[version 1; peer review: 2 approved with reservations]
No competing interests were disclosed.
Most adult cardiovascular disease begins in childhood ^{ 1 }. Given the burgeoning obesity pandemic in children worldwide ^{ 2 }, there is a need for precise and scalable surveillance methods to detect subclinical cardiovascular disease in children and adolescents. PWV directly measures artery wall stiffness, an early feature of atherosclerosis. Early detection allows early intervention and intensified primary prevention strategies in affected individuals.
PWV measurement involves measuring the time it takes the arterial pulse to travel a specific distance, and then dividing the distance by the transit time, to calculate the velocity. Transit time is obtained by measuring the interval delay between the pulse wave arriving at a proximal and distal sensor that are placed on fiducial points, most commonly over the external carotid and femoral arteries. Arrival of the pulse wave is identified using various devices that monitor the arterial pressure waveform. These methods of measuring transit time are generally highly reproducible and accurate. However, the distance estimations used for PWV calculation are obtained using a tape measure over the body surface and are vulnerable to error. A variety of methods exist using different surface anatomy landmarks and there is no clarity on the most appropriate method for growing children and adolescents.
Previous studies have highlighted the importance of standardizing methodologies, as the use of different arterial path length estimation methods produce noticeably different results ^{ 3– 5 }. This makes interstudy comparisons of PWV data very difficult and creates confusion regarding normal values for PWV in children. In adult patients (who are no longer growing in height), any inaccuracy in estimating the distance traveled is irrelevant because the true distance travelled will not change between one visit and the next. Therefore, a change in transit time in adults reliably reflects a change in PWV and thereby indicates progression of arteriosclerotic vascular disease. However, in growing children and adolescents, the distance travelled by the pulse wave may well change between one visit and the next. Therefore, a change in transit time in children or adolescents does not necessarily indicate a change in PWV.
We sought to investigate the fidelity of a variety of arterial path length estimation methods by comparing true arterial path length measured on computerized tomography (CT) scans, with estimations based on a variety of surface anatomy landmarks.
Using the Picture Archiving and Communication System (PACS) at Tygerberg Academic Hospital, Cape Town, we identified all archived CT scans of paediatric and adolescent patients, excluding those with congenital abnormalities of skeleton or any disease likely to distort the gross anatomy of the large vessels. Midluminal arterial lengths were measured using the multiplanar reformation (MPR) imaging software Intellispace Portal version 4 (Philips: Amsterdam). Surface anatomy measurements were obtained using the same MPR imaging software.
Comparisons were performed in segments, since there were no wholebody CT scans available. Segments of surface anatomy distances and arterial path lengths are presented in
Six surface anatomy distances  Abbreviation 


AS 

SX 

SI 

XU 

XI 

UI 
Six arterial path lengths  Abbreviation 

Origin of brachiocephalic

TC 
Origin of right

CB 
Carotid

BE 
Origin of brachiocephalic

TX 
Aorta at the

XA 

AF 
Surface anatomy

Arterial



Set 1  AS  TC+CB+BE 
Set 2  SX  TX 
Set 3  XI  XA+AF 
Set 4  XU+UI  XA+AF 
Set 5  SI  TX+XA+AF 
Set 6  SX + XI  TX+XA+AF 
Set 7  SX + XU +UI  TX+XA+AF 
Centerline paths of major vessels were created with the Advanced Vascular Analysis (AVA) application within Intellispace Portal, by placing serial markers along the vessel using the axial, sagittal, coronal, and 3D volume rendered images, as per Intellispace Portal operation manual. 3D Slicer with the Vascular Modeling Toolkit (VMTK) extension can be used as an alternative to AVA for computing vessel centerlines. After creating the vessel centerline, the vessel measurements were performed in the “measurement” stage of AVA application. Thereafter the rendering parameters of the 3D volume rendered image were changed to display skin surface to perform the surface anatomy measurement. All distances were measured in millimeters.
In the “vessel extraction” stage of the AVA application, serial markers were placed at the midpoint of the artery lumen, starting at the origin of the brachiocephalic trunk (
Illustrating the placement of the first marker (seed) on the coronal (
Illustration of vessel centerline TC+CB+BE on a curved coronal (
A similar method was used to measure the arterial path length TX+XA+AF. This is illustrated in the
Continuing in the “measurement” stage, the rendering parameters of the volume rendered image were changed to display skin surface. Thereafter the “magic glass window” feature was selected from the right click menu. This “magic glass window” feature is an enhanced visualizing window that can be superimposed on top of the volume rendered image of the skin surface. It is a moveable miniwindow which can be set with its own windowing, image enhancement and rendering parameters to enable the operator to “look through” the skin at the anatomical structures beneath. The rendering parameters inside the active “magic glass window” were adjusted to visualize the precise position of the underlying suprasternal notch (
Illustrating surface measurement AS on an anteriorposterior 3D volume rendered image (
Illustrating surface measurement AS on an oblique 3D volume rendered image (
A similar method was used to measure the other surface anatomy distances. These are illustrated in the
Ethical approval was sought from Health Research Ethics Committee of Stellenbosch University (Ethics Reference #: S15/05/113). A retrospective collection of CT scans between January 2010 and May 2018 were used. Since the images were part of an archive database, there was no direct interaction with patients and a request for a waiver of individual informed consent was approved from the ethics committee. Personal information was kept strictly confidential and identifying demographic information was not captured.
There is excellent correlation between all surface anatomy distances and the arterial path lengths they represent (see
Comparison  n  r ^{2}  pvalue  

Set 1  TC+CB+BE compared to AS  66  0.92  <0.0001 
Set 2  TX compared to SX  152  0.84  <0.0001 
Set 3  XA+AF compared to XI  105  0.99  <0.0001 
Set 4  XA+AF compared to XU+UI  107  0.99  <0.0001 
Set 5  TX+XA+AF compared to SI  18  0.98  <0.0001 
Set 6  TX+XA+AF compared to SX+XI  18  0.97  <0.0001 
Set 7  TX+XA+AF compared to SX+XU+UI  17  0.97  <0.0001 
Relationship between arterial path length TC+CB+BE (origin of the brachiocephalic trunk to the external carotid at the angle of the mandible on the right) and surface anatomy distance AS (suprasternal notch to the angle of the mandible) in children younger than 18 years. Linear regression analysis showed a strong positive correlation (r ^{2} =0.92). The regression equation to be used for mathematical conversion is presented in the block insert.
Relationship between arterial path length TX+XA+AF (origin of the brachiocephalic trunk to the right femoral artery at the inguinal ligament) and the surface anatomy distance SI (suprasternal notch to the midpoint of the right inguinal crease) in children younger than 18 years. Linear regression analysis showed a very strong positive correlation (r ^{2} =0.98). The regression equation to be used for mathematical conversion is presented in the block insert.
The age range and gender split for each Comparison Set is presented in the
The aim of the current study was to estimate the true intraluminal distance travelled by the pulse wave, which is equal to:
This may be estimated using the following component surface anatomy distances:
(TC+CB+BE) is accurately estimated by (AS), provided the surface anatomy distance (AS) undergoes mathematical conversion using the linear regression equation presented in the block insert on the Figure 5 scatterplot. Without the mathematical conversion, the surface anatomy distance (AS) consistently underestimates the true arterial path length (TC+CB+BE) by 8% to 12%.
(TX+XA+AF) is accurately estimated by the sum of the surface anatomy distances (SX) plus (XU+UI). Without the mathematical conversion using the linear regression equations presented in the block inserts on Figures 11 and 13, this combination of surface anatomy distances minimally over or underestimates the arterial path length (TX+XA+AF) by +2% to 1%.
(TX+XA+AF) is less accurately estimated by the sum of the surface anatomy distances (SX) plus (XI). Without the mathematical conversions using the linear regression equations presented in the block inserts on Figures 11 and 12, this combination of surface anatomy distances underestimates the arterial path length (TX+XA+AF) by 1% to 3%.
(TX+XA+AF) is even less accurately estimated by the surface anatomy distance (SI). Without the mathematical conversion using the linear regression equation presented in the block insert on Figure 6, the surface anatomy distance (SI) consistently underestimates the arterial path length (TX+XA+AF) by 5% to 6%.
Therefore, the true intraluminal distance travelled by pulse wave is most simply and reliably estimated by subtracting the adjusted surface anatomy distance between the suprasternal notch and the angle of the mandible (PWV recording site in the neck), from the unadjusted distance from the suprasternal notch to the umbilicus, through the midinguinal crease to the femoral PWV recording site. Substitution using the surface anatomy distances (SI), or (SX) plus (XI) may require mathematical conversion to retain reasonable accuracy.
The issue of accurate PWV measurement in growing children and adolescents is a crucial one, given the burgeoning obesity pandemic in children worldwide ^{ 2 } and the corresponding need for precise and scalable surveillance methods to detect subclinical cardiovascular disease in that population group. The present study was designed to investigate the most accurate method of estimating the true distance travelled by the aortofemoral pressure wave, using surface anatomy landmarks in growing children, allowing accurate calculation of carotidfemoral PWV.
PWV directly measures increasing arterial wall stiffness, a valuable precursor to atherosclerosis ^{ 9 }. Identifying progressive vascular disease early in its pathogenesis allows for early intervention to prevent progression. Automated PWV offers affordable and scalable surveillance for monitoring and identifying the early stages of arteriosclerosis.
The main finding of our study was that, although there is excellent correlation between the surface anatomy distances and their respective arterial path lengths, surface anatomy measurements require adjustment using the conversion formulae that we have provided, to accurately estimate the true distance travelled by the pulse wave. An exception may be the surface anatomy distances (SX) and (XU+UI), which differ minimally from the arterial path lengths they represent.
The combination that most accurately estimates the true distance travelled by the aortofemoral pressure wave are the surface anatomy distances (SX) plus (XU+UI) minus (AS). The distance (AS) needs to be mathematically converted (using the linear regression equation presented in the block insert on the
Our study is entirely novel in that, to the best of our knowledge, it is the first published attempt at investigating this question in growing children and adolescents. It is not surprising that our results are inconsistent with previous studies performed in adults ^{ 4, 5, 10– 12 }, since the bodies of growing children and adolescents are different in proportion and shape to adults.
Our data will result in more reliable PWV calculation in growing children and adolescents. More robust and accurate measurement of PWV will in turn enable healthcare workers to detect arterial stiffness in its early stages and allow for early interventions to prevent vascular events such as strokes and heart attacks later in life. Finally, our findings will enable more robust interstudy comparisons of carotidfemoral PWV data in children and adolescents.
Note that the surface distances obtained in the current study are equivalent to the distances one would find when using a sliding caliper. Therefore, the exaggerations of surface anatomy measurements caused by morbid obesity may be overcome by using a sliding caliper instead of a tape measure ^{ 13 }.
Our study had several limitations. First, although our results showed a very strong correlation between the surface anatomy measurements and their respective arterial path length measurement, the sample size was limited, particularly for comparisons requiring long scans stretching from the neck to the pelvis. We overcame this by comparing subsections of arterial path length (e.g. SX compared to TX; and XI compared to XA+AF).
Second, the surface anatomy measurements were performed using 3D volume rendered images. In a future study, the surface anatomy measurement could be performed on actual patients facetoface, and then compared to the arterial path length obtained from CT imaging.
Third, we were unable to determine whether there were any systematic ethnic differences in the measurements, because ethnicity information was not available.
Fourth, although we measured the length of the centerline of large vessels, we did not measure the internal diameter of the vessel, which may confound the speed at which the aortofemoral pressure wave travels. The latter was beyond the scope of the present study.
There is high correlation between the surface anatomy distances and the arterial path lengths they represent; however, these are not equal. Most surface anatomy measurements require adjustment using the formulae that we have provided, to accurately estimate the true distance travelled by the pulse wave.
Due to the large number of CT scans used (n=483) in this study and the size of these DICOM files that can be as big as 2.5 Gigabytes per scan. It is not feasible to share these data sets.
A reader/reviewer can request a copy of the data sets by submitting an application to the Tygerberg hospital research committee, specifically to Mrs. Dawn Marwood (
Figshare: DATA: Accurate arterial path length estimation for pulse wave velocity calculation in growing children and adolescents.
This project contains underlying path length measurements in the following files:
TC_CB_BE to AS.xlsx
TX to SX.xlsx
TX_XA_AF to SI.xlsx
TX_XA_AF to SX_XI.xlsx
TX_XA_AF to SX_XU_UI.xlsx
XA_AF to XI.xlsx
XA_AF to XU_UI.xlsx
Figshare: EXTENDED DATA: Accurate arterial path length estimation for pulse wave velocity calculation in growing children and adolescents.
Data are available under the terms of the
Carotidfemoral pulse wave velocity (PWV) is a surrogate marker of arterial wall stiffness. Calculation of PWV in growing children requires an accurate estimation of the true distance travelled by the aortofemoral pressure wave, using surface anatomy landmarks.
The authors compared the arterial path length measured on computerized tomography (CT) scans, with a variety of estimations based on surface anatomy landmarks using the same multiplanar reformation MPR imaging software as for the path length measurements.
They concluded that there is high correlation between the surface anatomy distances and the arterial path lengths they represent; however, most surface anatomy measurements require adjustment using formulae provided by the authors, to accurately estimate the true distance travelled by the pulse wave.
The authors are stating, "a variety of methods are used to estimate this distance, and these have not previously been investigated in growing children and adolescents”.
In fact, several studies have been conducted to standardize childhood distance measurement of PWV. Some of these were based solely on surface distance measurements (Kracht
The agreement between the results of the two methods (intraluminal and surface measurements) should be evaluated using BlandAltman plots. A good linear correlation does not necessarily mean that there is no bias in the estimates. Please use this analysis for comparison.
In adults, the recommended distance measurement is the direct measure between the carotid tonometry site to femoral tonometry site, applying a systematic correction for accurate values of PWV (factor 0.8). This question was also recently addressed by ref 3. Please comment.
Has the surface distance data obtained by CT and the data measured with a tape measure been compared? It would be worthwhile to examine this aspect of possible bias in a few subjects.
Is the work clearly and accurately presented and does it cite the current literature?
Partly
If applicable, is the statistical analysis and its interpretation appropriate?
Partly
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Is the study design appropriate and is the work technically sound?
Yes
Are the conclusions drawn adequately supported by the results?
Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
Reviewer Expertise:
Pediatric hypertension, pediatric CKD, pediatirc pransplantation, cardiovascular consequences of CKD in childhood
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
In the present study, the authors investigated different methods to assess pulse wave path distances for measuring carotid to femoral PWV, an important marker of early cardiovascular disease, in growing adolescents. They used computerised images from hospital CT scans in adolescents to reconstruct body anatomy and measure surface distance, and correlate them with vascular paths.
They come with equations using fiducial anatomic landmarks such as mandible angle, sternal notch, Xiphisternum, inguinal crease etc., and combination of measures between those points, correlated with true vascular path length.
The main finding is that all anatomical distances correlate well with corresponding arterial paths, but one equation is preferred: the true intraluminal distance travelled by a pulse wave is reliably estimated by subtracting the adjusted surface anatomy distance between the suprasternal notch and the angle of the mandible (PWV recording site in the neck), from the unadjusted distance from the suprasternal notch to the umbilicus, through the midinguinal crease to the femoral PWV recording site. Additional calibration is necessary by mathematical conversion to retain adequate accuracy.
The paper is very well constructed and written, the methodology is impressive and very well adapted to the aim of the authors. The results are convincing. I have, nevertheless, some remarks which would help, I hope, in applying the present findings to clinical research.
My main concern is about cumulated errors when measuring distances. Measuring distances on the skin using tape meters is associated with random errors which can reach +/ 1 cm, i.e. 5% when measuring once. If three measures are done (mandible to suprasternal notch to umbilicus then to inguinal crease then the error can be made 3 times and therefore cumulate. This then makes a potential error of 3 cm for 50 cm, i.e. 12% error, which is kind of a problem. This is why, in adults, we recommend to measure only one direct measure (carotid tonometry site to femoral tonometry site), and apply a systematic correction for accurate values of PWV (factor 0.8). In the present case, I would love to see estimations of error using the proposed combinations of distances, and how a direct skin measure (for instance mandible to inguinal crease), performs in terms of accuracy, precision, and expected errors. That could be done by duplicate the datasets (5 or 10), generate Gaussian noise with 0.5 cm SD on each distance measure, calculate paths using noisy distances, then reestimate the correlations with true vascular paths.
Another point is to estimate the influence of anatomical variants on the measurements, especially obesity, but also developmental age.
In adults, distance measurement is also a problem, when comparing populations and estimating normal values. The authors should quote and use the paper in adults for reference values (MattaceRaso
Is the work clearly and accurately presented and does it cite the current literature?
Partly
If applicable, is the statistical analysis and its interpretation appropriate?
Partly
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Is the study design appropriate and is the work technically sound?
Yes
Are the conclusions drawn adequately supported by the results?
Partly
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
Reviewer Expertise:
Arterial stiffness in adults, especially hypertension
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.