Pragmatic Impact of Proteomic Risk Stratification in Diabetes Mellitus
Phase: NA
Conditions: Type 2 Diabetes
Sponsor: University Hospitals Cleveland Medical Center

 
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PROTOCOL TITLE:  Pragmatic Impact of Proteomic Risk Stratification in Diabetes 
Mellitus (PORTRAIT-DM) 
 
 
PRINCIPAL INVESTIGATORS: 
 
Ian J. Neeland, MD, FACC, FAHA 
University Hospitals, Harrington Heart & Vascular Institute 
Associate Professor, Department of Internal Medicine 
Case Western Reserve University 
11100 Euclid Ave l Mailstop Lakeside 5038 
Cleveland, OH  44106 
P.216.844.5965  F.216.844.8954 
Ian.Neeland@UHhospitals.org 
 
 
OTHER DEPARTMENTS INVOLVED IN THIS STUDY (IF APPLICABLE):     
☐  N/A    
 
VERSION NUMBER:  Version 3 
 
DATE:  
 
11/23/2021  
 
Objectives  
 
Primary Aim: To determine whether risk stratification from 
SomaLogic’s Cardiovascular Risk in Type 2 Diabetes (CVD-T2D) test leads to risk-
concordant changes in prescriptions and/or medical management in patients with 
diabetes.   
 
Key outcome measures: The relation of prescription rates of cardioprotective 
medications (SGLT2i or GLP1 RA) to CVD-T2D test risk assessment in the Informed 
group vs. Uninformed group (primary outcome of the study). 
 
Secondary Aims:  
Secondary Aim 1: To evaluate the perspectives of healthcare providers on the impact of 
SomaLogic’s Cardiovascular Risk in Type 2 Diabetes (CVD-T2D) test risk calculator in 
clinical practice.  
 
Key outcome measure: Survey of healthcare providers on the impact of SomaLogic’s 
CVD-T2D calculator on patient care, medication prescription, and risk perception.  
 
Secondary Aim 2: To enable future health economic analyses of the impact of precision 
risk-stratified treatment.  
 

 
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Key outcome measure: Cost effectiveness of additional therapies using actual uptake 
and event rate reductions estimated from protein predicted risks  
 
 
Secondary Aim 3: In an open-label extension, to determine the impact of additional 
Metabolic Factor test results (beyond the SomaSignal Cardiovascular Risk in Type 2 
Diabetes (CVD-T2D)) on medical management of the previously uninformed group at 
the end of the study.  
 
Key outcome measure: Proposed change in medical management in the uninformed 
group after revealing the result at the end of the study  
 
Background 
Despite the development of novel lipid lowering (1,2,3), anti-inflammatory (4,5), 
antithrombotic (6), dual antiplatelet (7) and anti-diabetic (8,9) treatments, cardiovascular 
disease remains the leading cause of death and disability worldwide (10).  
In clinical practice, it has also been observed that the use of novel glycemia lowering 
therapies with cardioprotective features remains profoundly low (less than 10% of 
eligible patients) despite proven efficacy, professional society guideline endorsement, 
and regulatory labels for cardiovascular benefit (11). The overall prescribing deficiency 
seems particularly acute in individuals with type 2 diabetes, where it has been described 
in 2021 as a “Call for action to the cardiology community” (11). 
As current clinical trials and guidelines tend to “bundle” patients together, there is an 
absence of individualized assessment of residual cardiovascular risk. This leads to 
physicians, patients, and payors being uninformed as to the need for and/or benefits of 
such therapies in an individual. Simply giving every eligible patient a drug regardless of 
residual risk would be unaffordable and would create adverse effects and costs for 
people at low residual risk who might not actually benefit from the drugs. 
This problem arises because traditional cardiovascular risk factors report unresolved 
risk inadequately in vulnerable patients with high observed event rates (13-15) and 
because benefits occur independently of traditional risk factors (4, 5, 16, 8, 16, 17) as 
do adverse drug effects (18). Additionally, physicians’ traditional empirical use of some 
therapies, which is effective for lipids, blood pressure and glycemic control is militated 
against by the insensitivity to improvements of many traditional cardiovascular risk 
factors (age, sex, race, diabetes status and hypertension history) and imaging 
measures (calcium score, carotid, and coronary imaging). This is important because 
novel agents, such as sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-
like peptide 1 receptor agonists (GLP-1 RA) or anti-inflammatory drugs like 
canakinumab, reduce cardiovascular risk independently of changes in these factors.  
Precision risk assessment tools can be helpful in identifying individuals at highest 
cardiovascular risk, who can be targeted with intensive preventive therapies. Proteomic 
analysis has shown promise in risk stratification owing to simultaneous evaluation of 
multiple pathophysiologic mechanisms implicated in the development of cardiovascular 

 
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disease. SomaLogic has performed the largest ever proteomic program to date with 
over 36,000 samples from 26,000 participants in eleven clinical studies, for a total of 
over 180,000,000 protein measurements, to develop and validate a proteomic surrogate 
endpoint for cardiovascular outcomes. The SomaSignal Cardiovascular Risk in Type 2 
Diabetes (CVD-T2D) test, a 27-protein model encompassing ten biologic systems was 
validated to predict the four-year likelihood of myocardial infarction, stroke, 
hospitalization for heart failure or death. Outcomes prediction in six validation datasets 
was consistent across morbidities, demographics, and geographic regions and superior 
to a clinical model using typical risk-factors and laboratory measurements: the Net 
Reclassification Index was +0.43, AUCs were 0.73 vs. 0.63. Event rates in four defined 
risk categories were 5.6%, 11.2%, 20.0% and 43.4% (the latter commonly viewed by 
our practitioners as catastrophically high). There are no risk calculators currently 
available specifically for a higher risk population. SomaLogic developed a clinical model 
derived from the ASCVD risk score (Pooled cohort equation or PCE), scaled to a 4-year 
prediction and calibrated to the higher event prevalence in a higher risk population 
(Manuscript submitted). The validation datasets were divided into quintiles based on 
event rates and compared the ratio of event rates from the highest risk quintile to the 
lowest risk quintile.   The ratio of observed event rates from quintile 5 to quintile 1 was 
7.8 for the 27-protein model and 2.9 for the derived clinical model.  
The table shows the key results and comparisons with the PCE-derived clinical model 
using demographic, medical and laboratory measures, and how the SomaSignal CVD-
T2D test responds more consistently to changes in risk than any one of the common 
biomarkers of risk: 
Table 1: Discrimination capabilities of Somalogic’s CVD-T2D assessment tool in high risk 
populations
 
 

 
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In summary, compared to the PCE-derived clinical risk factor model, the SomaSignal 
Cardiovascular Risk in Type 2 Diabetes (CVD-T2D) test has a superior dynamic range 
of stratification, a greater ability to find patients whose risks are under assessed by 
traditional risk factors, and an improved discrimination between patients with different 
risks. Compared to typical biomarkers that might be used to capture some of the 
benefits of these novel mechanistic drugs, it is more sensitive and more consistently 
responsive to changes in risk.  Elevated cardiovascular risks were also correctly 
detected in non-cardiovascular conditions with known higher cardiovascular event rates: 
diabetes, cancer, rheumatoid arthritis and smoking. 
Additionally, an in-silico assessment of protein-based risk stratification as a tool to 
identify patients who would most benefit from enhanced cardio-protection was 
performed in the archived samples and data from the EXSCEL study (19) of 
approximately 5000 participants with type 2 diabetes. During the study, the random 
“drop-in” rate of additional novel cardioprotective-antidiabetic drugs (SGLT2i) was 
approximately 15%. When stratifying this population with the SomaSignal 
Cardiovascular Risk in Type 2 Diabetes (CVD-T2D) test, the rate of predicted vs. 
observed events were found to be accurate (Table 2). Equally important, SGLT2i 
utilization reduced the cardiovascular event rates in the sub-group at “high” risk defined 
by protein-based risk stratification when compared with those “high” risk sub-group who 
did not receive additional cardioprotective medications. Of note, the allocation of 
additional medications during the study showed no relation to protein risk prediction (i.e. 
physicians making these therapeutic decisions were unaware of actual residual risks). 
Table 2. SomaSignal CVD-T2D Test stratification and 4-year observed event rate in the 
presence/absence of drop- in medications in the EXSCEL trial 
Risk Bin 
Drop in CP 
Medication 
(%)* 
4-year Event 
Rate 
(Events) 
Ha
zar
d 
Rat
io 
Log-estimated 
Hazard Ratio (HR)  
p-value 
(logHR) 
Low Risk 
(N = 115) 
Yes = 17  
(14.8%) 
0% 
(N = 0) 
N/
A 
-18.274 
0.998 
No = 98 
(85.2%) 
7.14% 
(N = 7) 
Medium-Low 
Risk 
(N = 1,759) 
Yes = 222 
(12.6%) 
9.01% 
(N = 20) 
0.9
40  
 
-0.062 
0.782 
No = 1,537 
(87.4%) 
9.63% 
(N = 148) 
Medium-High 
Risk 
(N = 1,944) 
Yes = 238 
(12.2%) 
14.7% 
(N = 35) 
0.9
57  
-0.044 
0.790 
No = 1,706 
(87.8%) 
15.0% 
(N = 256) 

 
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High Risk 
(N = 1,387) 
Yes = 162 
(11.7%) 
25.9% 
(N = 42) 
0.7
12  
-0.340 
0.030 
No = 1,225 
(88.3%) 
32.8% 
(N = 402) 
 
The SomaSignal CVD-T2D test has also been tested and found to be robust for 
consistency over time, insensitivity to interfering substances and to differences in sample 
quality. It is currently commercially available as a laboratory developed test under CAP 
accreditation /CLIA certification from SomaLogic’s central laboratory in Boulder, CO. It is 
also in-use by several pharmaceutical companies in their clinical trials programs. 
Our overarching hypothesis is that the provision of precise, individualized protein-based 
cardiovascular risk assessment to the clinician and the patient results in risk-concordant 
prescription of novel cardioprotective therapies in individuals with type 2 diabetes, such 
that the patients with the highest residual risk are more likely to receive additional therapy 
than the patients at low risk. Furthermore, we will explore the impact of the Metabolic 
Factors panel of tests include testing for Liver Fat, Glucose Tolerance, Alcohol Impact, 
Cardiorespiratory Fitness (VO2 max), Resting Energy Rate, Body Fat Percentage, 
Visceral Fat, and Lean Body Mass. 
      
Inclusion and Exclusion Criteria for Patients (Participants) 
Participants’ eligibility will be determined by study staff.     
 
Inclusion Criteria  
 
Patients receiving care at a University Hospitals location  
 
Patients 40-89 year of age 
 
Diagnosis of Type 2 Diabetes Mellitus   
 
Eligible for but not currently prescribed a SGLT2i or GLP1RA per drug 
label. This includes a diagnosis of type 2 diabetes plus established 
atherosclerotic cardiovascular disease or high risk for atherosclerotic 
cardiovascular disease (including age ≥55 years with coronary, carotid, or 
lower-extremity atherosclerotic disease) or heart failure or chronic kidney 
disease with or without albuminuria.  
 
Patients that are able to provide consent  
  
Exclusion Criteria  
 
Intolerance or contraindication for use of both GLP1RA and SGLT2i 
 
Use of SGLT2i or GLP1RA within the 3 months prior to enrollment 
 
History of, an active, or untreated malignancy, in remission from a 
clinically significant malignancy (other than basal or squamous cell skin 
cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less 

 
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than 5 years prior to, or are receiving or planning to receive therapy for 
cancer, at screening 
 
Patients that have Systemic Lupus Erythematous (SLE) 
 
End-stage renal disease 
 
Pregnancy (as determined by self-report)  
 
Inability to understand English (since must be able to understand risk 
report which is not translated by the manufacturer) 
 
Inclusion and Exclusion Criteria for Providers 
Providers’ eligibility will be determined study staff based on the eligibility of their 
patients.     
 
Inclusion Criteria  
 
Provider of care for patients eligible for inclusion in the study 
  
Exclusion Criteria  
 
Unwilling to participate in the study 
 
Not a provider of an eligible patient for the study 
 
 
Number of Research Participants 
Up to 600 participants at UHCMC.   
 
Number of Providers of Research Participants 
Up to 600 providers at UHCMC (possible 1:1 participant to provider ratio).   
 
Recruitment Methods  
We will apply for waiver of HIPAA for identification of eligible patients. We will review 
medical records to ascertain inclusion/exclusion criteria for eligible patients. Eligible 
providers will be identified based on whether they have a treating relationship with 
eligible patient participants. Providers of eligible patients will then be contacted via email 
with a REDCap link that will direct them to the information sheet and survey to 
determine if they elect to participate. If the provider agrees to participate, the 
corresponding patient will then be approached at their clinical encounter (clinic visit, 
imaging testing, etc) in a private area for study overview and informed consent.  
 
A participant-screening log will be maintained throughout the study. The log will record 
all participants considered for enrollment in the trial and indicate whether they were 
enrolled or not enrolled. In the case of non-enrollment, an explanation will be provided 
on the log as to the reason for their exclusion.  
 
Setting 
Study procedures will be performed at a UH facility (hospital or health center) based on 
the patient’s treatment location. We will screen all patients who have an appointment for 
coronary artery calcium scoring, primary care physicians, endocrinologists and 
cardiologists at UH who meet inclusion and exclusion criteria. Study personnel will 

 
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identify potential research participants through screening the eligibility criteria. Study 
personnel will provide study information to the eligible providers (see recruitment 
method above) and eligible patient participants at the UH location and obtain informed 
consent. Demographic and clinical information will be obtained and phlebotomy will be 
performed for SomaSignal Cardiovascular Risk in Type 2 Diabetes (CVD-T2D) and 
Metabolic Factors testing. Study personnel will then send the blood specimen for 
processing and shipping. Based on the protocol allocation, the SomaSignal 
Cardiovascular Risk in Type 2 Diabetes (CVD-T2D) and Metabolic Factors test 
information will then be provided to the patient’s treating physicians/providers.  
 
Consent Process 
Providers of patient participants consenting to participation in the study will be contacted 
(as described above in Recruitment) and asked to complete a survey. Since the 
completion of the survey implies consent but we will not collect a signature, we are 
requesting a waiver of signature for providers. 
Physical (face-to-face) electronic informed consent with an electronic signature will be 
obtained for all patients prior to participation through REDCap.  
Consent will take place in a private location where a study staff member will spend 
approximately 15 minutes reviewing the goals of the study, inclusion/exclusion criteria, 
risks and benefits of participation, and procedures involved in participation. Sufficient 
time will be given to read, comprehend, and understand the goals and procedures of the 
study. Participants will provide a summary of their role in this research study to the 
study personnel to ensure complete understanding of the study prior to signing the 
consent form. After the electronic signature is obtained from both the participant and the 
study team member reviewing the consent, the patient will have the option of having a 
copy of the consent emailed or printed for their records.   
Tablets will be protected with a case that also allows for disinfecting in between 
volunteers.  
If in some rare occurrence the tablets do not allow for proper informed consent and 
electronic signatures, patients will be given a written paper copy to review and sign. The 
consent will then be uploaded to REDCap for secure storage and privacy. The patient 
will be given a paper copy for their records. 
 
Sharing of Results with Research Participants 
For Arm 1 (Informed arm), the results for the SomaSignal Cardiovascular Risk in Type 2 
Diabetes (CVD-T2D) test will be provided to the care team (physician participants) 
approximately 4 weeks after the blood draw.  Sharing of this information with patients 
will be left to the discretion of the clinical care providers. The additional Metabolic 
Factors test will be provided to the care team (physician participants) approximately 12 
weeks after the blood draw in the second phase (open label extension) of the study.  
 

 
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For Arm 2 (Uninformed arm), the clinicians will provide standard of care without the 
SomaSignal Cardiovascular Risk in Type 2 Diabetes (CVD-T2D) test result in the first 
phase of the study. The results for the SomaSignal Cardiovascular Risk in Type 2 
Diabetes (CVD-T2D) and the additional Metabolic Factors test will be provided to the 
care team (physician participants) approximately 12 weeks after the blood draw in the 
second phase of the study.  
 
Study Design 
Single-center, prospective, 2:1 randomized controlled parallel-group study, with an open 
label extension to evaluate SomaSignal Informed Medical Management (informed) 
versus Standard of Care (uninformed).   
 
Study Procedures 
Randomized Clinical Study: 2:1 Randomized Controlled Parallel-Group   
Arm 1: SomaSignal Cardiovascular Risk in Type 2 Diabetes (CVD-T2D) Test Informed 
Medical Management (Informed). The SomaSignal Metabolic Factors test results will be 
provided in the Open Label Extension; results will not be provided to provider and 
participant until study conclusion. 
Arm 2: Standard of Care (Uninformed). The SomaSignal Cardiovascular Risk in Type 2 
Diabetes (CVD-T2D) and Metabolic Factors test results will be provided in the Open 
Label Extension; results will not be provided to provider and participant until study 
conclusion.   
 
Participants’ eligibility will be determined by study staff.   
Once deemed eligible based on the inclusion/exclusion criteria, participants will be 
enrolled after informed consent.  Eligible patient identification and consent may be 
carried out prior to the clinic/test visit, as allowed by local regulatory policies.  
 
Participants will be randomized using permuted mixed block randomization, in a 2:1 
ratio, i.e., 2 participants to Group 1 (informed of their test results) and 1 participant to 
Group 2 (uninformed of their test results)  
 
Procedures   
 
Patient Intake Questionnaire 
Participants will be asked to complete an intake questionnaire about their past medical 
history, diet and lifestyle. Survey completion will take approximately 15 minutes. All 
surveys will use the REDCap database platform for collection and storage. 
 
Biological Sample Collection  
During the research visit consent will be obtained. After consent occurs, medical history 
will be collected from the subject and/or his/her medical records. A blood sample 
(approximately 5ml) will be collected using an EDTA tube.  The blood sample will be 
processed following the SomaSignal Collection, Processing, and Shipment Instructions. 
The samples will be sent to SomaLogic, Inc. at a frequency agreed by the Principal 
Investigator and SomaLogic, Inc. for analysis. The individual results will be delivered 

 
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to UHCMC using secure electronic means.  Participants will be compensated 20$ for 
their time for participating in the study.  
 
Medical Record Review 
Clinical Data Abstraction will occur during the study (baseline, 8 weeks, and 16 weeks). 
Participants will be provided a SomaLogic patient information booklet at the time of 
recruitment  
 
Communication of Risk 
In the informed groups (arm 1, and open-label extension of arm 2), a risk report will be 
provided to providers (primary care, cardiologists, endocrinologists) involved in the 
patient care. Providers will receive a report by email approximately 2-4 weeks after 
blood draw. A copy of the report will also be scanned into the AEMR for permanent 
storage and view by other providers.  
 
Open Label Extension   
Aims: The open label extension phase will be conducted in participants randomized to 
both arms. This phase is designed to gather additional data on the impact of providing 
CV and metabolic risk information to care team of participants on prescription rates of 
cardiovascular preventive therapies. The clinicians will discuss results of the 
SomaSignal Tests with the participant and make any adjustments to the care plan as 
needed.  Medical treatment decisions and recommendations will be confirmed by 
established clinical methods, including blood pressure monitoring, BMI, lipids, and 
clinical judgement.  This information will be documented in a case report form.    
  
Provider Survey: 
A simple survey will be emailed to providers of participants approximately 8 weeks after 
providing risk report in arm 1 (informed) and 8 weeks after unblinding/open-label 
extension of participants in arms 1 and 2. The survey includes information on provider’s 
perspectives on the risk communication and its impact on patient care.  
 
Study Design  
  

 
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Study Timeline 
The overall study participation will be 20 weeks (primary study plus open label 
extension). 
 
2 Parallel Group Study  
Treatment Arm  
Intervention  
Arm 1:  
SomaSignal Informed 
Medical Management 
(CVD-T2D Test 
Informed)  
Blood draw for SomaSignal Cardiovascular Risk in Type 2 
Diabetes (CVD-T2D) and Metabolic Factors tests at 
baseline  
  
SomaSignal Cardiovascular Risk in Type 2 Diabetes (CVD-
T2D) test results will be sent to the clinicians and 
participants.   
  
Medical record will be reviewed by the study team to 
evaluate changes in treatment strategy.  
 
Arm 2:  
Standard of Care (CVD-
T2D Test Uninformed)  
 
Blood draw for SomaSignal Cardiovascular Risk in Type 2 
Diabetes (CVD-T2D) and Metabolic Factors Tests at 
baseline  
  
However, results the test will not be provided to clinicians in 
this phase of the study. 
  
Medical record will be reviewed by the study team to 
evaluate changes in treatment strategy  
   
Open Label 
Extension: 
Both Arm 1 and 2 
Arm 1 - Metabolic Factors test results will be sent to the 
clinicians and participants in the open label extension at the 
conclusion of the primary study phase.  
Arm 2 - SomaSignal Cardiovascular Risk in Type 2 
Diabetes (CVD-T2D) test results will be sent to the 
clinicians and participants in the open label extension at the 
conclusion of the primary study phase.   
 
Event  
Baseline   4 weeks 
  
12 
weeks 
 
20 
weeks 
Informed Consent   
X 
 
Inclusion/Exclusion Criteria 
X 
 
Randomization  
X 
 
 
 
AEMR Medical Record Review 
X 
X 
X 
X 

 
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Concomitant Medications  
X 
X 
X 
X 
SomaSignal Test  
-Blood draw  
-Sample Prep & Shipping  
X 
 
SomaSignal Cardiovascular Risk 
in Type 2 Diabetes (CVD-T2D) 
test results of Arm 1 (informed) 
 
X 
 
 
Assess Treatment changes and 
reasons in Arm 1 
X 
 
Provider Survey in Arm 1 
 
 
X 
 
Cardiovascular Risk in Type 2 
Diabetes (CVD-T2D) (Arm 2) 
and Metabolic Factors test 
results (Arms 1 and 2) in Open 
Label Extension  
X 
 
Assess Treatment changes and 
reasons in both Arms 
 
 
 
X 
Provider Survey in both Arms 
 
 
 
X 
 
Data to be Collected for your study  
(AFTER consent and HIPAA Authorization have been obtained) 
Upon enrollment in the study, the information listed below will be obtained for each 
participant from the existing AEMR medical record from clinical interactions that 
are part of their standard of care visits. Data will be captured on the study-specific case 
report forms, to be developed by the study team in paper and/or electronic format. All 
data   
 
Participant’s Date of Birth (DOB)   
 
Participants ID number (MRN)   
 
General demographic information   
o Participant’s contact information   
o Age, gender, height, weight, body mass index (BMI)   
o Race and ethnicity   
 
Medical history    
 
Documentation of presence or absence of typical CV risk factors 
 
Vital signs and physical examination (i.e., blood pressure, heart rate, 
oxygen saturation) as available   
 
Concomitant Medications  
 
Changes to any treatment regimen, including any medical management   
 
Outcome Measurements:   
The following measurements will be made:  
1. Changes in cardioprotective prescription medications and lifestyle interventions  

 
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2. Comparison of SomaSignal Cardiovascular Risk in Type 2 Diabetes (CVD-T2D) and 
Metabolic Factors test results with standard of care risk assessments (laboratory 
results, CAC, BMI) 
3. Provider surveys 
   
Record Retention 
The Principal Investigator and/or designated study team member are responsible 
for maintaining accurate, complete, and current records relating to the conduct of the 
investigation, in accordance with ICH GCP E6 (R2) guidelines and CFR. Refer to ICH 
GCP E6(R2) 8.1 to 8.4 for a list of essential documents for retention.  
   
In addition, the Principal Investigator and and/or authorized study team member are 
responsible for retaining any additional documents as required by UHCMC, in 
accordance with departmental and/or institutional records retention policy.  
   
If there is inadequate records storage space at any Intermountain facility, all or part of 
the clinical study records can be sent to an Intermountain-approved archival storage 
facility that has a current executed service contract with Intermountain. As appropriate, 
the study sponsor and other stakeholders will be notified.  
   
If the Principal Investigator transfers custody of all or part of the clinical study records to 
another person or entity, the IRB must be notified within 10 working days after the 
transfer occurs. In addition, and as appropriate, the study sponsor and other 
stakeholders will be notified.  
   
Data Analysis Plan 
Sample Size Calculation 
In this study, there are 2 arms – 1) the Informed group and 2) the Uniformed group so 
we will collect samples for 600 patients total with 400 patients in the Informed group and 
200 patients in the uniformed group (with 2:1 randomization) 
In the Informed group, out of the 400 patients, we anticipate at least 160 individuals 
(40%) to be prescribed medication. Under this circumstance, we will be able to detect a 
17% or greater difference between the high-risk individuals in the informed group and 
the control/uninformed group with 80% power and a 5% Type I error rate. In other 
words, if we assume that the Uninformed/control group has even prescribing rates 
across all risk levels (which is 25% across all levels), then we will be able to detect a 
prescribing rate of 42% or higher in the high-risk group or a prescribing rate of 8% or 
lower in the low-risk group. 
 
Statistical Analysis and Methods 
We will summarize the prescribing rates in each bin using frequency tables and 
histograms. Our primary analysis will be in the informed group, where we will perform a 
multivariate goodness-of-fit test using the multinomial test under the null hypothesis that 

 
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the prescribing rates in each risk set are equal to each other (and thus are all equal to 
25%). 
Following this analysis, we will examine the data from the informed arm. If the numbers 
are large enough, we will use Poisson models to determine if the total number of 
individuals prescribed medication are statistically significantly different between the 
control and informed arm, allowing for a different slope or bin effect for the different 
treatment arms. If sample sizes allow, we will include random intercepts as needed 
(e.g., for clinician). If sample sizes are small, particularly in the control group, we will 
again employ multinomial tests, chi-square goodness-of-fit tests, tests for equal 
proportions, and/or Fisher’s Exact Test and adjust p-values for multiple testing. 
 
Risks to Research Participants 
-Questionnaire: Participants will be asked about sensitive topics such as their health 
status which may create discomfort. Participants will be made aware that they are 
always free to skip a question that makes them feel uncomfortable. 
 
-Blood draw- risks associated with phlebotomy include pain as the needle enters the 
participant’s vein and the risk of bruising at the site of blood draw have been minimized 
by using existing trained staff.  In the event that a participant has a reaction to the blood 
draw, staff will follow standard clinical procedures.     
 
- -Breach in confidentiality- risk of inadvertent disclosure of PHI. Study 
Information sent from UHCMC to SomaLogic will be sent such that the participant 
cannot be identified: site, age, and gender are not enough to identify these 
individuals.  SomaLogic will not have access to the link between number and 
participant name as that will be maintained within UHCMC. In the event of a 
breach, HIPAA reporting requirements will be followed.  
 
Provisions to Protect the Privacy Interests of Research Participants 
Information sent from UHCMC to SomaLogic will be sent such that the participant 
cannot be identified: site, age, and gender are not enough to identify these 
individuals.  SomaLogic will not have access to the link between number and participant 
name as that will be maintained within UHCMC. In the event of a breach, HIPAA 
reporting requirements will be followed.  
 
Potential Benefit to Research Participants 
-Potential benefits:  
-There may be no direct benefit to participation. If the study hypotheses are 
confirmed, there is potential for direct benefit but this cannot be guaranteed. 
These potential benefits if study hypotheses are confirmed include: 
-Increased patient engagement and satisfaction from increased 
personalized medical knowledge   
-Potential for increased patient recruitment and retention from 
offering cutting-edge innovation and technology  

 
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-There is potential benefit to society including: 
-More efficient resource allocation and improved cost-effectiveness of 
pharmaceutical interventions through enhanced patient risk stratification   
-Improved patient outcomes through personalized risk stratification, more 
precise clinical care, and improvements in triage of medical interventions 
and education   
 
Withdrawal of Research Participants 
Voluntary Withdrawal of Consent 
Participants shall have the ability to withdraw consent for study participation, and/or 
withdraw the use of their clinical information and/or biological samples at any time, 
without penalty or loss of benefit to which the participant is otherwise entitled, by 
contacting the Principal Investigator or a designated member of his research team. This 
must be done in writing and addressed to the Principal Investigator at the 
address indicated on the cover page of the Informed consent form.  
   
If a participant enrolled in this study decides to withdraw from the research, or an 
Investigator decides to terminate his/her participation, study investigators must follow 
accepted standard practices regarding the management of collected data about these 
participants, as follows:  
   
• Investigators must document in the research record each instance of a participant’s 
withdrawal, including the reasons for the withdrawal, if known.  
 • Previously collected blood samples, information that has been gathered, and all 
material from the participant's identifiable blood samples that they have at the time of 
the participant's withdrawal from the study will remain in the study to maintain the 
integrity of the research, in accordance with current FDA regulations.  
• The investigator(s) may ask the participant whether he/she will agree to continued 
follow-up and further collection of clinical information following his/her withdrawal.  
• If the participant withdraws and does not agree to the continued follow-up and 
collection of clinical information, the investigator(s) will discontinue access to the 
participant’s medical record or other confidential records, for purposes related to the 
study.  
• Following the participant’s withdrawal from the study, the study team will no longer 
contact the participant nor have access to his/her medical records for research 
purposes (unless specific informed consent has been obtained as described 
above).  
  
Lost to Follow-Up Participants 
Because this study will have periods of time between research-related interactions, 
retention of participating participants until study completion may have challenges. 
To facilitate participant retention, specific information will be obtained during the first 
research encounter and updated at all subsequent encounters. Although critically 
important to the successful completion of the study, if a participant expresses concern 
and/or refuses to provide this information, they will not be excluded from the research.  

 
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The following specific information will be collected and used for this purpose:  
   
 
Contact information of the participant (i.e. address, phone number, email)  
 
Contact information of one or more contact persons (close friend or family 
member) not living with the participant  
   
This contact information will be stored in a secure database and will not be shared 
outside of the study-specific research staff.  
   
If a research participant becomes lost to follow-up, the research team will contact the 
participant or designated individuals named by the participant. A maximum of 3 
telephone calls and/or email will be attempted. If there is no response, an IRB-approved 
certified letter signed by the Principal Investigator requesting for a response may be 
sent. If contact is reestablished, interest in continued participation will be verbally 
confirmed and documented, and the participant will return to active study participation 
as appropriate, based on their status/time point in the research. With failure to re-
establish contact after three direct attempts and a certified letter in the mail, and failure 
to find new contact information, the participant will be considered lost to follow up. 
Participant’s that are lost to follow-up will be followed by electronic medical records.  
 
End of Study Considerations  
A participant will be considered as having completed the study if he/she has met the 
following:  
 
Completed the SomaSignal Tests described in this protocol  
 
Has reasonably responded to the follow-up visits (in-person, telephone, 
video chat, or FaceTime)  
 
Has voluntarily provided the blood samples required by this study  
 
Has continued to allow the Principal Investigator and/or his duly 
designated study staff to access his/her medical records  
 
 
Costs to Research Participants 
This study is funded by SomaLogic, Inc.  
The tests and procedures listed below are considered non-standard of care and will be 
paid for by the study budget.  All other tests, procedures, and study visits are either 
conducted by study personnel (e.g. questionnaire administration, etc.) or charged to the 
patient as routine, standard of care activities.   
 
The budget, contract, and financial agreements will be available in a separate 
document.   
 
 Non-standard of care tests and procedures covered by the study budget are as 
follows:  
 
SomaSignal Test  

 
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 
Blood collection for the SomaSignal Test  
    
Disclosure of Conflicts of Interest    
   
The Principal Investigator, Co-Principal Investigator, Sub-Investigators and protocol 
authors declare that they have no conflicts of interest relevant to this study.  
  
Research Participant Compensation 
Participants will be reimbursed $20 via check for their participation.  They will be given 
the check after completion of the blood draw. To receive payment the participant must 
agree to complete a W-9 form which requires an address and social security number to 
the University Hospitals accounting department. This payment may be considered 
taxable income by the IRS. The participant will be issued a 1099-Misc form only if 
payment exceeds $600 from all studies in which they are participating, in a fiscal year. 
 
Providers will be compensated $20 for their time completing Physician Surveys. 
 
The investigators and their research team will not receive any monetary or other forms 
of direct compensation for conducting this research study.  Payment is made directly to 
UHCMC to cover the costs of study conduct.  
 
Provisions to Monitor the Data to Ensure the Safety of Research Participants 
 
Monitoring 
A safety officer will be appointment for the trial. The safety officer will be a qualified 
individual who does not have any affiliation with the study. A formal safety officer charter 
will be developed. The safety officer will review recruitment, adverse events, 
and stopping criteria at a minimum of every 6 months. The Safety Officer charter will be 
kept on file at UHCMC. Monitoring plans will be provided to SomaLogic, Inc. upon 
request as required by current applicable regulations.  
  
Safety Reporting 
In the event of a safety issue, safety-related data for this study will be collected on 
standardized reporting forms (paper and/or electronic). Safety-related events will be 
defined in accordance with ICH GCP E6(R2), the CFR, UHCMC research policy, and all 
current applicable regulations. All events that meet the definition of an Unanticipated 
Problem will be reported to IRB) within the required time period as defined 
by IRB’s unanticipated problem policy.  
 
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Hypertriglyceridemia. The New England journal of medicine 380, 11-22 (2019).  
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Cardiovascular Disease. The New England journal of medicine 376, 1713-1722 (2017)  

 
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