Phase II Novel Low Cost QTc Meter for Long QT Syndrome Screening in Primary Care
Phase: NA
Conditions: Long QT Syndrome
Sponsor: Mayo Clinic

 
 
Phase II Novel Low Cost QTc Meter for Long 
QT Syndrome Screening in Primary Care 
 
NCT04441892 
 
July 24, 2019 

 
 
 
 
 
 
 
 
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prototype used in phase I), validate the new algorithm in a cohort of 1,000 newborns/children and 
demonstrating the ability of the QTc meter to screen newborns for LQTS and help clinicians to improve patient 
management and save lives. The phase II project will finalize the algorithm design from phase I and fully 
validate its performance in a study informed by the phase I pilot evaluation. 
 
Aim 1: Assemble a prototype system to enable the recording of the surface ECGs with the technical 
specification fitting the standard technical requirements for FDA-approved clinical ECG devices. Use 
the upgraded prototype developed base off results from the Phase I study to record ECGs in a cohort of 1,000 
newborns/children to form a learning dataset for the Aim 2. This includes 500 control subjects and 500 with 
LQTS. 
 
Aim 2: Evaluation of the usability and performances of the QTc Meter in a validation study conducted at the 
Mayo Clinic’s LQTS Clinic 
 
Objective: 
 
We propose a novel inexpensive diagnostic device specifically designed to support widespread screening for 
LQTS in the primary care setting. The device will be physically small, easily cleanable, battery powered, and 
Bluetooth connected to obtain recordings on an associated device. It will connect to the patient with conductive 
pads that are held against the patient’s chest (connections RA, LL, and RL). The objective of the proposed 
project is to specify, develop, and evaluate a diagnostic algorithm suitable for use in an inexpensive diagnostic 
instrument suitable for screening for LQTS in the primary care environment. The follow-on phase II project will 
finalize the algorithm design, test the newly developed prototype, and fully validate its performance in a study 
informed by the phase I pilot evaluation. 
 
 
The envisioned end product will be based off of the results obtained from phase II of the study. At an infant 
well-child checkup in the primary care environment, a technician/study coordinator will press the device to the 
infant’s chest for 30 seconds.  The device will be paired with Bluetooth that can be connected to either an app or 
laptop that displays the results from that recording and stored via the cloud. It will be designed to be very easy 
to use. The proposed project concentrates on algorithm design. The phase I prototype will be assembled using 
an FDA approved ECG that the PI designed for QRS Diagnostic, LLC that will be modified to collect data in 
support the proposed development activities. A follow-up phase of the project will be used to test a more 
advanced prototype from the results obtained in phase I. Enrollment may also be discussed and arranged prior to 
the patient’s visit via telephone. 
 
Background (Include relevant experience, gaps in current knowledge, preliminary data, etc.):   
 
Infants, children, adolescents, and young adults are vulnerable to undiagnosed and potentially lethal 
cardiovascular diseases. The younger age range includes the clinically important group of infants at risk for 
sudden infant death syndrome (SIDS). Long QT syndrome (LQTS) is a genetic disorder characterized by QT 
prolongation, and is associated with potentially life-threatening cardiac arrhythmias that may lead to syncope, 
seizures, cardiac arrest, or sudden death. Although LQTS is potentially lethal, very effective therapies are 
available once LQTS is diagnosed. The development of an accurate and inexpensive instrument that screens for 

 
 
 
 
 
 
 
 
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neonates may be higher than 1 in 2,000 (3). Finally, among patients with a definite clinical diagnosis of LQTS, 
approximately 20% are still genotype-negative. Thus, a LQTS prevalence of 1 in 2,000 in screened infants may 
still be a conservative estimate. With respectively 4 and 5.2 million live births per year in the United States and 
Europe (27 countries), the 1/2000 prevalence estimate predicts about 2,000 and 2,600 new cases of LQTS 
annually. Nationwide studies in Denmark and the Netherlands suggest that 50-60% of sudden unexpected 
deaths in children 1-18 years of age were due to inherited cardiac diseases (11).  
 
Available data (3) suggest when to perform neonatal screening and how to design a reasonable protocol. In the 
3rd-4th week of life, the QT pattern has stabilized which is still in the timeframe prior to the most common 
window for SIDS vulnerability (i.e. 2–4 months of age). As errors in measurement are possible and 
developmental changes may still occur (12), it is recommended to act only on the basis of a second ECG which 
should be performed whenever the first ECG shows a QTc of 450-460 ms. If the second ECG has a QTc 
(Bazett’s correction) exceeding 460 ms (1.3/1,000, Figure 1), LQTS genetic testing involving at least the 3 
major LQTS susceptibility genes is performed. If the QTc is >470 ms (0.7/1000), or if a mutation is identified, 
β-blocker therapy is recommended. In the more common situation that the first QTc is between 450 and 460 ms 
(0.4/1000), it may be decided to obtain one or more follow-up ECGs over a short period of time to make an 
evaluation contingent on the outcome of multiple ECGs. In all cases, family history is considered as well as 
ECG assessment in first-degree relatives. In the prior study, >40% of the infants with a QTc >470 ms had a 
disease causing mutation, and >90% of the infants whose QTc remained prolonged at 1 year of life had a 
positive genetic test (3). See Figure 1 below for a graphical representation of this protocol. 
 
Even though screening in the neonatal period enables the identification of “at risk” infants prior to the peak 
incidence of SIDS (2-6 months), screening in the elementary schools has a strong rationale as well, especially 
when feasibility is concerned, as shown by the large program ongoing in Japan. The most recent report from the 
Kanazawa City Prefecture assessed the prevalence of genetically identifiable LQTS in a population of 7961 1st 
and 7th graders who underwent ECG screening and determined that at least 1 in 2653 subjects had an 
identifiable LQTS mutation (13). This is remarkably similar to the prevalence of LQTS found by Schwartz et 
al. in neonates (3), particularly considering that the data on SIDS (4) suggest that some LQTS neonates may not 
survive past 1 year of age. Approximately 12-15% of newly identified patients with LQTS have de novo 
mutations, while the rest are inherited paternally or maternally, which may be undiagnosed in other family 
members. Once the infant with LQTS is diagnosed, the family members can be screened phenotypically, and 
when a disease-causing mutation has been found in the proband, mutation-specific “cascade screening” (14,15) 
is performed in the family. The overall process has the potential to identify both neonates and older related 
individuals who are affected, and to importantly reassure those family members that test negative for the 
mutation, a multiple bonus that increases the benefits that accrue from this approach.  
 
Significant questions have been raised regarding the effect of false positive findings as an unwanted cost of 
ECG screening for LQTS (16,17). It is important to understand that the threshold QTc used for diagnosis is the 
primary determinant of the test sensitivity and specificity. Raising the threshold QTc for screening diagnosis 
would increase the specificity and significantly reduce the number of false positives. The available data (3) 
point to a low expected false positive rate for those with a QTc >460 ms (<1/1,000, ~38/43,080 neonates in 
Figure 1), but to about 4.5/1000 for those with a QTc >450 ms. Thus, the false positive rate will be dependent 
on the QTc cut-off determined for follow-up.   

 
 
 
 
 
 
 
 
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Figure 1: LQTS diagnostic protocol at 3 to 4 weeks of life. 
 
Cost Effectiveness and the Commercial Potential of LQTS Screening 
 
Cost-effectiveness analysis is useful to assess the societal cost of specific medical interventions. This is 
especially true when the performance of comprehensive, population-based studies may be biased by 
predetermined public opinion or government policy. Using parameters such as cost per life-year saved, or 
quality adjusted life-year saved, the value of the intervention can be assessed in relation to a standard threshold 
value that is societally accepted. For example, the cost of ECG screening in infants can be compared to the costs 
of vaccination for childhood infection, dialysis for chronic renal failure, or stenting for atherosclerotic coronary 
artery disease. 
 
The available cost-effectiveness studies on screening approaches for the identification of asymptomatic youth at 
risk for SCD have had some common findings. First, because of its very low expense and relatively high 
sensitivity, the ECG is clearly a good candidate test to screen for the relevant diagnoses which may include 
other diseases besides LQTS. However, with the possible exception of Wolff-Parkinson-White syndrome, none 
of these diseases meet the criteria mentioned above for a successful screening effort as completely as LQTS. 
Second, the low prevalence of these diseases and imperfect specificity of the ECG necessarily result in some 
false positive screenings. As mentioned above, QTc values in excess of 470 and 460 ms have been associated 
with a low number of false positive findings, i.e. <1/1000 for two QTc measurements >460 ms (3).  
 
Two earlier studies have examined directly the utility of ECG screening for LQTS in infants and newborns 
(18,19). Zupancic et al. estimated the cost of universal screening performed for LQTS at day three of life to be 
about $18,000 per life-year saved (18). This figure rose to over $50,000 per life-year saved if the efficacy of β- 
blocker therapy at preventing sudden death was reduced from 100% to 35%, illustrating the importance of 

 
 
 
 
 
 
 
 
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therapy efficacy. However, this study estimated the prevalence of LQTS at 1/10,000 (5 times lower than the 
current estimates), assumed that screening was performed in the maternity ward at day 3 of life, when the 
number of false positives is high (12), and targeted only decreases in mortality due to SIDS. Quaglini et al. 
provided a model with somewhat different goals and assumptions, based on ECG screening performed between 
3 and 4 weeks of life and with the focus on prevention of sudden deaths due to LQTS not only in infancy (when 
they would be labeled as SIDS) but also later in life as well (19). They calculated a cost-effectiveness of under 
€12,000 per life-year (about US $16,000). 
 
Neither of these informative models included the cost of genetic testing, which was not commercially available 
at the time. Using the paradigm in Figure 1, (9) and with the conservative estimate of 1.4/1,000 infants with a 
QTc >460 ms, one can expect approximately 6-7,000 infants per year undergoing genetic testing in the United 
States and in Europe. The advent of genetic testing will have differential effects on cost-effectiveness according 
to the country involved, as cost varies between €1,300 (US $1,700) in Europe and US $5,000 in the US. This 
will elevate the cost of the initial evaluation, but may possibly decrease total costs by appropriate 
reclassification of false positive patients, particularly as genetic identification of cases improves. Finally, it 
should be recognized that for all cost-effectiveness studies, the 1/2,000 prevalence of LQTS has direct and 
important effects on the results. 
 
Commercial Potential 
The proposed screening device is preliminarily planned be sold into primary care under the product line of 
National Biomedical Corporation. National Biomedical designed, manufactured, and sold the QRS Diagnostic 
(www.qrsdiagnostic.com) product line of cardiovascular diagnostic instruments (electrocardiographs, 
spirometers, ambulatory blood pressure meters, Holter monitors, etc.). National Biomedical has established 
worldwide distribution for the QRS Diagnostic electrocardiograph technology through a broad and diverse set 
of representatives and distributers. National Biomedical is seeking new cardiac-related products to engage its 
worldwide distribution. Other distribution plans are also under consideration. 
 
 
 
(b) Innovation 
The proposed concept of conducting widespread LQTS screening using automated and focused analysis of just 
the patient’s QTc in an inexpensive instrument specifically designed for the primary care environment is novel. 
To achieve QTc screening efficiently, it is desirable to create a specialized ECG acquisition and automated 
processing apparatus that is less expensive and easier to use in a primary care environment than existing 
diagnostic ECG machines. A simple instrument with press-to-chest electrodes (no lead wires) that  provides a  
single output of QTc in milliseconds and a warning indicator does not exist presently. There are of course other 
single lead ECGs available, but they are not designed for simple, extremely low cost use in the primary care 
environment. No disposables are required in the proposed instrument. Recent technology innovations including 
a family of multichannel, simultaneous sampling, 24-bit, delta-sigma analogto- digital converters with built-in 
programmable gain amplifiers, internal reference, and an onboard oscillator, incorporate all of the features that 
are commonly required for ECG machines in a single very low cost integrated circuit (IC). With these high 
levels of integration, the new ICs enable the development of scalable ECG systems at significantly reduced size, 
power, and overall cost. The ICs suitable for the proposed application are about $4 each. 
 

 
 
 
 
 
 
 
 
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Phase I Prototype 
 
Phase II Prototype 
 
Potential risks to the patient: 
 
Potential risks of the protocol include skin reactions to the ECG electrodes or ultrasound gel 
This device currently does not have an indicated use for patients with cardiac devices therefore to avoid this 
unknown risk we will not be enrolling any patients with a pacemaker/ICD. 
 
 
Resources:  Describe the available resources to conduct the research (personnel, time, facilities, mentor 
commitment, etc.):  
 
Screening will utilize the study coordinator and nurse of Mayo Clinic’s LQTS Clinic who will review the 
schedule of returning, established LQTS children who would meet the study’s eligibility criteria. If eligible, the 
infant/child’s parents would be contacted at their annual clinical evaluation and informed of the study. If the 
parent agrees, consent will be obtained prior to the child’s clinical 12-lead ECG in the Gonda SL ECG Lab. The 
study procedure, i.e. the application of the QTc Meter, will be initiated following consent. 
 

 
 
 
 
 
 
 
 
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4. 
  Tests & Procedures:  Collection of data through noninvasive tests and procedures routinely employed 
in clinical practice that may include: MRI, surface EEG, echo, ultrasound, moderate exercise, muscular 
strength & flexibility testing, biometrics, cognition testing, eye exam, etc.  (Specify in the Methods section) 
 
5. 
  Data (medical record, images, or specimens):  Research involving use of existing and/or prospectively 
collected data. 
 
6. 
  Digital Record:  Collection of electronic data from voice, video, digital, or image recording. (Specify in 
the Methods section) 
 
7. 
  Survey, Interview, Focus Group:  Research on individual or group characteristics or behavior, survey, 
interview, oral history, focus group, program evaluation, etc.  (Specify in the Methods section) 
 
 
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