinkSono scan should be performed before the duplex ultrasound 
scan, or after the duplex ultrasound scan but before any treatment/intervention has 
occurred. If a patient was already on anticoagulation before the duplex ultrasound scan, 
then they can undergo a ThinkSono scan while on anticoagulation, as these conditions 
will be the same between the two scans.  
3. Local imaging specialists fail to scan the patient or fail to produce a conclusive imaging 
diagnosis. 

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4. Incomplete ThinkSono Guidance scan due to logistical or other issues such as pain, lack of 
patient cooperation, barriers such as a cast or other physical limitations. 
5. Pregnant subjects   
 
3.5 
Vulnerable Subjects  
The study will not include vulnerable subjects as defined by federal regulations and institutional 
policies.  
4. 
Study Methods and Procedures 
4.1 
Sources of Data / Materials  
The primary sources of data/materials will be venous ultrasound scans of the lower extremities of 
patients conducted utilizing ThinkSono Guidance. Additional information may be retrieved from 
patients’ medical records as required.   
 
4.2 
Variables of interest     
The primary sources of information will be the standard of care and ThinkSono Guidance scans.  
Primary Endpoints:  
At least 75% of the data collected by non-specialist operators of the study team via the ThinkSono 
Guidance App is adequate for interpretation (i.e., with an ACEP score equal to or greater than 3) as 
rated by a remote qualified clinician.  
For clarification, this means a lower 95% confidence interval (CI) limit of at least 60% needs to be 
achieved in this study to pass the primary endpoint. 
The lower 95% CI for sensitivity for overall triage performance (triage sensitivity) is at least 85% 
relative to standard of care comparison.8 
The lower 95% CI for specificity for overall triage performance (triage specificity) is at least 30% 
relative to d-dimer comparison.8  
The lower 95% CI  for specificity for prioritizing patients (prioritization specificity) is at least 93% 
relative to standard of care comparison.8  
 
 

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Secondary Endpoint:  
Measure the negative predictive value and positive predictive value of ThinkSono Guidance for 
proximal lower extremity DVT.  
Additional Analyses: 
Estimate serial ultrasound sensitivity according to a guideline-recommended 1 week repeat scan. 
Further details and endpoint definitions are discussed in the Statistical Analysis Plan.  
4.4 
Device  
The investigational device is the ThinkSono Guidance System, consisting of the ThinkSono 
Guidance Mobile App (“Mobile App”) which guides non-specialist operators (e.g., registered nurses) 
to collect compression ultrasound data, and the ThinkSono Guidance Cloud-based Software (Cloud- 
based Software”, also referred as “Cloud-based Dashboard”) used by remote or local qualified 
clinicians to review collected ultrasound cine loop clips and to document image quality and vein 
compressibility assessments.   
4.5   Indications for Use  
The Indications for Use are defined as: 
 
The ThinkSono Guidance software is intended to triage suspected DVT patients.  
ThinkSono Guidance is a guidance, data acquisition and communication tool. It guides non-
ultrasound-trained healthcare professionals to collect point of care compression ultrasound data 
related to deep vein thrombosis (DVT), in the deep venous system of the lower extremity, for 
interpretation by qualified clinicians. To be used for patients aged 18 or older, for whom a lower 
extremity compression ultrasound is indicated.  
ThinkSono Guidance consists of the ThinkSono Guidance Mobile App and the ThinkSono Guidance 
Cloud-based Dashboard.  
 
The ThinkSono Guidance Mobile App is indicated to guide non-ultrasound-trained healthcare 
professionals (“operators”) in the acquisition of point of care compression ultrasound cine loops of 
the deep venous system of the leg. The ThinkSono Guidance Mobile App interfaces with a compatible 
ultrasound device, analyzing its output and providing guidance to the operator for recording venous 
compressions.  
The ThinkSono Guidance Cloud-based Dashboard is indicated to present acquired ultrasound data 
to qualified clinicians, for review and interpretation of compression ultrasound cine loops and 
communicating with the operators. 

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In this study, the ThinkSono Guidance System software will be used in addition to a standard 
ultrasound scan for a population of adult patients who present with symptoms suggestive of a DVT.   
The standard clinical pre-test probability algorithm will be used for all presenting patients and the 
software will be used in a double-blinded manner as described above whenever a compression 
ultrasound is indicated. Patients will receive a full duplex scan by a trained technologist as per the 
standard of care, and the ThinkSono Guidance System will be used as an adjunctive data collection 
tool.  
This ThinkSono Guidance System software will guide the user to conduct a multi-point 
compression ultrasound. This involves finding specific areas of the leg and compressing the veins to 
collect compression ultrasound data that follows the American College of Emergency Physicians 
(ACEP) Guidelines.  
The multi-point exam involves the groin to assess the common femoral vein, points along the thigh 
to assess the femoral vein, and the popliteal fossa to test the popliteal vein.   
Once a scan is carried out using ThinkSono Guidance System, the data will be sent to remote 
qualified clinicians (RQC) for assessment.   
Each RQC will rate each ThinkSono Guidance System scan using the ACEP image quality 1 to 5 
scale. An average rating of 3 or more will mean the image data presented meet or exceed the 
minimal criteria for a diagnosis (‘diagnostic quality scan’).   
Subsequently each remote clinician will make their own assessment if the data shows fully 
compressible, not compressible, or indeterminate results.   
These results will then be compared to a local imaging specialist (in a blinded manner) to measure 
the agreement made by the RQC agree with the local imaging specialist.    
4.6 
Concomitant therapy  
The ThinkSono Guidance System software is being investigated as a data collection device in 
parallel with the current standard of care. All patients will receive the standard of care diagnostic 
evaluation--a full duplex compression ultrasound by a trained technologist in addition to ThinkSono 
Guidance System evaluation. The usage of the ThinkSono Guidance System software will not 
interfere with or preclude any standard care.   
4.7 
Adverse Events Definition and Reporting  
The definitions to be applied to adverse events recorded in this study are given in table below. As 
this is a study involving ultrasound scans collecting US data from patients who may have a DVT, 
events of interest are those related to symptomatic venous thrombotic events, which are also study 
outcomes. 
  
Term  
Definition  

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Serious Adverse 
Event (SAE)   
Respectively any adverse event that:  
·       results in death  
·       is life-threatening*  
·       requires inpatient hospitalization or prolongation of existing hospitalization 
·       results in persistent or significant disability or incapacity  
·       consists of a congenital abnormality or birth defect  
·       is otherwise considered medically significant by the investigator.   
Unexpected   
Related Serious 
Adverse Event  
A serious adverse event, the nature or severity of which is not consistent with the 
known risks of ultrasound scans  
Adverse Event 
(AE) 
Untoward medical occurrence, unintended disease or injury, or untoward clinical 
signs (including abnormal laboratory findings) in subjects, users or other  
persons, whether or not related to the investigational medical device and 
whether anticipated or unanticipated.   
Adverse Device  
Effect (ADE)  
Adverse event related to the use of an investigational medical device.  
Note 1 to entry: This definition includes adverse events resulting from 
insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the investigational 
medical device.  
 
Note 2 to entry: This definition includes any event resulting from use error or 
from intentional misuse of the investigational medical device.  
 
Note 3 to entry: This includes ‘comparator’ if the comparator is a medical 
device.   
Serious Adverse  
Device Effect  
(SADE)  
Adverse device effect that has resulted in any of the consequences characteristic 
of a serious adverse event.   
Unanticipated  
Adverse Device  
Effect  
Any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device 
that relates to the rights, safety, or welfare of subjects.   
 

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Any other adverse or serious adverse event not listed above will not require recording. All SAE will 
be reported within 24 hours to the ThinkSono sponsor contact and to the IRB according to local 
reporting policies.  
 
4.8 
Recruitment, enrollment, and retention  
Adult DVT patients will be identified in one of two ways:  
1. A member of the site team, trained as part of the study, will review clinical lists and medical 
records to identify potentially eligible patients, prior to their appointments or scans. 
Providers will refer potential candidates to the approved research team staff to provide more 
study information to a patient. 
2. If the participant's appointment is imminent, on arrival at the facility, potential participants 
will be asked if they are willing to hear more about the research study, while they wait for 
their diagnostic scan in the routine care clinical pathway. 
Patients will be assessed for eligibility to enter the study according to the criteria set out above. If 
patients are eligible for entry into the study following initial screening, consent for entry into the 
study will be sought.  
Participants will be considered eligible for enrollment in this study if they fulfil all the inclusion 
criteria and none of the exclusion criteria previously detailed.  
Enrollment will occur as soon as possible after consent and screening for entry into the study has 
been obtained. Background data (patient characteristics) will be collected. 
It should be noted that all the above are part of the normal care for a patient with a suspected DVT.  
Participants will also be asked if they are participating in any other research studies relevant to deep 
vein thrombosis and if yes, the name(s) of the study/studies which will be recorded. This is 
significant because if the other study they are in can potentially impact the screening, diagnosis, or 
treatment of deep vein thrombosis then there could be bias on the results.  
4.9  
End of Study and follow-up  
The study will be considered closed when an adequate number of patients have been recruited, the 
study data have been cleaned and analyzed, the database locked, and archiving arrangements are in 
place.  
5. 
Data Analysis and Data Monitoring 
All analysis will be conducted according to the Statistical Analysis Plan.  
Annual progress reports will be submitted to the IRB with the continuing review submissions.  

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6. 
Data Storage and Confidentiality 
Confidentiality will be fully preserved by the research team in accordance with regulatory and local 
IRB requirements. Subjects will not be identified by any of the positive identifiers in any publication.  
7. 
Risk/Benefit Assessment 
7.1   
Risk and Protection Against Risks  
The potential risks of the intervention are minimal. As the ultrasound probe will be applied by a 
relatively inexperienced operator, there is a risk that too much or too little compression will be 
applied.  Too little compression might lead to a failed scan — however, the instructions that are 
provided by the ThinkSono Guidance System software will mitigate this likelihood, because if the 
probe does not pick up the requisite information, it will direct the operator to repeat the scan.    
Too much compression or just having a second scan could lead to increased discomfort for the 
patient. It will be made clear to the participant that they can stop or withdraw at any time. As the 
study scan is not used to direct clinical care there is no risk from a failed scan.   
Other data that may be reviewed are part of the standard electronic medical record system. Data will 
be recorded anonymously in a database using a unique identifier that does not link the subjects to 
their patient information. In publications of this research, subject data will remain de-identified. The 
principal investigator of the study will ensure patient privacy is protected. The risk of breach of 
confidentiality is nonzero given the use of patient-specific information; although, given the use of 
unique identifiers and minimal handling of PHI, we anticipate this risk to be low.   
7.2   
Potential Benefits to the Subjects  
There are no anticipated benefits to the participants directly, but the potential benefits of successfully 
developing the ThinkSono Guidance System software include:  
• 
Rapid access to an assessment by a qualified clinician 
• 
Point of care scanning, reducing the need for patients to attend hospital radiology 
departments and hospital emergency departments 
• 
Reduced need for prophylactic anticoagulation whilst waiting for a scan, thereby reducing the 
potential risk to patient of bleeding whilst taking an anticoagulant medication 
• 
Reduced cost for diagnosis due to no longer requiring radiology-specific compression 
ultrasound services and reduced use of anticoagulation 
• 
Higher patient satisfaction with their clinical pathway 
 
 
8. 
Ethics / Protection of Human Subjects 
IRB approval must be obtained before initiation of human subjects research activities.   

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8.1   
Informed Consent  
Patients with a suspected DVT will be discovered upon medical record review and referred to the 
study team. After provider receives patient’s verbal permission to be contacted, the study team 
member will see the patient to explain the study, provide the information sheet, and give the patient 
ample time (up to a few hours) to consider participating in the study. Written and verbal versions of 
the participant information sheet and informed consent will be presented to the participants detailing: 
the exact nature of the study; what it will involve for the participant; the implications and constraints 
of the protocol; the known side effects and any benefits or risks involved in taking part. It will be 
clearly stated that the participant is free to withdraw from the study at any time.  
The participant will consider the information and have the opportunity to question the research team 
to decide whether they will participate in the study.   
Written informed consent will then be obtained by means of participant dated signature and dated 
signature of the person on the study team who presented and obtained the informed consent. The 
person who conducts the informed consent process and obtains informed consent must be suitably 
qualified and experienced and have been authorized to do so by the Principal Investigator. A copy of 
the signed informed consent will be given to the participant. The original signed form will be 
retained at the study site and a copy filed in the medical notes.  
The participant must personally sign and date the latest approved version of the informed consent 
form before any study specific procedures are performed. Informed consent will be obtained in line 
with guidance provided by the relevant institutional regulations and statutory laws.  
 
Participants are free to withdraw their consent to participate in the study at any time, without their 
care being affected and with no obligation to give the reason for withdrawal. If the participant 
voluntarily gives a reason for withdrawal, this should be recorded. If participants withdraw, they may 
withdraw completely or may allow data collection to continue.  Any data collected up to the point of 
withdrawal will be kept and used for the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9. 
References 
1. Prandoni P, Kahn SR. Post-thrombotic syndrome: prevalence, prognostication and need 
for progress. Br J Haematol. 2009 May;145(3):286-95. doi: 10.1111/j.1365-
2141.2009.07601.x. Epub 2009 Feb 13. PMID: 19222476. 
2. Roberts LN, Patel RK, Donaldson N, Bonner L, Arya R. Post-thrombotic syndrome is an 
independent determinant of health-related quality of life following both first proximal and 
distal deep vein thrombosis. Haematologica. 2014 Mar;99(3):e41-3. doi: 
10.3324/haematol.2013.089870. Epub 2014 Jan 17. PMID: 24441147; PMCID: 
PMC3943331. 
3. Douketis JD, Kearon C, Bates S, Duku EK, Ginsberg JS. Risk of fatal pulmonary 
embolism in patients with treated venous thromboembolism. JAMA. 1998 Feb 
11;279(6):458-62. doi: 10.1001/jama.279.6.458. PMID: 9466640. 
4. Apptg.org.uk. VTE in Cancer Patients [Internet]. London: All-Party Parliamentary 
Thrombosis Group; 2015 [cited 2023 May 8]. Available from: 
http://apptg.org.uk/wpcontent/uploads/2016/12/VTE-in-Cancer-Patients-2015.pdf. 
5. Kearon C, Julian JA, Newman TE, Ginsberg JS. Noninvasive diagnosis of deep venous 
thrombosis. McMaster Diagnostic Imaging Practice Guidelines Initiative. Ann Intern 
Med. 1998 Apr 15;128(8):663-77. doi: 10.7326/0003-4819-128-8-199804150-00011. 
Erratum in: Ann Intern Med 1998 Sep 1;129(5):425. PMID: 9537941. 
6. Grosse SD, Nelson RE, Nyarko KA, Richardson LC, Raskob GE. The economic burden 
of incident venous thromboembolism in the United States: A review of estimated 
attributable healthcare costs. Thromb Res. 2016 Jan;137:3-10. doi: 
10.1016/j.thromres.2015.11.033. Epub 2015 Nov 24. PMID: 26654719; PMCID: 
PMC4706477. 
7. Poulikidis KP, Gasparis AP, Labropoulos N. Prospective analysis of incidence, extent and 
chronicity of lower extremity venous thrombosis. Phlebology. 2014 Feb;29(1):37-42. doi: 
10.1258/phleb.2012.012086. Epub 2013 May 6. PMID: 23131597.  
 
8. Bhatt M, et al. Diagnosis of deep vein thrombosis of the lower extremity: a systematic 
review and meta-analysis of test accuracy. Blood Advances. 2020 Mar; 4(7), 1250–1264. 
doi: 10.1182/bloodadvances.2019000960. 
 

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Statistical Analysis Plan 
Methods 
Categorical variables will be presented as proportions, normally distributed continuous variables will 
be presented as mean + standard deviation and skewed continuous variables will be presented as 
median [interquartile range]. Assumptions will be checked, non-parametric alternatives (such as 
Mann-Whitney U test), and mathematical transformations (such as Box-Cox) will be considered as 
needed for skewed distributions. Univariate and multivariable analysis will be performed with 
candidate variables and outcome measures. Statistical significance will be tested using a two-sided 
alpha level of 0.05 and with appropriate multiple testing correction (Bonferroni or Benjamini- 
Hochberg) approach when needed. 
For the primary endpoint, the proportion of image adequacy for interpretation as rated by RQCs will 
be computed via majority voting across reviewers per patient. Additionally, the lower confidence 
interval according to the Clopper-Pearson method will be computed. For each individual RQC the 
proportion exams rates as adequate quality images (ACEP score equal to or above 3) will be 
reported. For the secondary endpoint, sensitivity and specificity of RQCs’ compressibility 
assessments will be computed against the ground truth established by the local imaging technologist 
performing standard of care ultrasound on the same patients, as a part of the standard of care 
diagnostic evaluation. 
The number of confirmed DVTs is defined as the number of patients for which the local imaging 
specialist ground truth scan reports incompressible. The number of false negatives is defined as all 
outcomes rated as compressible by the reviewer (which implies an adequate image quality of ACEP 
score above 3) which are confirmed as incompressible by the local imaging specialist scan. The 
number of true negatives is defined as all outcomes rated as compressible by the reviewer which are 
confirmed as compressible by the local imaging specialist scan. And the number of false positives is 
defined as all outcomes rated as incompressible by the reviewer which are not confirmed as 
incompressible by the local imaging specialist scan. 
If a reviewer assesses a scan as indeterminate which the local imaging specialist deems 
incompressible, that DVT should still be considered towards the overall number of DVTs in the 
dataset, as the patient will be triaged correctly.  Sensitivity and specificity will be reported per 
individual reviewer, as majority voting and via a bootstrapping analysis. The total number of images 
with “Indeterminate” overall compressibility assessments will be reported. Furthermore, sensitivity 
and specificity will be reported per individual RQC following the same inclusion and exclusion 
criteria. As ThinkSono Guidance is intended for a proximal point of care compression ultrasound 
exam, only confirmed thrombosis according to the reference ultrasound scan report that have been 
found in anatomical regions covered by the ACEP guidelines for proximal compression ultrasound 
will be included as “Incompressible” ground truth. Otherwise, the ground truth is considered 
“Compressible”. 

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Endpoints  
Adequate Image Quality 
Definition 
The proportion of adequate image quality measures the amount of ThinkSono Guidance ultrasound 
scans acquired by non-ultrasound-trained operators which have been rated as adequate image quality 
by qualified clinician reviewers. 
Image quality represents the critical safety gate for all triage decisions in the ThinkSono Guidance 
workflow. Each ThinkSono Guidance scan is first reviewed by a qualified clinician before a triage 
decision is made. The clinician assigns an image-quality score using the ACEP Emergency 
Ultrasound Reporting and Quality Assurance Guidelines scale. 1 
A score of ≥ 3 is defined by ACEP as “structures recognizable and diagnosis supportable,” indicating 
that the study meets minimal criteria for diagnostic interpretation. Scans scoring < 3 are 
automatically labeled indeterminate and immediately referred to an ultrasound scan by an imaging 
specialist for confirmation in the same care episode. This structure ensures that when an image of 
adequate quality is presented, the subsequent decision on vein compressibility is made by a qualified 
clinician using interpretable data, thereby preserving patient safety by design. 
Sensitivity and Specificity 
Triage Sensitivity 
Definition 
Triage sensitivity measures the proportion of patients with DVT confirmed by duplex ultrasound 
who are correctly identified by the ThinkSono Guidance workflow as incompressible or 
indeterminate (i.e., not ruled out). It reflects the system’s ability to safely detect DVT cases during 
initial triage. 
Triage Specificity 
Definition 
Triage specificity measures the proportion of patients without DVT on duplex ultrasound who are 
correctly ruled out by the ThinkSono Guidance workflow, i.e., classified as compressible by a 
qualified clinician reviewer. It quantifies the efficiency of the device in safely reducing unnecessary 
confirmatory imaging. 

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Prioritization Specificity 
Definition 
A high prioritization specificity means that there are very few false-positives that end up being 
prioritized unnecessarily. The measure quantifies how reliably the device’s incompressible outcome, 
i.e. when the qualified clinician reviewer is convinced of the presence of a DVT, identifies patients 
who merit high-urgency imaging specialist assessment. 
Every incompressible or indeterminate triage outcome in the ThinkSono Guidance workflow 
proceeds to a scan by an imaging specialist. However, distinguishing between indeterminate and 
incompressible referrals provides institutions with an additional prioritization tool. High 
prioritization specificity ensures that when a patient is referred with an incompressible finding, i.e. 
when the qualified clinician reviewer is convinced of the presences of a DVT, the local institution 
implementing the standard of care ultrasound pathway can trust that an incompressible outcome very 
likely represents a true-positive case. 
Safety is ensured because all indeterminate and incompressible cases are confirmed by duplex scan. 
This metric complements the triage sensitivity (safety of rule-out) and the triage specificity 
(efficiency of rule-out). Together, they show that the ThinkSono Guidance Workflow: 
• 
captures the vast majority of true DVTs 
• 
safely reduces unnecessary imaging for ruled-out patients 
• 
provides a tool for scan prioritization that minimizes unnecessary priority escalation, aligned 
with imaging specialist compression ultrasound performance. 
Statistical Assumptions 
The endpoints are defined as follows: 
 
 
 

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• 
# true positive triage is defined as the number of all confirmed DVTs as per references 
standard that have been correctly referred to an imaging specialist scan by the assessment of 
the qualified clinician. 
• 
# total positives is defined as the number of all confirmed DVTs as per reference standard in 
the studies. 
• 
# false negatives are defined as the number of scans rated as adequate image quality and all 
individual cine-loops of the exam have been rated as compressible by the reviewer though the 
reference standard scan in the studies has confirmed the presence of DVT. 
• 
# true negative triage is defined as the number of scans in which DVT has been correctly 
ruled out by the review of the qualified clinician, i.e the all scans rated as adequate image 
quality and all individual cine-loops of the exam have been rated as compressible by the 
reviewer and the reference standard scan in the studies has confirmed no evidence of DVT. 
• 
# total negatives is the number of all scans where the reference standard confirmed no 
evidence of DVT. 
• 
# false positives is defined as the number of scans rated as adequate image quality and at least 
one cine-loop has been rated as incompressible and the remaining cine-loops of the exam 
have been rated as compressible by the reviewer and reference standard has confirmed no 
evidence of DVT for these scans. 
The proportion of correctly avoided imaging specialist ultrasound will be reported per study site as: 
 
• 
# true negatives is defined as the number of scans rated as adequate image quality and all 
individual cine-loops of the exam have been rated as compressible by the reviewer and SOC 
has confirmed no evidence of DVT for these scans. 
• 
# total scans is defined as the number of all exams in the dataset (complete and incomplete) 
Negative-predictive-value and positive-predictive-value 
The negative-predictive-value (NPV) and positive-predictive-value (PPV) of ThinkSono Guidance 
(based on reviews of qualified clinicians) will be reported. We do expect the PPVpriority to be higher 
than the PPVtriage. 
 
 
 
 

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• 
# true negatives is defined as the number of scans rated as adequate image quality and all 
individual cine-loops of the exam have been rated as compressible by the reviewer and SOC 
has confirmed no evidence of DVT for these scans. 
• 
# compressible assessments is the number of all ThinkSono Guidance reviews reported as 
compressible and adequate quality. 
• 
# true positives is defined as the number of scans rated as adequate image quality and at least 
one individual cine-loop of the exam have been rated as incompressible, and none of the 
cine-loops is rated as indeterminate by the reviewer and SOC has confirmed evidence of 
DVT for these scans. 
• 
# incompressible assessments is the number of all ThinkSono Guidance reviews reported as 
incompressible and adequate quality. 
• 
# confirmed incompressible assessments is the number of all scans where the reference scan 
confirmed a DVT and the ThinkSono Guidance reviewer assessed the exam as adequate 
quality and incompressible. 
Meta-analytic NPV/PPV and CIs will be derived from meta-analytic sensitivity/specificity, their 
confidence intervals and overall study DVT prevalence. 
Serial Ultrasound Sensitivity 
Clinical practice guidelines for proximal compression ultrasound recommend a repeat scan within a 
week if the initial scan is negative. 2 This follow-up is intended to identify thrombi that were not 
detectable at the first visit but subsequently progress to become evident. 
In the ThinkSono studies, repeat scanning is not performed as all patients will receive a full-leg 
duplex scan as their standard of care assessment, leaving no justification for an additional follow-up 
scan. This is consistent with many prior studies in the field, e.g., Goodacre et al. 3 

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Brateanu et al. report that 7% of patients who test negative initially on lower extremity proximal 
compression ultrasound test positive on a repeat scan. 4 
We estimate the serial ultrasound sensitivity as follows: 
 
where 
• 
SUS = Estimated serial ultrasound sensitivity, 
• 
Pr = Prevalence of proximal DVT, 
• 
Pd = Proportion of initially negative patients who develop DVT by follow-up, 
• 
Sen = Estimated single-scan meta-analytic sensitivity of ThinkSono Guidance. 
 
14. References 
1. Liu RB, Blaivas M, Moore C, Sivitz AB, Flannigan M, Tayal V. Emergency Ultrasound 
Standard Reporting Guidelines. American College of Emergency Physicians; June 2018. 
Web. Last accessed 26 October 2025. https://www.acep.org/siteassets/uploads/uploaded-
files/acep/clinical-and-practice-management/policy-statements/information-
papers/emergency-ultrasound-standard-reporting-guidelines---2018.pdf 
2. W. Lim et al., “American Society of Hematology 2018 guidelines for management of venous 
thromboembolism: diagnosis of venous thromboembolism,” Blood Advances, vol. 2, no. 22, 
pp. 3226–3256, Nov. 2018, doi: 10.1182/bloodadvances.2018024828. 
3. S. Goodacre, F. Sampson, S. Thomas, E. van Beek, and A. Sutton, “Systematic review and 
meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis,” BMC 
Med Imaging, vol. 5, no. 1, Oct. 2005, doi: 10.1186/1471-2342-5-6. 
4. Brateanu A, Patel K, Chagin K, Tunsupon P, Yampikulsakul P, Shah GV, Wangsiricharoen S, 
Amah L, Allen J, Shapiro A, Gupta N, Morgan L, Kumar R, Nielsen C, Rothberg MB. 
Probability of developing proximal deep-vein thrombosis and/or pulmonary embolism after 
distal deep-vein thrombosis. Thromb Haemost. 2016 Mar;115(3):608-14. doi: 10.1160/TH15-
06-0503. Epub 2015 Dec 10. PMID: 26660731.