Genomic Medicine Pilot for Hypertension and Kidney Disease in Primary Care
Phase: NA
Conditions: Hypertension, Chronic Kidney Disease, Genomics
Sponsor: Icahn School of Medicine at Mount Sinai

       
 
 
 
Genetic testing to Understand and Address Renal Disease Disparities (GUARDD) 
 
 
 
Principal Investigator: ​Carol R. Horowitz, MD, MPH 
 
 
ClinicalTrials.gov Identifier:​ NCT02234063  
 
Protocol version: ​March 16, 2016 
 
 
1 
 

       
 
 
 
Genetic testing to Understand and Address Renal Disease Disparities (GUARDD)
 
 
 
Principal Investigator: Carol R. Horowitz, MD, MPH
 
 
ClinicalTrials.gov Identifier: NCT02234063
 
Protocol version: March 16, 2016 
 
 
1 
 

TABLE OF CONTENTS 
1.
BACKGROUND AND SIGNIFICANCE
3 
1.1
Overview
3 
1.2
Study Aims
5 
2.
ENDPOINTS
7 
2.1
Primary Endpoints
7 
2.2
Secondary Endpoints
7 
3.
STUDY DESIGN
8 
3.1
Study Arms & Design
8 
3.2
Randomization
8 
3.3
Blinding
9 
3.4
Sample Size
9 
3.5
CCARP Genomics Subcommittee- Stakeholder Engagement
9 
4.
STUDY POPULATION
9 
4.1
Inclusion Criteria
9 
4.2
Exclusion Criteria
10 
5.
RECRUITMENT AND ENROLLMENT PROCEDURES
10 
5.1
Participating Sites
10 
5.2
Provider Recruitment, Consent and Survey
10 
5.3
Participant Identification and Recruitment Strategies
10 
5.4
Screening Procedures
11 
5.5
Participant Consent Process
11 
5.6
Participant Discontinuation/Withdrawal from the Study
12 
5.7
Lost to Follow-Up
12 
5.8
Risks
12 
5.9
Benefits
13 
5.10
Costs to the Participants
13 
5.11
Compensation to Participants
13 
6.
STUDY PROCEDURES
13 
6.1
Provider Surveys
13 
6.2
Baseline Study Visit
13 
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6.3
Follow-Up Assessments
14 
6.4
Specimen Collection
15 
6.5
Specimen Transfer and Genetic Testing Procedures
15 
6.6
Return of Genetic Results
15 
6.7
Electronic Health Record Data Extraction
16 
6.8
Study Retention
18 
7.
SAFETY ASSESSMENT AND MONITORING
18 
7.1
Distress from Return of Results
18 
7.2
Elevated Blood Pressure Readings
18 
8.
STATISTICAL ANALYSIS PLAN AND SAMPLE SIZE
18 
8.1
Sample Size Determination
18 
8.2
General Statistical Methods
19 
8.3
Population for Analyses
19 
8.4
Analysis of the Secondary Endpoints
19 
8.5
Handling of Missing Data
19 
9.
DATA MANAGEMENT
19 
9.1
Data Entry and Record Keeping
19 
9.2
Database Management and Quality Control of Data
20 
10.
ETHICAL AND HUMAN SUBJECTS CONSIDERATIONS
20 
10.1
Institutional Review Board
20 
10.2
Large Scale Data Sharing
20 
11.
PROTOCOL DEVIATIONS
21 
REFERENCES
22 
 
 
1. BACKGROUND AND SIGNIFICANCE 
1.1
Overview 
 
Approaches and experiences of ongoing early adopter programs for incorporating genomic information in 
clinical care have to date been largely limited to examples conducted at a small group of academic institutions in 
few highly-specialized areas, including pharmacogenetics (​1​, ​2​), tumor-based screening (​3​, ​4​), family 
history-based decision support (​5​, ​6​), and diagnostic whole exome/genome sequencing (​4​, ​7​). However, studies 
that develop robust systems to consent, screen, return results, and that evaluate processes and outcomes of 
incorporating genomic risk information in clinical care for common chronic diseases are missing and urgently 
3 
 

needed. We propose that hypertension-attributable chronic kidney disease has emerged as a highly-relevant 
opportunity for a ‘prototype’ genomic medicine demonstration project that addresses common chronic illnesses 
managed in primary care settings. Hypertension-attributable chronic kidney disease (CKD) is characterized by  
●
high prevalence affecting millions of Americans (​8​), 
●
high burden of morbidity and mortality related mainly to increased cardiovascular disease risk and kidney 
failure or end stage renal disease (​8​),  
●
progression to kidney failure that can be modified by appropriate pharmacological interventions (​9-11​),  
●
a disproportionate burden for African Ancestry and major health disparity (​12​) (​13-16​)​ (​17​)​ (​18​),  
●
a substantial and testable population selective genomic risk that explains most of the excess burden of 
hypertension-attributable CKD risk in African Ancestry populations (​19​) (​20​) (​21​) (​22​). 
 
Synthesis of evidence and formulation of study rationale 
Synthesis: Chronic Kidney Disease (CKD), Hypertension and Blood Pressure Control. ​CKD is a common, 
complex disease affecting 26 million Americans adults (​8​). CKD is most commonly attributable to diabetes 
(40% of CKD cases) and hypertension (28% of cases). African Ancestry populations with hypertension (HTN) 
have 2- to 3-fold higher risk of developing CKD, and a 5-fold increased risk to progress to end stage renal 
disease (ESRD) when compared with whites. ​HTN is an established risk factor for progression of CKD and for 
increased cardiovascular risk with CKD. Thus targeting blood pressure control as a modifiable risk factor may 
both reduce CVD in people with CKD and reduce progression of CKD to end stage disease (​9-11​).  
 
Synthesis: Poor adherence with renal care practice guidelines puts participants at risk for kidney failure 
Importantly, major goals of practice guidelines for renal care in hypertensive participants remain unmet in 
clinical practice today: among Medicare participants with hypertension without diabetes, only 1 in 25 receives 
recommended simple lab tests (creatinine and urine albumin) to evaluate CKD, and less than half of all 
participants with moderate to advanced stages of CKD in the Kidney Early Evaluation Program (KEEP) are 
aware that they are affected (​23​). Among younger participants of African Ancestry CKD awareness is 
particularly low (​23​) and progression to kidney failure is typically accelerated resulting in excessive rates of 
ESRD (​13​) (​18​).  
Improved CKD awareness and access to primary care or nephrology referral for individuals with or at 
risk of CKD are considered critical to improve CKD-related outcomes (​24​, ​25​). Factors associated with 
progression of CKD and with increased cardiovascular risk are overlapping to a large extent, including 
hypertension. There is strong evidence that blockade of the renin-angiotensin system  is a blood pressure 
lowering strategy which is more effective in reducing risk of kidney and cardiovascular disease in the presence 
of albuminuria, a marker of CKD (​26​). ​Thus, in order to improved renal care and reduce risk for kidney failure 
in this population at excess risk, we urgently need new strategies:  
●
to improve comprehension of CKD risk and CKD awareness among participants with CKD or at risk for 
CKD and among their providers, and  
●
to increase adherence with practice guidelines targeting those risk factors that are modifiable may both 
reduce cardiovascular disease in people with CKD and reduce progression of CKD to end stage kidney 
disease.  
 
Synthesis: ​APOL1​ G1 and G2 risk alleles and non-diabetic kidney diseases. 
A locus containing the myosin heavy chain 9 (MYH9) gene for non-diabetic kidney disease in African ancestry 
individuals was initially identified by admixture mapping (27, 28). Recently, three non-synonymous coding 
4 
 

variants in the neighboring ​APOL1​ gene defined two allele, termed G1 and G2 with stronger effect on 
non-diabetic kidney disease than MYH9 variants (​19​). The authors suggested that G1 and G2 alleles are 
exceedingly rare in non-African ancestry genomes, but in African ancestry genomes, 22.5% and 14.6% of 
chromosomes carry the mutually-exclusive G1 and G2 risk alleles because they were selected for by providing 
protection against Trypanosomiasis (sleeping sickness) in West Africa (​19​).  
APOL1​-associated kidney disease risk is best explained using a recessive model, and approximately 13% 
of African Americans are estimated homozygous for G1 / G2 risk alleles, suggesting that more than 3 million 
AA are at markedly increased risk for non-diabetic CKD (​20​). In our IPM Biobank, 15% of more than 5,000 AA 
participants were found to carry [2] risk alleles, and the odds for hypertensive CKD in this cohort were 2.7. We 
recently analyzed the effect of APOL risk alleles on severity of hypertension-attributed kidney disease in the 
African American Study of Kidney Disease and Hypertension (AASK) cohort (Table 1). ​APOL1​ risk alleles are 
highly significantly associated with CKD attributed to essential hypertension in non-diabetic AASK participants, 
and the odds for advanced kidney disease (significant proteinuria or serum creatinine >3 mg/dl) were >4-fold in 
carriers of [2] risk alleles compared to [0,1] risk alleles (​22​). Heterozygous G1 or G2 risk allele status does not 
appear to increase kidney disease risk. 
 
 
 
Table 1​. Logistic regression model of the effect of APOL1 risk alleles on clinical phenotype AASK cases and 
controls 
 
In summary, [2] ​APOL1​ G1 / G2 homozygous risk allele status  
●
explains practically all of the substantial excess genetic risk for non-diabetic CKD in African ancestry 
populations, 
●
is present in 1 out of 7 African American participants genotyped at Mount Sinai, 
●
is strongly and consistently associated with hypertension-attributable CKD (odds >2.7) 
●
is strongly and consistently associated with progressive and proteinuric states of hypertension-attributable 
CKD (odds >4.0) or with hypertensive ESRD (odds 7.3).  
 
5 
 

Thus, published evidence and our own Mount Sinai results strongly support our hypothesis that carriers of [2] 
APOL1​ risk alleles have an increased genomic risk for hypertension-attributable CKD and its progression to 
kidney failure.  
 
1.2
Study Aims  
GUARDD is multifaceted and has elements that involve qualitative research for a formative study to better 
information development of the randomized trial. This protocol is focused on the randomized controlled trial. 
 
AIM II. Develop systems and evidence-based advice messages to enable point of care Clinical Decision 
Support (CDS) for primary care providers advising renal care practice guidelines with or without 
genomic ​APOL1​ risk information  
 
Rationale. ​One of the highly anticipated quality improvement advantages offered by EHRs and ‘meaningful 
use’ is the potential for point of care Clinical Decision Support (CDS). CDS provides clinicians or participants 
with knowledge presented at appropriate times to improve healthcare. In this context, CDS also has the potential 
to increase the awareness of and adherence to, standard of care processes. Mount Sinai’s IPM conducts several 
early adopter projects testing utility and adoption of pharmacogenomic CDS for clinicians in real-time at the 
point of care. We will develop new functionality for our existing CLIPMERGE Risk Assessment Engine 
database (CRAE database) to deliver CDS for renal care practice guidelines based on conventional kidney 
disease risk assessment with or without ​APOL1​ genomic kidney disease risk information. Importantly, we will 
for the first time develop interfaces that will allow CRAE to disseminate standardized CDS to independent Epic 
EHR implementations across different primary care practice settings at IFH and MSMC.  
 
Sub-Aim 2.1. Modification of CLIPMERGE Risk Assessment Engine (CRAE) technology for multiple 
EHR (IFH and MSMC) and renal care CDS capabilities.  ​CRAE houses phenotypic and gene variant data 
necessary for the evaluating enrolled participants’ data relevant to the guidelines to be implemented for this 
study.  The CRAE database will be populated only for enrolled participants. The CRAE database itself houses 
very strictly de-identified data (only).  A separate function named the Broker handles all necessary translation 
between identified data (as needed for participant enrollment, for transactions flowing from and to Epic, and for 
receipt of genomic results from the CLIA lab) and de-identified data.  
The ​CLIPMERGE-EPIC Integration.   ​The CLIPMERGE database will include longitudinal clinical data 
extracted from Mount Sinai’s and IFH’s Epic EHR systems, for all consented participants enrolled in the 
research study; including CLIA-grade ​APOL1​ genotype and G1 G2 risk allele data from those that have been 
genotyped. Our CLIPMERGE Risk Assessment Engine (CRAE) includes this database and a rules engine that 
relates genome-based advice messages (renal care advice messages incorporating ​APOL1​ genomic risk 
information with conventional risk data) or conventional risk based advice messages to standard of care clinical 
decision support messages. During the first six months of year 1, the CLIPMERGE and Epic team at Mount 
Sinai will work with the Epic team at IFH to build HL7 interfaces customized between CRAE and the specific 
Epic version installed for IFH sites.  
Reference and educational material.  ​Upon presentation of a BPA, providers will have the opportunity to 
directly access reference content that further describes the evidence base for the CDS through a clickable link in 
the Epic SmartSet.  
6 
 

 
Sub-Aim 2.2. Development and usability testing of a library of evidence-based renal care advice messages 
customized for assessment of risk with and without ​APOL1​ G1 G2 risk allele information, and for 
adherence to practice guidelines for renal care in non-diabetic African ancestry participants with 
hypertension  
Rationale. ​CKD awareness among participants and providers, appropriate use of tests for biochemical markers 
of CKD (creatinine and urinary albumin excretion) to screen for presence of CKD in those at risk, and 
appropriate use of pharmacological and life style interventions in those at risk for CKD progression are 
considered critical to improve CKD-related outcomes (ESRD, CVD, and mortality (​24​, ​25​). As summarized in 
the paragraph “​Synthesis: Poor adherence with renal care practice guidelines puts participants at risk for 
kidney failure” ​at the beginning of the APPROACH section, major goals of practice guidelines for renal care in 
hypertensive participants remain unmet in clinical practice today. Blacks have higher prevalence of hypertension 
(41% vs. 28%), younger age of onset, and poorer control of hypertension than Whites ​(​17​). ​Blacks also have​, ​a 
2-3x the risk for developing CKD (​12​), and the adjusted prevalence rate for ESRD is 4.1-fold higher in AA 
when compared with Whites (​14-16​). The differences in CKD are most pronounced among those with 
hypertension. Thus, it is imperative to uncover new strategies to screen and engage AAs with hypertension into 
programs to improve BP control and participant outcomes.  
 
The Kidney Disease Improvement Global Outcomes (KDIGO) evidence-based practice guidelines advise 
the appropriate use of tests for biochemical markers of CKD (creatinine and urinary albumin excretion) to screen 
for presence of CKD in those at risk, and appropriate use of pharmacological and lifestyle interventions in those 
at risk for CKD progression are considered critical to improve CKD-related outcomes (ESRD, CVD, and 
mortality (​24​, ​25​). Practice guidelines, including the Joint National Commission 7 (JNC7) guidelines, 
recommend specific medications (ACE inhibitors and ARBs) as preferred first line agents and more intensive 
blood pressure goal in participants with hypertensive CKD (​9-11​). 
Several reports demonstrate that ​APOL1​ risk alleles are highly significantly associated with CKD 
attributed to essential hypertension in non-diabetic AASK participants, and the genetic association was most 
robust in individuals with progressive renal functional decline (​22​) (see our AASK Cohort data in Table 1). 
Because of the overwhelming strengths of the evidence, we propose to establish ​APOL1​ genomic risk status in 
non-diabetic AA participants and to incorporate the ​APOL1​ G1/G2 risk allele status in a recessive model 
together with conventional risk factors in CKD and CKD progression advice messages.  
 
Aim  III​. Conduct a randomized trial assigning eligible participants to immediate genetic testing or 
delayed genetic testing arms in a seven (immediate testing) -to- one (delayed testing) ratio.  
 
Sub-Aim 3.1:  To examine whether increase in practice guideline-appropriate renal laboratory test ordering 
(renal care endpoint) will be achieved in ​APOL1​-positive group vs ​APOL1​-negative group. 
 
Sub-Aim 3.2. To examine whether systolic blood pressure will decline more in the ​APOL1​-positive group 
compared with ​APOL1​-negative group.  
 
7 
 

2.
ENDPOINTS 
2.1
Primary Endpoints 
The study has two primary endpoints, comparing patients who are ​APOL1​ positive (high risk) 
and ​APOL1​ negative at three months after enrollment. One primary aim is a renal care endpoint, the correct 
utilization, by clinicians, of urine albumin tests. The other primary aim is reduction of systolic blood pressure.  
2.2
Secondary Endpoints 
Secondary endpoints include differences between APOL1 positive participants in the intervention and 
participants in the control group, impact on primary outcomes at 12 months, psycho-behavioral differences of 
participants between groups and over time, clinician knowledge, attitudes and beliefs at baseline and 12 months, 
and differences in outcomes between those tested and not tested immediately. 
 
3.
STUDY DESIGN 
3.1
Study Arms & Design 
This is a prospective, multicenter, unblinded, randomized clinical trial (RCT) (​Figure 1​). The study was 
designed to randomize 2050 participants to immediate ​APOL1​ gene testing and return of results (ROR) 
(intervention) or delayed​ APOL1​ gene testing and ROR (control) in a 7:1 ratio. Outcome measures will be 
compared among three arms of the GUARDD study, the ​APOL1​-positive and ​APOL1​-negative intervention 
(immediate ​APOL1​ genetic testing and return of results) groups, and the control (delayed ​APOL1​ testing and 
return of results) group.  
  
8 
 

  
Figure 1.​ GUARDD study flowchart. 
 
3.2
Randomization 
Eligible participants will be randomized in a 7:1 allocation to Intervention (i.e., immediate ​APOL1​ gene testing 
and ROR to participant and provider) and Control arms (delayed ​APOL1​ gene testing and ROR to participant 
and provider) to optimize the proportion of participants with immediate ​APOL1​ genetic testing compared with 
delayed genetic testing at completion of study. Randomization will be stratified by clinical site with a random 
block size within site. 
3.3
Blinding 
GUARDD randomization assignments will not be blinded to any participants, providers or study personnel.  To 
minimize bias in the measurement of the primary outcome, randomization assignments will only be revealed 
after baseline survey responses and blood pressure readings have been collected. Digital blood pressure devices 
(such as BpTru portable blood pressure machine (29)) will be used to measure blood pressure, and blood 
pressure will be measured as the mean of the second and third blood pressure readings for each participant at 
each study visit. 
9 
 

3.4
Sample Size 
 The total number of people expected to participate is 2,050. Of the 1800 intervention participants, 
approximately 250 will test positive. We will thus have approximately 250 high risk, 250 control, and 1550 
normal risk participants. The sample size for the study was calculated assuming a 10% improvement in practice 
guideline-appropriate renal function test ordering in the ​APOL1​-positive group (40% estimated) vs. 
APOL1​-negative group (30% estimated) to yield 87% power to detect the difference of interest using a 
two-sided chi-square test. Specifically, this includes measurement of serum creatinine and urine microalbumin. 
The blood pressure sub-aim, 5mmHg improvement in systolic blood pressure at 3-month follow up in 
APOL1​-positive compared with ​APOL1​-negative group, can be detected with 95% power.  
3.5
CCARP Genomics Subcommittee- Stakeholder Engagement 
 
The CCARP Genomics Subcommittee members comprised of clinicians, researchers and community leaders 
will be in every stage of the research, including: choosing the study approach, tailoring and shaping the patient 
education materials, developing and implementing recruitment and retention strategies, deciding what to 
evaluate with survey questions, and disseminating our findings to the community.  
 
4.
STUDY POPULATION 
4.1
Inclusion Criteria 
●
Self-reported African American/Black or having African Ancestry 
●
English speaking 
●
Age 18-70 years 
●
Have diagnosis of hypertension  
o
Diagnosis of hypertension is defined by either: 
ICD9 diagnosis codes (present in encounter diagnosis or in problem list) and/or 
Taking anti-hypertensive medications or 
2 systolic blood pressure readings >140 mm Hg or 2 diastolic readings >90 at least six 
months apart. 
●
Received primary care from one of the participating clinical sites ≥1 within the past 2 years.  
●
Do not have diabetes by self report, or defined by: 
ICD9 diagnosis codes (present in encounter diagnosis or in problem list) or 
HbA1c ≥ 6.5 at least one time in the last year  
●
Do not have CKD by self report or defined by either:  
1) ICD9 codes OR 
GFR < 60 ml/min 
4.2
Exclusion Criteria 
●
Have diabetes measured or by self report 
●
Have CKD measured or by self report 
●
Pregnancy at time of enrollment by self report 
10 
 

●
Too cognitively impaired to provide informed consent and/or complete the study protocol measured by 
mini mental status exam 
●
Institutionalized or too ill to participate (i.e. terminally ill, incarcerated, in psychiatric or nursing home 
facility) by self report 
●
Plan to move out of the area within 12 months of enrollment by self report 
●
Not a patient under the care of a provider for their hypertension at a participating site by self report 
●
Previously participated in the ​APOL1​ qualitative pilot study or have previously undergone ​APOL1 
testing 
 
5.
RECRUITMENT AND ENROLLMENT PROCEDURES 
5.1
Participating Sites 
Recruitment will be from primary care clinics within Mount and Institute for Family Health. 
5.2
Provider Recruitment, Consent and Survey 
We will present the study to providers at participating clinics and ask them to complete a short form consent 
explaining the purpose and the voluntary nature of their participation in the study. They will also receive the 
GUARDD APOL1 Provider Baseline Survey to be completed upon enrollment where we will ask questions 
about their current knowledge of genomics and personalized medicine and clinical decision support. At this 
time, we will also ask providers to give us permission to contact their patients who may be eligible to participate 
in the randomized trial and to have a recruitment letter sent to their patients signed by them or their practice. 
Providers who prefer to have a recruitment letter sent from them will provide a signature on a copy of the letter. 
As new providers join practices, we will also obtain their permission to contact their patients and ask them to 
complete the survey.  
We will ask providers at participating sites to complete the GUARDD APOL1 12 Month Follow-Up Survey
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
approximately 12 months after study enrollment. This questionnaire will contain similar questions asked at baseline, in
 
 
 
 
 
 
 
 
 
 
 
 
  
  
addition to reactions to any clinical decision aids or exposure to APOL1 genetic testing over the course of the study. A
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
list of participating providers will be kept by the study team to track completion of questionnaires and training
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
attendance at the different study sites.  
5.3
Participant Identification and Recruitment Strategies 
Participant Identification 
Electronic Health Record (EHR) Data Runs for Eligible Participants  
Potential participants will be primarily identified through data runs using the inclusion criteria mentioned 
above. Lists with PHI identifying potential participants are emailed to the Program Manager via a secure, 
password protected Excel file. Participant’s, date of birth, address and phone numbers, primary care provider 
name and clinic site extracted from the EHR are imported into the Redcap study database.  
Referral 
Participants may self-refer from any advertisement materials (posters, flyers). They may also be referred by a 
family member or friend, or by a provider who has agreed to allow their participants to participate in the study. 
11 
 

If a participant is referred, the Study Coordinator should check the REDcap database to ensure the participant is 
not already in the database and proceed accordingly.  
 
Participant Recruitment 
There are three main scenarios for recruitment: 
●
Via recruitment letter:​ ​Study Coordinators will be assigned participants (from the list of potentially 
eligible participants obtained through an Epic data run) and mail study recruitment letters to them. 
Letters are mailed in a bright blue envelope and postmarked with the GUARDD and clinic site logo to 
assist participants with recall and recognition. Participants can call us upon receiving the letter and they 
will then be screened for study eligibility. Study Coordinators will wait approximately 2 weeks after this 
mailing for a participant to return the letter refusing to participate, to call them, or to meet them at an 
upcoming clinic visit.  
●
During a phone call:​ If a participant does not return the refusal letter or contact us within 2 weeks of 
mailing, the Study Coordinator assigned to him/her will contact the participant by telephone. Using the 
recruitment phone script they will remind them about the letter that was mailed to them, introduce or 
reintroduce the study, screen them for eligibility, and answer any questions about the study.  
●
During a clinic visit:​ ​The Program Manager will receive a weekly list of which participants/potentially 
eligible participants have a scheduled clinic appointment and will notify the Study Coordinator assigned 
to that clinic site so s/he will plan to meet the participant at that time. The clinical Study Coordinator 
will discuss the study with the participant, screen them for eligibility, and answer any questions about 
the study.  
Study Coordinators will then schedule all eligible and interested participants for a baseline visit. A baseline visit 
may occur at the time of recruitment (if approached at a clinic visit) or at a later date. 
5.4
Screening Procedures 
Study Coordinators will use a recruitment script during recruitment phone calls or clinic intercepts to inform the 
potential participant about the study and screen participants for eligibility using the study inclusion/exclusion 
criteria. If the participant is eligible and interested, a baseline visit will be scheduled that same day or for a 
future date. 
5.5
Participant Consent Process 
If a participant is interested and eligible, Study Coordinators will review the consent document at the start of the 
baseline study visit. Prospective research participants will have the opportunity to ask questions before providing 
written consent. Study Coordinators will provide the participant with a copy of the consent document. If the 
individual chooses not to sign the consent form, the Study Coordinator will inform him/her they are unable to 
participate in the study. The participant will also be provided the option to be contacted for future research. 
 
5.6
Participant Discontinuation/Withdrawal from the Study  
Participants may stop participating or withdraw from the study at any point in time. All information and data 
collected from the participant up to that point can be used in the study. Withdrawal of consent to participate in 
12 
 

the research study can be verbal or in writing. Study Coordinators should attempt to obtain a reason for 
withdrawal from the participant and record it in the study database.  
 
Participants may withdraw from the study at any time by writing to the PI or by verbally informing the study 
coordinator or Program Manager. Any data collected up until withdrawal may be analyzed for study purposes 
but no new information will be collected. 
5.7
Lost to Follow-Up 
Losses to follow-up may be minimized and retention maximized through various mechanisms, including offering 
study visits during evening and weekend hours, collecting information for and contacting family members when 
participants cannot be reached, approaching research participants at clinic appointments, and completing surveys 
over-the-phone (although research participant should still attend study visits for blood pressure measurement). 
Certified letters may also be sent to those not reached by phone. Study Coordinators can confirm the best contact 
information for the participant at each study visit. Study Coordinators may also obtain permission to contact 
participants via text message or email and may send additional correspondence during the study. Participants 
may be assigned to a specific Study Coordinator at the site in order to maintain continuity and build rapport. 
5.8
Risks 
This research presents minimal risks to participants. Possible risks are described below. 
 
Blood Pressure 
Participants may feel some arm pressure when the blood pressure cuff is briefly inflated. 
 
Blood Draw 
The risks of a blood draw include pain, bruising, and the slight possibility of infection at the location of needle 
insertion. Some participants may feel dizzy or may faint during or after a blood draw. 
 
Saliva Collection 
Some people may feel discomfort because they cannot eat, drink, smoke or chew gum for 30 minutes before 
giving a saliva sample. 
 
Psychological Distress Learning of Test Results 
Results of the genetic test may show that a participant is at an increased risk of kidney disease. This knowledge 
may cause anxiety or psychological distress​.​ Study staff will be trained to recognize anxiety and psychological 
stress and talk through this discomfort with the participant. All participants will have the option to speak with a 
genetic counselor if they choose.  
5.9
Benefits 
Participants may not receive any benefit from taking part in this research.  Others may not benefit either. 
However, participants and their providers will obtain clinically-relevant genomic risk information to guide 
evaluation and treatment of hypertension and renal functioning, thus providing some indirect benefit to 
participant health. 
 
13 
 

5.10
Costs to the Participants  
The costs of study-related genomic testing are covered by the study and will not be billed to participants. Taking
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
part in this research study may lead to minor added costs including, for example, transportation to attend study
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
visits. Participants (and/or their health care payer) will still be billed for the costs of their regular medical care
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
that are not part of this study. 
5.11
Compensation to Participants 
Study participants will receive $40 in gift cards (to a variety of local retailers) at each of the Baseline, 3 Month 
and 12 Month follow-up visits. If a participant withdraws from the study before all visits are completed, they 
will be paid for any completed visits. If a participant is able to complete a survey over the phone for a follow up 
visit, but is unable to come in-person for a blood pressure measurement within the visit window, they will only 
receive a $20 gift card, which may be mailed to them at the address they provide.  
 
6.
STUDY PROCEDURES 
6.1
Provider Surveys 
Prior to first enrollment at a site, at one of their existing meetings, providers will be asked to complete a consent 
form to contact their potentially eligible participants and to complete the Baseline Provider Survey to assess 
demographics, knowledge, beliefs and practices around ​APOL1​ testing specifically and genetic testing more 
generally.  This survey is anonymous. A GUARDD clinical champion will present the study to the providers of 
each site 
6.2
Baseline Study Visit 
Consent 
The Study Coordinator will follow appropriate consenting protocol to consent interested and eligible 
participants.  
Survey 
After participants sign the informed consent, the Study Coordinators will confirm participant contact 
information and administer the GUARDD Baseline Survey using the REDCap database. Study Coordinators 
also have the option of administering surveys on paper and entering the responses in the RedCap database at a 
later date.  
Biological Measures 
Study Coordinators will obtain blood pressure using study specific protocols (outlined in the MOP) for blood 
pressure measurement using the BPTru portable blood pressure machine (29). If after several attempts, the 
study coordinator is unable to obtain an arm blood pressure measurement because the participant’s arm is too 
large for the arm cuff or another reason, blood pressure will be measured using the Omron HEM 670IT wrist 
monitor and make a note in the participant’s Redcap record. Study Coordinators will record the second and third 
blood pressure measurement in which will calculate the average blood pressure reading.  
14 
 

Study Coordinators will also measure participant height using the Charder HM200P portable stadiometer (at 
Baseline Visit only) and weight using the Detecto DR550C portable high capacity platform scale and input this 
information into the RedCap database which will calculate BMI.  
Study Coordinators will record the average blood pressure and participant height and weight on the Personal 
Health Screening Form along with estimated dates for study follow up for the participant’s personal records.  
 
If the participant has a blood pressure reading greater than 190/110 during the study visit, study staff must 
complete an Elevated Blood Pressure Note for the participant, record the reading on REDCap, inform participant 
that they have very high blood pressure and strongly advise that they get urgent and appropriate evaluation and 
care from a healthcare provider. Study staff must also inform study PIs. 
Specimen Collection 
Participants will be randomized via the REDCap randomization tool using a stratified randomization scheme by 
clinical site in a 7:1 ratio of immediate or delayed ​APOL1​ genetic testing. The Study Coordinator informs the 
participant of their randomization outcome. A blood (preferred) or saliva sample is collected from participants 
randomized to immediate testing by the Study Coordinator. Study Coordinators will obtain a genetic sample for 
control participants at their 12 month visit. Participants are informed that their result will be ready in 2-4 weeks.  
 
The baseline visit will take approximately 1.5 hours to complete. Participants will receive $40 in gift cards when 
they have completed their baseline visit.  
 
6.3
Follow-Up Assessments 
All participants will be advised that they will be contacted to complete a follow-up study visit at 3 months and 
12 months after enrollment (duration of the observation period). During follow-up visits, Study Coordinators 
will follow study protocol (outlined in the MOP) to conduct surveys, measure blood pressure, and obtain 
participant weight in order to calculate body mass index. They will enter this data directly into REDCap using 
tablets/laptops. The follow-up visits will take approximately 45 minutes to complete. Participants will receive a 
$40 gift card for each follow-up visit completed. 
 
Follow-up visits will be completed between 14 days prior and one month after the projected follow-up date 
(projected 3 month study visit due date = 3 months from date of baseline visit completion; projected 12 month 
study visit due date = 12 months from date of baseline visit completion). Whenever possible, participants will 
meet with the same Study Coordinator for follow-up visits to maintain continuity.  
 
If the participant has a blood pressure reading greater than 190/110 during any follow up visit, study staff must 
complete an Elevated Blood Pressure Note, inform the participant that they have very high blood pressure and 
strongly advise that they get urgent and appropriate evaluation and care from a healthcare provider. Study staff 
must also inform study PIs. 
6.4
Specimen Collection 
Blood Specimen: ​At the baseline visit, Study Coordinators will consent participants if not previously consented, 
administer the baseline survey, take 3 blood pressure readings, measure participant height and weight and, if 
15 
 

trained in phlebotomy, collect 1 purple tops EDTA tube (approximately 3-5 mL) of venous blood from 
participants willing to provide a blood sample. If the Study Coordinator is not trained in phlebotomy, the 
participant will have their blood drawn by a trained phlebotomist. Participants will then be randomized to the 
Control or Intervention arm. Study Coordinators will label the tube with the participant ID, date of birth, sex and 
the date sample was collected, and follow the MOP for the collection, storage, and delivery of the sample to the 
laboratory.  
 
Saliva Specimen: ​In the event that it is not possible to obtain a blood sample or participants prefer saliva 
collection, Study Coordinators will use an Oragene OG-500 kit to collect a saliva sample. They will label the 
sample and follow the saliva collection protocol for the collection, storage, and delivery of the sample to the 
laboratory as outlined in the MOP​.  
 
6.5
Specimen Transfer and Genetic Testing Procedures 
Study Coordinators should store and directly transport specimens to the Mount Sinai Genetics Testing 
Laboratory, a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, according to 
procedures outlined in the MOP. Specimens will be accepted by the lab twice a week and processed on a weekly 
basis.  
 
The ​APOL1​ G1/G2 genotype testing incorporates Polymerase Chain Reaction (PCR) and multiplex Allele 
Specific Primer Extension (ASPE) with Tm Bioscience’s proprietary Universal Tag sorting system on the 
Luminex® 100 xMAP™ platform. Three SNP genotype in exon 6 are tested (RS73885319, RS60910145, 
RS71785313) to determine G1 and G1 allele status. To validate this genotyping method, at least three 
intra-assay and inter-assay runs involving 50 positive controls and 8 negative controls were performed.  The 
positive control DNAs include samples which are heterozygous or homozygous for G1 and G2 genotypes. 
Negative controls are WT DNA for G1 and G2 alleles. Assays were 100% concordant reproducibly between the 
Luminex genotyping method and Sanger sequencing for each of the control samples.  
 
6.6
Return of Genetic Results  
Result reporting will occur approximately 1-4 weeks after the samples are obtained (see Fig. 1 Study flow 
chart). The laboratory will notify the study Program Manager of when results are ready to be returned. The 
Program Manager will in turn alert Study Coordinators. Return of results will be done by their assigned Study 
Coordinators. Study Coordinators​ ​will be trained by Randi Zinberg, Director of Mount Sinai Genetic 
Counseling Program, to return risk assessment results and recommendations. They will use a Return of Results 
Script for this visit. ​APOL1​ negative participants will have their tests results returned by phone (participants in 
the formative study said they did not want to come back in person for a negative results) and those that are 
APOL1​ positive will be scheduled for an in person return of results visit. If an in person return of results visit is 
not able to be scheduled for an ​APOL1​ positive participant, we will offer the participant the opportunity to 
receive their results over the phone. During return of results, the Study Coordinator will disclose the genetic test 
result, provide simple, clear information and use “speak back” or “teach back” technique to maximize 
participants’ comprehension of their result. In addition to verbal ROR, participants will also receive lay 
explanations of their test results in writing and the educational booklet about ​APOL1​, blood pressure and kidney 
16 
 

disease. ​APOL1​ positive participants will review the informational booklet at the time of their return of results, 
APOL1​ negative participants will receive their written test results and informational booklet in the mail.  
 
If we are unable to return an ​APOL1​ positive test result to the participant for at least 3 months we will notify 
their primary care provider so that the result can be noted in their electronic health record and the participant 
can be notified of their results when they get in contact with their provider, even if that is after the study has 
ended. 
 
All participants will be given the option to speak to a genetic counselor after their return of results in person or 
by telephone, at no charge. If a participant chooses to speak with a genetic counselor, the Study Coordinator 
will contact the genetic counselor on behalf of the participant, and the genetic counselor will then follow-up 
directly with the participants.  
 
Once a result is returned to the participant, the Study Coordinator completes the corresponding fields in Redcap 
that prompts CLIPMERGE to fire a Best Practice Alert (BPA) in the participant’s electronic health record the 
next time a primary care provider opens it. The BPA will pop up once per unique provider.  A provider can 
choose to open the BPA and has the option of clicking on and viewing and printing information for the 
participant and information for him/herself. In addition to the BPA, the lab will also place a copy of the ​APOL1 
genetic test results in the participant’s electronic medical record. Electronic Health Record Data Extraction 
 
6.7
Electronic Health Record Data Extraction 
Electronic health data relevant to the study endpoints will be pulled for the period of 12 months prior to 
randomization and 12 months after randomization for all enrolled participants.  
 
Figure 2​. ​APOL1 ​positive BPA Alert 
 
 
 
 
 
 
 
 
 
 
 
 
17 
 

6.8
Study Retention 
Carefully trained, dedicated Study Coordinators that are from the same demographic groups and neighborhoods 
as participants will recruit participants, and will facilitate retention using relationship building, continuity with 
their assigned participants, sending personalized birthday and holiday cards, sending a 6 month check in 
postcard, placing a 9 month check in phone call, and collecting multiple contacts and modes of contact (e.g., 
phone, mail, text, email, intercepting at upcoming clinical appointments) from study participants. They will also 
“intercept” participants at clinical visits should they have clinical visits during the follow-up windows. If 
participants are unable to come to the practice for the entire visit, they can be surveyed by phone and come for 
blood pressure check, and if they cannot come at all, they can be surveyed by phone.  
 
7.
SAFETY ASSESSMENT AND MONITORING 
 
The GUARDD Study is an observational-type study that does not include a drug or device intervention. For this 
reason, no adverse events will be collected or recorded in the study database. Adverse events suspected to be 
related to study interventions should be reported to the Mount Sinai and Institute for Family Health IRBs 
according to their local policies. 
7.1
Distress from Return of Results 
Distress from return of results will be monitored at participant visits. If the participant seems overly distressed 
by the outcomes of the genetic test results, the Research Coordinator will offer the participant the opportunity to 
speak to the genetic counselor. If the genetic counselor is not immediately available, the Research Coordinator 
will help coordinate a phone call or meeting with the genetic counselor based on participant’s preference. The 
study coordinator will also inform the Project Manager and PI, document the event in the notes field of the 
participant’s study database record, and follow-up with participant. 
7.2
Elevated Blood Pressure Readings 
If systolic blood pressure exceeds 190 mm Hg or diastolic exceeds 110 mm Hg during any study visit, the 
participant will be strongly advised to seek urgent and appropriate evaluation and care from a healthcare 
provider. The Research Coordinator may facilitate this by assisting the participant in contacting their primary 
care provider, urgent care, or clinic staff on site including the Principal Investigator (if study visit is taking place 
in a clinical setting) and by completing the Elevated Blood Pressure Note that participants may share with their 
provider.  
 
8.
STATISTICAL ANALYSIS PLAN AND SAMPLE SIZE 
8.1
Sample Size Determination 
The study will randomize 2050 patients to either immediate or delayed genetic testing in a ratio of 7:1
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
respectively. We anticipate that of the 1800 patients who will be tested immediately approximately 250 will test
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
positive. For this aim, we hypothesize that APOL1 positive patients will achieve 40% correct utilization of
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
serum creatinine and/or urine albumin tests for “standard renal care” in patients with hypertension, compared to
 
 
 
 
 
 
 
 
 
  
 
 
 
  
18 
 

30% for APOL1 negative patients. With an estimated 250 APOL1 positive and 1550 APOL1 negative we will
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
have 87% power to detect the difference of interest using a two sided chi-square test.  
 
Power calculations for this sub-aim are based on reduction of systolic blood pressure at three months after
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
enrollment. For patients who test APOL1 positive we anticipate a 5 mmHg reduction in systolic blood pressure,
 
 
 
 
 
 
 
 
   
 
  
 
 
 
compared to no change in patients who test APOL1 negative. Assuming that the standard deviation for
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
differences in blood pressure between baseline and 3 month in both arms is 20 mmHg, a total of 250 patients
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
testing positive and 1550 testing negative provides approximately 95% power to detect a difference of 5 mmHg
 
 
 
 
 
 
 
 
 
  
  
 
  
 
in SBP between these two groups. If the standard deviation is larger than assumed, say 25 mmHg, power will
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
still exceed 80%.  Power is based on a 0.05 level two-tailed t-test of the difference in SBP at 3 months. 
8.2
General Statistical Methods 
We will use mean and standard deviation to describe continuous variables, proportions for categorical variables;
 
 
 
 
 
 
  
 
 
 
 
 
 
 
t-tests or analysis of variance (ANOVA) to compare continuous variables, and chi-square or Fisher’s exact test
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
to compare categorical variables by groups. To test significance of changes within groups over time, we will use
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
paired t-tests for continuous and McNemar’s tests for categorical variables. We will use linear mixed models to
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
test the difference in SBP change over time between ​APOL1 positives and negatives by entering the interaction
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
term of time and ​APOL1 ​status and adjusting for confounders, and generalized estimating equation methodology
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
to test the change in controlled SBP status and renal function testing overtime between ​APOL1 ​positives and
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
negatives, and similarly between ​APOL1​ positives and controls. 
8.3
Population for Analyses 
Patients will be from academic, community and safety-net practices in New York City. Inclusion criteria are:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
self-identified AA; age 18–70 years; hypertension EHR diagnosis and/or taking antihypertensive medications,
 
 
 
 
 
 
 
 
 
 
 
 
and/or 2 SBP readings >140mmHg at least six months apart; community-dwelling; English speaking; and
  
 
 
 
 
 
 
 
 
 
 
 
 
receiving primary care at participating site in the past year. Exclusion criteria are: diabetes; CKD; pregnancy;
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
moving away during the study period; and cognitive impairment. 
8.4
Analysis of the Secondary Endpoints 
Secondary outcomes include differences in SBP and urine testing in an enriched intervention group (​APOL1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
positives) vs. controls, and psycho-behavioral patient factors between groups and over time. 
8.5
Handling of Missing Data 
Missing data will be analyzed as intention to treat. 
 
9.
DATA MANAGEMENT  
9.1
Data Entry and Record Keeping 
Data will be entered and stored in a REDCap database to track and monitor participants. The database was 
adapted from the data dictionary to include MRNs and participant IDs, inclusion criteria, baseline, 3- and 
12-month participant contact logs and surveys, calendar and reminder functions, and ability for recruiters, 
19 
 

managers and investigators to track workflow and perform queries to assess the status of participants (i.e., who 
is outstanding for a 3-month ROR1 visit). 
 
9.2
Database Management and Quality Control of Data 
A REDCap database​ ​will be developed to track and monitor participants. This includes MRNs and participant 
IDs, inclusion criteria, baseline, 3- and 12-month participant contact logs and surveys, calendar and reminder 
functions, and ability for recruiters, managers and investigators to track workflow and perform queries to assess 
the status of participants (i.e., who is outstanding for a 3-month visit). Data will be entered into REDCap using 
tablets/laptops. Study staff will be trained on how to enter data and will receive a unique user identification and 
password to access data entry forms for their site. Access codes should not be shared and are non-transferable.  
Study Coordinators will always have paper survey copies as backup should Redcap be down or they experience 
technical difficulties.  
 
Genetic test results are uploaded directly into the REDCap database through a CLIPEMERGE interface and 
verified by the Program Manager. The database includes password protection and internal quality checks, such 
as automatic range limits and regular checks to identify data that appear inconsistent, incomplete, or inaccurate. 
The Program Manager and study biostatistician will review the data on a regular basis as part of quality control. 
The check will review the data for errors, outliers, missing fields, inconsistencies, etc.  
10.
ETHICAL AND HUMAN SUBJECTS CONSIDERATIONS 
 
10.1
Institutional Review Board 
This study will be initiated only after all required documentation has been reviewed and approved by the Mount 
Sinai and Institute for Family Health Institutional Review Boards (IRBs).  
 
10.2
Large Scale Data Sharing  
 
The sharing of our dataset will follow the requirements set forth by the NIH policy for data sharing and 
guidelines for NIH Data Set Preparation. The de-identified and anonymized phenotype and genotype data will 
may be made available in NIH’s database of Genotypes and Phenotypes (dbGaP) repository for sharing to the 
larger scientific community.  
 
Databases, like dbGAP, were created to meet the needs of the medical genetics community by storing medical
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
information from many studies conducted at many different places. Researchers can then study the combined
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
information to learn even more about health and many different diseases.  Some databases are publicly
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
accessible and some are restricted. Anyone on the Internet can access the information shared in publicly
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
accessible databases. However, only researchers who apply to restricted databases and are approved can access
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
databases, like dbGAP. The current study will limit sharing of data to only those databases, which are restricted
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
and require approval to access, like dbGAP that maintain Certificates of Confidentiality.  
 
 
20 
 

11.
PROTOCOL DEVIATIONS 
 
A protocol deviation is defined as an event where the Investigator or site personnel did not conduct the study 
according to the protocol. Protocol deviations will be reported to the GUARDD Program Manager, Principal 
Investigator and Mount Sinai and Institutes for Family Health IRB according to their policies. 
 
 
 
 
 
 
21 
 

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https://doi.org/10.1097/00126097-200106000-00008 
 
 
 
 
 
 
 
24 
 

needed. We propose that hypertension-attributable chronic kidney disease has emerged as a highly-relevant 
opportunity for a ‘prototype’ genomic medicine demonstration project that addresses common chronic illnesses 
managed in primary care settings. Hypertension-attributable chronic kidney disease (CKD) is characterized by  
●
high prevalence affecting millions of Americans (8),
●
high burden of morbidity and mortality related mainly to increased cardiovascular disease risk and kidney 
failure or end stage renal disease (​8​),  
●
progression to kidney failure that can be modified by appropriate pharmacological interventions (​9-11​),  
●
a disproportionate burden for African Ancestry and major health disparity (12) (13-16) (17) (18),
●
a substantial and testable population selective genomic risk that explains most of the excess burden of 
hypertension-attributable CKD risk in African Ancestry populations (​19​) (​20​) (​21​) (​22​). 
 
Synthesis of evidence and formulation of study rationale
Synthesis: Chronic Kidney Disease (CKD), Hypertension and Blood Pressure Control. CKD is a common, 
complex disease affecting 26 million Americans adults (​8​). CKD is most commonly attributable to diabetes 
(40% of CKD cases) and hypertension (28% of cases). African Ancestry populations with hypertension (HTN) 
have 2- to 3-fold higher risk of developing CKD, and a 5-fold increased risk to progress to end stage renal
disease (ESRD) when compared with whites. ​HTN is an established risk factor for progression of CKD and for 
increased cardiovascular risk with CKD. Thus targeting blood pressure control as a modifiable risk factor may 
both reduce CVD in people with CKD and reduce progression of CKD to end stage disease (​9-11​).  
Synthesis: Poor adherence with renal care practice guidelines puts participants at risk for kidney failure 
Importantly, major goals of practice guidelines for renal care in hypertensive participants remain unmet in 
clinical practice today: among Medicare participants with hypertension without diabetes, only 1 in 25 receives 
recommended simple lab tests (creatinine and urine albumin) to evaluate CKD, and less than half of all
participants with moderate to advanced stages of CKD in the Kidney Early Evaluation Program (KEEP) are 
aware that they are affected (​23​). Among younger participants of African Ancestry CKD awareness is 
particularly low (​23​) and progression to kidney failure is typically accelerated resulting in excessive rates of 
ESRD (13) (18).
Improved CKD awareness and access to primary care or nephrology referral for individuals with or at 
risk of CKD are considered critical to improve CKD-related outcomes (​24​, ​25​). Factors associated with 
progression of CKD and with increased cardiovascular risk are overlapping to a large extent, including 
hypertension. There is strong evidence that blockade of the renin-angiotensin system  is a blood pressure
lowering strategy which is more effective in reducing risk of kidney and cardiovascular disease in the presence 
of albuminuria, a marker of CKD (​26​). ​Thus, in order to improved renal care and reduce risk for kidney failure 
in this population at excess risk, we urgently need new strategies:  
●
to improve comprehension of CKD risk and CKD awareness among participants with CKD or at risk for
CKD and among their providers, and  
●
to increase adherence with practice guidelines targeting those risk factors that are modifiable may both 
reduce cardiovascular disease in people with CKD and reduce progression of CKD to end stage kidney 
disease.
 
Synthesis: APOL1 G1 and G2 risk alleles and non-diabetic kidney diseases. 
A locus containing the myosin heavy chain 9 (MYH9) gene for non-diabetic kidney disease in African ancestry 
individuals was initially identified by admixture mapping (27, 28). Recently, three non-synonymous coding
4 
 

variants in the neighboring ​APOL1​ gene defined two allele, termed G1 and G2 with stronger effect on 
non-diabetic kidney disease than MYH9 variants (​19​). The authors suggested that G1 and G2 alleles are 
exceedingly rare in non-African ancestry genomes, but in African ancestry genomes, 22.5% and 14.6% of 
chromosomes carry the mutually-exclusive G1 and G2 risk alleles because they were selected for by providing
protection against Trypanosomiasis (sleeping sickness) in West Africa (​19​).  
APOL1​-associated kidney disease risk is best explained using a recessive model, and approximately 13% 
of African Americans are estimated homozygous for G1 / G2 risk alleles, suggesting that more than 3 million 
AA are at markedly increased risk for non-diabetic CKD (20). In our IPM Biobank, 15% of more than 5,000 AA
participants were found to carry [2] risk alleles, and the odds for hypertensive CKD in this cohort were 2.7. We 
recently analyzed the effect of APOL risk alleles on severity of hypertension-attributed kidney disease in the 
African American Study of Kidney Disease and Hypertension (AASK) cohort (Table 1). ​APOL1​ risk alleles are 
highly significantly associated with CKD attributed to essential hypertension in non-diabetic AASK participants,
and the odds for advanced kidney disease (significant proteinuria or serum creatinine >3 mg/dl) were >4-fold in 
carriers of [2] risk alleles compared to [0,1] risk alleles (​22​). Heterozygous G1 or G2 risk allele status does not 
appear to increase kidney disease risk. 
 
 
Table 1. Logistic regression model of the effect of APOL1 risk alleles on clinical phenotype AASK cases and 
controls
 
In summary, [2] ​APOL1​ G1 / G2 homozygous risk allele status  
●
explains practically all of the substantial excess genetic risk for non-diabetic CKD in African ancestry
populations, 
●
is present in 1 out of 7 African American participants genotyped at Mount Sinai, 
●
is strongly and consistently associated with hypertension-attributable CKD (odds >2.7) 
●
is strongly and consistently associated with progressive and proteinuric states of hypertension-attributable
CKD (odds >4.0) or with hypertensive ESRD (odds 7.3).  
 
5 
 

Thus, published evidence and our own Mount Sinai results strongly support our hypothesis that carriers of [2] 
APOL1​ risk alleles have an increased genomic risk for hypertension-attributable CKD and its progression to 
kidney failure.  
1.2
Study Aims  
GUARDD is multifaceted and has elements that involve qualitative research for a formative study to better 
information development of the randomized trial. This protocol is focused on the randomized controlled trial.
 
AIM II. Develop systems and evidence-based advice messages to enable point of care Clinical Decision 
Support (CDS) for primary care providers advising renal care practice guidelines with or without 
genomic APOL1 risk information
 
Rationale. One of the highly anticipated quality improvement advantages offered by EHRs and ‘meaningful 
use’ is the potential for point of care Clinical Decision Support (CDS). CDS provides clinicians or participants 
with knowledge presented at appropriate times to improve healthcare. In this context, CDS also has the potential
to increase the awareness of and adherence to, standard of care processes. Mount Sinai’s IPM conducts several 
early adopter projects testing utility and adoption of pharmacogenomic CDS for clinicians in real-time at the 
point of care. We will develop new functionality for our existing CLIPMERGE Risk Assessment Engine 
database (CRAE database) to deliver CDS for renal care practice guidelines based on conventional kidney
disease risk assessment with or without ​APOL1​ genomic kidney disease risk information. Importantly, we will 
for the first time develop interfaces that will allow CRAE to disseminate standardized CDS to independent Epic 
EHR implementations across different primary care practice settings at IFH and MSMC.  
Sub-Aim 2.1. Modification of CLIPMERGE Risk Assessment Engine (CRAE) technology for multiple 
EHR (IFH and MSMC) and renal care CDS capabilities.  CRAE houses phenotypic and gene variant data 
necessary for the evaluating enrolled participants’ data relevant to the guidelines to be implemented for this 
study.  The CRAE database will be populated only for enrolled participants. The CRAE database itself houses
very strictly de-identified data (only).  A separate function named the Broker handles all necessary translation 
between identified data (as needed for participant enrollment, for transactions flowing from and to Epic, and for 
receipt of genomic results from the CLIA lab) and de-identified data.  
The CLIPMERGE-EPIC Integration.   The CLIPMERGE database will include longitudinal clinical data
extracted from Mount Sinai’s and IFH’s Epic EHR systems, for all consented participants enrolled in the 
research study; including CLIA-grade ​APOL1​ genotype and G1 G2 risk allele data from those that have been 
genotyped. Our CLIPMERGE Risk Assessment Engine (CRAE) includes this database and a rules engine that 
relates genome-based advice messages (renal care advice messages incorporating APOL1 genomic risk
information with conventional risk data) or conventional risk based advice messages to standard of care clinical 
decision support messages. During the first six months of year 1, the CLIPMERGE and Epic team at Mount 
Sinai will work with the Epic team at IFH to build HL7 interfaces customized between CRAE and the specific 
Epic version installed for IFH sites.
Reference and educational material.  Upon presentation of a BPA, providers will have the opportunity to 
directly access reference content that further describes the evidence base for the CDS through a clickable link in 
the Epic SmartSet.  
6 
 

 
Sub-Aim 2.2. Development and usability testing of a library of evidence-based renal care advice messages 
customized for assessment of risk with and without APOL1 G1 G2 risk allele information, and for 
adherence to practice guidelines for renal care in non-diabetic African ancestry participants with
hypertension  
Rationale. CKD awareness among participants and providers, appropriate use of tests for biochemical markers 
of CKD (creatinine and urinary albumin excretion) to screen for presence of CKD in those at risk, and 
appropriate use of pharmacological and life style interventions in those at risk for CKD progression are
considered critical to improve CKD-related outcomes (ESRD, CVD, and mortality (​24​, ​25​). As summarized in 
the paragraph “​Synthesis: Poor adherence with renal care practice guidelines puts participants at risk for 
kidney failure” at the beginning of the APPROACH section, major goals of practice guidelines for renal care in 
hypertensive participants remain unmet in clinical practice today. Blacks have higher prevalence of hypertension
(41% vs. 28%), younger age of onset, and poorer control of hypertension than Whites ​(​17​). ​Blacks also have​, ​a 
2-3x the risk for developing CKD (​12​), and the adjusted prevalence rate for ESRD is 4.1-fold higher in AA 
when compared with Whites (​14-16​). The differences in CKD are most pronounced among those with 
hypertension. Thus, it is imperative to uncover new strategies to screen and engage AAs with hypertension into
programs to improve BP control and participant outcomes.  
 
The Kidney Disease Improvement Global Outcomes (KDIGO) evidence-based practice guidelines advise 
the appropriate use of tests for biochemical markers of CKD (creatinine and urinary albumin excretion) to screen 
for presence of CKD in those at risk, and appropriate use of pharmacological and lifestyle interventions in those
at risk for CKD progression are considered critical to improve CKD-related outcomes (ESRD, CVD, and 
mortality (​24​, ​25​). Practice guidelines, including the Joint National Commission 7 (JNC7) guidelines, 
recommend specific medications (ACE inhibitors and ARBs) as preferred first line agents and more intensive 
blood pressure goal in participants with hypertensive CKD (9-11).
Several reports demonstrate that ​APOL1​ risk alleles are highly significantly associated with CKD 
attributed to essential hypertension in non-diabetic AASK participants, and the genetic association was most 
robust in individuals with progressive renal functional decline (​22​) (see our AASK Cohort data in Table 1). 
Because of the overwhelming strengths of the evidence, we propose to establish APOL1 genomic risk status in
non-diabetic AA participants and to incorporate the ​APOL1​ G1/G2 risk allele status in a recessive model 
together with conventional risk factors in CKD and CKD progression advice messages.  
 
Aim  III. Conduct a randomized trial assigning eligible participants to immediate genetic testing or
delayed genetic testing arms in a seven (immediate testing) -to- one (delayed testing) ratio.  
 
Sub-Aim 3.1:  To examine whether increase in practice guideline-appropriate renal laboratory test ordering 
(renal care endpoint) will be achieved in APOL1-positive group vs APOL1-negative group.
 
Sub-Aim 3.2. To examine whether systolic blood pressure will decline more in the ​APOL1​-positive group 
compared with ​APOL1​-negative group.  
7 
 

2.
ENDPOINTS 
2.1
Primary Endpoints 
The study has two primary endpoints, comparing patients who are ​APOL1​ positive (high risk) 
and APOL1 negative at three months after enrollment. One primary aim is a renal care endpoint, the correct
utilization, by clinicians, of urine albumin tests. The other primary aim is reduction of systolic blood pressure.  
2.2
Secondary Endpoints 
Secondary endpoints include differences between APOL1 positive participants in the intervention and 
participants in the control group, impact on primary outcomes at 12 months, psycho-behavioral differences of
participants between groups and over time, clinician knowledge, attitudes and beliefs at baseline and 12 months, 
and differences in outcomes between those tested and not tested immediately. 
 
3.
STUDY DESIGN
3.1
Study Arms & Design 
This is a prospective, multicenter, unblinded, randomized clinical trial (RCT) (​Figure 1). The study was 
designed to randomize 2050 participants to immediate ​APOL1​ gene testing and return of results (ROR) 
(intervention) or delayed APOL1 gene testing and ROR (control) in a 7:1 ratio. Outcome measures will be
compared among three arms of the GUARDD study, the ​APOL1​-positive and ​APOL1​-negative intervention 
(immediate ​APOL1​ genetic testing and return of results) groups, and the control (delayed ​APOL1​ testing and 
return of results) group.  
8 
 

  
Figure 1. GUARDD study flowchart. 
 
3.2
Randomization
Eligible participants will be randomized in a 7:1 allocation to Intervention (i.e., immediate ​APOL1​ gene testing 
and ROR to participant and provider) and Control arms (delayed ​APOL1​ gene testing and ROR to participant 
and provider) to optimize the proportion of participants with immediate ​APOL1​ genetic testing compared with 
delayed genetic testing at completion of study. Randomization will be stratified by clinical site with a random
block size within site. 
3.3
Blinding 
GUARDD randomization assignments will not be blinded to any participants, providers or study personnel.  To 
minimize bias in the measurement of the primary outcome, randomization assignments will only be revealed
after baseline survey responses and blood pressure readings have been collected. Digital blood pressure devices 
(such as BpTru portable blood pressure machine (29)) will be used to measure blood pressure, and blood 
pressure will be measured as the mean of the second and third blood pressure readings for each participant at 
each study visit.
9 
 

If a participant is referred, the Study Coordinator should check the REDcap database to ensure the participant is 
not already in the database and proceed accordingly.  
 
Participant Recruitment
There are three main scenarios for recruitment: 
●
Via recruitment letter: ​Study Coordinators will be assigned participants (from the list of potentially 
eligible participants obtained through an Epic data run) and mail study recruitment letters to them. 
Letters are mailed in a bright blue envelope and postmarked with the GUARDD and clinic site logo to
assist participants with recall and recognition. Participants can call us upon receiving the letter and they 
will then be screened for study eligibility. Study Coordinators will wait approximately 2 weeks after this 
mailing for a participant to return the letter refusing to participate, to call them, or to meet them at an 
upcoming clinic visit.
●
During a phone call: If a participant does not return the refusal letter or contact us within 2 weeks of 
mailing, the Study Coordinator assigned to him/her will contact the participant by telephone. Using the 
recruitment phone script they will remind them about the letter that was mailed to them, introduce or 
reintroduce the study, screen them for eligibility, and answer any questions about the study.
●
During a clinic visit: ​The Program Manager will receive a weekly list of which participants/potentially 
eligible participants have a scheduled clinic appointment and will notify the Study Coordinator assigned 
to that clinic site so s/he will plan to meet the participant at that time. The clinical Study Coordinator 
will discuss the study with the participant, screen them for eligibility, and answer any questions about
the study.  
Study Coordinators will then schedule all eligible and interested participants for a baseline visit. A baseline visit 
may occur at the time of recruitment (if approached at a clinic visit) or at a later date. 
5.4
Screening Procedures
Study Coordinators will use a recruitment script during recruitment phone calls or clinic intercepts to inform the 
potential participant about the study and screen participants for eligibility using the study inclusion/exclusion 
criteria. If the participant is eligible and interested, a baseline visit will be scheduled that same day or for a 
future date.
5.5
Participant Consent Process 
If a participant is interested and eligible, Study Coordinators will review the consent document at the start of the 
baseline study visit. Prospective research participants will have the opportunity to ask questions before providing 
written consent. Study Coordinators will provide the participant with a copy of the consent document. If the
individual chooses not to sign the consent form, the Study Coordinator will inform him/her they are unable to 
participate in the study. The participant will also be provided the option to be contacted for future research. 
 
5.6
Participant Discontinuation/Withdrawal from the Study
Participants may stop participating or withdraw from the study at any point in time. All information and data 
collected from the participant up to that point can be used in the study. Withdrawal of consent to participate in 
12 
 

trained in phlebotomy, collect 1 purple tops EDTA tube (approximately 3-5 mL) of venous blood from 
participants willing to provide a blood sample. If the Study Coordinator is not trained in phlebotomy, the 
participant will have their blood drawn by a trained phlebotomist. Participants will then be randomized to the 
Control or Intervention arm. Study Coordinators will label the tube with the participant ID, date of birth, sex and
the date sample was collected, and follow the MOP for the collection, storage, and delivery of the sample to the 
laboratory.  
 
Saliva Specimen: In the event that it is not possible to obtain a blood sample or participants prefer saliva
collection, Study Coordinators will use an Oragene OG-500 kit to collect a saliva sample. They will label the 
sample and follow the saliva collection protocol for the collection, storage, and delivery of the sample to the 
laboratory as outlined in the MOP​.  
6.5
Specimen Transfer and Genetic Testing Procedures 
Study Coordinators should store and directly transport specimens to the Mount Sinai Genetics Testing 
Laboratory, a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, according to 
procedures outlined in the MOP. Specimens will be accepted by the lab twice a week and processed on a weekly
basis.  
 
The ​APOL1​ G1/G2 genotype testing incorporates Polymerase Chain Reaction (PCR) and multiplex Allele 
Specific Primer Extension (ASPE) with Tm Bioscience’s proprietary Universal Tag sorting system on the
Luminex® 100 xMAP™ platform. Three SNP genotype in exon 6 are tested (RS73885319, RS60910145, 
RS71785313) to determine G1 and G1 allele status. To validate this genotyping method, at least three 
intra-assay and inter-assay runs involving 50 positive controls and 8 negative controls were performed.  The 
positive control DNAs include samples which are heterozygous or homozygous for G1 and G2 genotypes.
Negative controls are WT DNA for G1 and G2 alleles. Assays were 100% concordant reproducibly between the 
Luminex genotyping method and Sanger sequencing for each of the control samples.  
 
6.6
Return of Genetic Results
Result reporting will occur approximately 1-4 weeks after the samples are obtained (see Fig. 1 Study flow 
chart). The laboratory will notify the study Program Manager of when results are ready to be returned. The 
Program Manager will in turn alert Study Coordinators. Return of results will be done by their assigned Study 
Coordinators. Study Coordinators will be trained by Randi Zinberg, Director of Mount Sinai Genetic
Counseling Program, to return risk assessment results and recommendations. They will use a Return of Results 
Script for this visit. ​APOL1​ negative participants will have their tests results returned by phone (participants in 
the formative study said they did not want to come back in person for a negative results) and those that are 
APOL1 positive will be scheduled for an in person return of results visit. If an in person return of results visit is
not able to be scheduled for an ​APOL1​ positive participant, we will offer the participant the opportunity to 
receive their results over the phone. During return of results, the Study Coordinator will disclose the genetic test 
result, provide simple, clear information and use “speak back” or “teach back” technique to maximize 
participants’ comprehension of their result. In addition to verbal ROR, participants will also receive lay
explanations of their test results in writing and the educational booklet about ​APOL1​, blood pressure and kidney 
16 
 

disease. ​APOL1​ positive participants will review the informational booklet at the time of their return of results, 
APOL1​ negative participants will receive their written test results and informational booklet in the mail.  
 
If we are unable to return an APOL1 positive test result to the participant for at least 3 months we will notify
their primary care provider so that the result can be noted in their electronic health record and the participant 
can be notified of their results when they get in contact with their provider, even if that is after the study has 
ended. 
All participants will be given the option to speak to a genetic counselor after their return of results in person or 
by telephone, at no charge. If a participant chooses to speak with a genetic counselor, the Study Coordinator 
will contact the genetic counselor on behalf of the participant, and the genetic counselor will then follow-up 
directly with the participants.
 
Once a result is returned to the participant, the Study Coordinator completes the corresponding fields in Redcap 
that prompts CLIPMERGE to fire a Best Practice Alert (BPA) in the participant’s electronic health record the 
next time a primary care provider opens it. The BPA will pop up once per unique provider.  A provider can
choose to open the BPA and has the option of clicking on and viewing and printing information for the 
participant and information for him/herself. In addition to the BPA, the lab will also place a copy of the ​APOL1 
genetic test results in the participant’s electronic medical record. Electronic Health Record Data Extraction 
6.7
Electronic Health Record Data Extraction 
Electronic health data relevant to the study endpoints will be pulled for the period of 12 months prior to 
randomization and 12 months after randomization for all enrolled participants.  
Figure 2. ​APOL1 ​positive BPA Alert 
 
 
 
 
 
 
 
 
 
17