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Rachmiel et al, Bone age by ultrasound
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Bone age assessment by a quantitative sonometer
Short title: Bone age by ultrasound
Marianna Rachmiel, MD 1,2
, Larisa Naugolni, MD 1, Kineret Mazor-Aronovitch, MD
2,3, Amnon
Levin 4, Nira Koren-Morag, PhD
5, Tzvi Bistritzer, MD
1,2. Ze’ev Hochberg, MD PhD
6
1Pediatric Endocrinology Clinic, Assaf Haroffeh Medical Center, Zerifin Israel,
2Sackler School
of Medicine, Tel Aviv University, Tel Aviv, Israel,3Pediatric Endocrinology Unit, Shebba
Medical Center, Israel, 4SonicBone Medical Company, Rishon Lezion, Israel ,
5 Department of
Epidemiology and Preventive Medicine, Sackler Faculty of Medicine, Tel-Aviv University
6 Pediatric Endocrinology, the Technion – Israel Institute of Technology, School of Medicine,
Haifa. Israel
Corresponding author: Marianna Rachmiel, Pediatric Diabetes Service, Division of pediatrics,
Assaf-Harofeh Medical Center, Zerifin, 70300, Israel.
Tel: 972-8-9542007, Fax: 972-8-9779156, E.mail:rmarianna@gmail.com
Key terms: short children, skeletal maturation, x-ray, bone age assessment, ultrasound,
SonicBone, sonometer
Conflict of Interest:
The study was funded by SonicBone (Rishon Lezion, Israel).
AL is an employee of SonicBone and ZH is an independent consultant
Words count: 2109
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Abstract
Objective: Bone maturation is currently assessed by repeated radiography using eye-balling
subjective readings, or automated comparison of the characteristics of hand and wrist bones. The
aim of the study was to evaluate the concordance and reproducibility of a new portable device
(SonicBone's BAUSTM
) that utilizes quantitative ultrasonographic (US) technology measuring
the speed of sound (SOS) of US waves propagating along measured bone, and to compare it to
the current irradiating methods of bone age (BA) assessment (Greulich and Pyle (GP), Tanner-
Whitehouse 3 (TW3)).
Methods: The study population included 150 participants, 76 males, age 10.63.3 years,
attending an endocrine clinic. X-ray scans were evaluated independently by 4 observers.
Separate readings for wrist, carpal and phalanx were averaged for child's BA assessment. Data
from 100 subjects were utilized to assess the correlation between the speed-of-sound (SOS) and
attenuation (ATN) parameters against the manual BA by GP method, and to establish a
conversion equation for BA assessment by SonicBone. Fifty participants were assigned to assess
validity. BA assessment by SonicBone was correlated for manual GP, automated GP and TW3
methods.
Results: The coefficient of determination, R2 ,for the conversion equation including gender, SOS
and ATN was 0.80 for manual GP, 0.81 for automated GP and 0.82 for automated TW3
(p<0.001 for all). Pearson correlation between Sonographic BA and manual GP, automated GP
and automated TW3 demonstrated significant validity, r=0.89, r=0.91, r=0.91 (p<0.001 for all),
respectively.
Conclusion: BA assessment by SonicBone is comparable to the assessment by all three X-ray
based methods: manual GP, automated GP and TW3
Rachmiel et al, Bone age by ultrasound
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.
Introduction
Skeletal maturity assessment, defined also as ‘bone age’ (BA), is frequently used for evaluating
growth and puberty in children and adolescents. It is recommended as part of the routine clinical
care workup of a child with short or tall stature, precocious and delayed puberty, and more 1, 2
.
Repeated BA assessments are an important clinical tool utilized during the follow-up of such
patients, especially when treated by growth and puberty-related interventions1, 2
. BA is currently
assessed by radiography of the hand, using eye-balling or automated comparison of the shape
and size of the wrist and hand bones to a standard series of representative radiographic films of
hands according to the 1959 Radiographic Atlas of Skeletal Development by Greulich and Pyle
(GP) 1, 3
, or to the scoring method by Tanner and Whitehouse, currently in its 2001 third edition
TW3 1, 4, 5
.
To address the disadvantage of repeated irradiation, the need for specialized radiation centers,
heavy equipment and subjective reading1, 6-8
a new device, SonicBone (SB) (Rishon Lezion,
Israel) was developed. SB utilizes a quantitative ultrasonographic (QUS) technology of
ultrasonic (US) waves, propagating along a measured bone distance9, 10
.
Here, we report the validity and reproducibility of BA by SB, as compared to eye-balling BA by
the GP method and an automated reading by both the GP and TW3 methods.
Patients and Methods:
Study design: This was a cross sectional study. The study subjects (n=150, 76 males) were
recruited consecutively in a pediatric endocrine clinic. All BAs performed by X-ray scans and
QUS were conducted prior to data analysis. The participants were then randomized to an
’Analysis group’ (n=100, 40 males) and a 'Validation group’ (n=50, 27 males). Analysis
Rachmiel et al, Bone age by ultrasound
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performed on data obtained from the ’Analysis group’ enabled to establish a conversion equation
for BA assessment by SonicBone. Analysis performed on data obtained from the ‘Validation
group’ assessed the relationship between QUS against the manual GP method, automated GP
method, and automated TW3 method.
The study protocol was approved by the institutional review board and by the Helsinki
Committee of the Israeli Ministry of Health, and registered at www.clinicaltrials.gov
(NCT01346618). Written informed consent was obtained from each legal guardian, and the
participant assented for the study.
Study population: Patients ranging between 4-17 years of age were recruited from the Pediatric
Endocrinology Clinic at Assaf Haroffeh Medical Center, Israel. Inclusion criteria included all
patients who performed hand x-ray scan as part of their clinical care. Exclusion criteria included
children with bone diseases or those who within the last year took medications which might
change bone metabolism or mineralization (such as: high dose steroids, biphosphonates, high
dose Vitamin D, calcitriol).
BA assessment by the manual GP method: Hand x-ray scans were reviewed and assessed
independently by four pediatric endocrinologists being blinded to each other’s findings. They
assigned a separate BA to the long bones (Radius and Ulna, the carpalsand the short bones, and
the mean of the three readings was defined as the child’s BA , as previously described 11, 12
. The
mean of four observers was defined as the child’s BA by GP.
Automated BA assessment: The images were analyzed using the BoneXpert version 2.1
automated method for BA determination (Visiana, Denmark), which determines both GP and
TW3 BA 13, 14
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Ultrasonic BA assessment: The SonicBone (SB) device (Rishon Lezion, Israel) is a small (50cm
X 25cm X 25cm), portable, bone sonometer (Figure 1), which measures two parameters: a)
speed of propagation through bone (speed-of-sound, SOS, m/sec) of inaudible high frequency
waves of a short ultrasound pulse; and b) attenuation (ATN; the decay rate) of the sound wave by
the bone as a function of the distance it travels between a transmitter probe and a receiver
probe15
. The hand was measured by (Figure 1): 1- wrist (W), measuring SOS and ATN at the
distal radius and ulna secondary ossification centers of the epiphyses; 2-metacarpals (MC),
measuring SOS and ATN at the distal metacarpal epiphyses; and 3- phalange (P), measuring
SOS and ATN along the bent proximal third phalanx shaft, growth plate and epiphysis. The
average of those 3 readings was defined as the child’s BA by SB. All ultrasonic examinations
were conducted at the Pediatric Endocrinology Clinic, by trained personnel. The examiners were
blinded to the clinical background and to the BA by GP or TW3. Each subject underwent two
readings by two observers. Eight additional repeated readings were performed for 10 subjects, 5
boys and 5 girls, aged 6-16 to ensure reproducibility and precision positioning assessment.
Statistical Analysis: Data was analyzed with SPSS software version 21.0 (SPSS Inc. Chicago, Il,
USA). The estimation of within subject repeatability was calculated by a one way analysis of
variance (ANOVA) model. The outcome measures of the study included the correlation and
hypothesis testing of equality of BA by SB and BA by manual GP, automated GP and automated
TW3. The immediate side effects were also examined, by counting the numbers of incidents, the
nature of inconveniencies and other complaints. The first phase analysis, performed on all study
population (n=150), using Pearson correlation coefficient, demonstrated, the linear relationship
between BA by GP and measurements of SB, SOS and ATN parameters. The second phase
analysis of 100 subjects (‘Analysis group’) established a conversion equation for estimating BA
by SB out of the multivariate linear regression coefficients involving gender and the SB
parameters. These equations provided the best R² result .
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The third phase analysis was performed on data collected from the ‘Validation Group’ (n=50)
using the equations generated at phase 2 .The correlation between BA by X-ray and by SB was
analyzed by the Pearson correlation coefficient. Comparison of the differences between the BA
by SB and by X-ray based methods was conducted by the paired t test and further presented by
95% confidence intervals.
Results
The study population included 150 subjects (76 males), mean age 10.63.3 years (4.1-17.4
years), recruited between June 2011 and March 2012. At the time of research investigation they
were diagnosed with short stature and failure to thrive (46%), growth hormone deficiency (9%),
precocious or early puberty (23%) overweight and obesity (8%), normal and healthy (14%). The
clinical, demographic and body composition characteristics of the analysis and validation groups
were similar (Table 1).
According to measurements conducted independently in the same environment by two
examiners, the performance analysis of SB revealed high reproducibility and repeatability
Upon performing 10 repeated readings, on 10 subjects, the percent of relative standard deviation
(%RSD) for SOS were smaller than 0.73% for all the children, with a maximum standard
deviation of 13.7%. The %RSD for ATN was less than 3.5% for all the children with a
maximum standard deviation of 1.4%.
The distribution of SOS and ATN measurements according to skeletal area (W, MC, P) in the
study population (n=150) is presented in Figure 2. The SOS measurements ranged from 1604 -
2647 m/sec and the ATN surrogate distance ranged from 29.5 - 82.7 mm.
In the first phase analysis we correlated between BA by manual and automated GP and
automated TW3 against SOS and ATN from SonicBone in all study population (n=150). A
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significant correlation for both SOS ( r2=0.68, 0.68, 0.69 for manual GP, automated GP and
automated TW3, respectively) and ATN (r2=0.88, 0.88, 0.89 for e manual GP, automated GP and
the automated TW3, respectively) was found.
In phase 2, multiple linear regression analysis was utilized in order to estimate the BA by the
three methods using gender, SOS and ATN. The linear regression coefficients are presented in
Table 2. For all three methods, both SOS and ATA were significantly strong predictors for BA.
SOS was an important and significant predictor for BA above and beyond the ATN; the
coefficient of determination R2 significantly increased using SOS. As much as 82% of the total
variation in BA is explained by ATN and SOS. Table 2 also shows the un-standardized
coefficient b that are used for predicting future outcomes, and the standardized coefficients beta
that were used to evaluate the relative strength of the relationship to BA.
In the third phase analysis, the only data from the ‘Validation group’ was compared to the
assessment of BA, as delivered by the device according to the conversion equation performed in
the second phase (BA by SB), to the three hand X-ray based methods. The results demonstrate a
significant correlation between BA by SB and the BA by manual GP (r=0.89, P<0.001),
automated GP (r=0.91, P<0.001) and automated TW3 (r=0.91, P<0.001). There were no clinical
or statistical significance differences between methods, using paired comparisons (P=0.887;
Table 3).
Discussion
In the dialectics of human anthropology and auxology, ‘BA is an expression of the skeletal
maturity of a child. Inferring from bone maturity, the clinician contemplate diagnostic
considerations and evaluate height prediction, and would recommend sport activity and dancing,
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or the timing for orthodontic procedures and orthopedic surgery. This is accomplished in a
variety of methods, all of which utilize X-ray technology and compare a given film to various
standards, followed by designation of a BA. The problematical utilization of repeated X-ray
evaluations is well-appreciated. Here, we present the applicability of radiation-free BA
assessment by QUS and its concordance with currently employed BA valuation by X-ray-based
methods.
This is not the first attempt to apply QUS technology for BA assessment; other attempts failed to
enter clinical practice. Castriota-Scanderbeg et al17, 18
attempted to assess skeletal maturation by
quantifying the cartilage overlying layer of the femoral head. They demonstrated a decrease in
cartilage thickness with age. Yet, a comparison with the BA by GP showed poor agreement18
.
Shimura et al,14
and Khan et al,19, 20
assessed skeletal maturation by SOS through a single site at
the head of the ulna (similar to W site in the current study), that often differs from other bones,
not testing the sites available by SB device.
2, 11, 12
.
The SB device provides three independent measurements of the Radius and Ulna epiphyses, of
metacarpals and of phalanges, similar to clinical practice assessments of hand x-ray scans. While
the sites assessed by SB and by the X-ray methods are not identical, we demonstrate a significant
correlation between BA by SB and BA by GP and TW3 methods at each site separately and by
the mean BA 11
.
The BA by SB result was generated by the equation for BA assessment by QUS, which was
integrated in the device, according to the data retrieved from the analysis of 100 subjects,
including SOS, ATN and the manual reading by the GP method. It was then validated in 50
subjects against both manual and automated GP reading as well as the automated TW3 methods
showing a high performance of reliability and significant concordance.
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The ultrasound technique used by SonicBone is the "through transmission technique", as
described in Figure 1. An ultrasound wave is propagated perpendicularly through a medium
containing soft tissue and bone, from transmitter to receiver. Two parameters are used in this
method: The primary parameter is SOS (time of flight) of the US wave over the distance from
transmitter to receiver. SOS correlates strongly with the structure and density of the bone.
However, bone is attenuative and dispersive. The attenuation is seen in the change in amplitude
of a travelling wave and in the values of the reflection coefficients. The dispersion contributes to
the distortion of the wave, and we therefore included in the equation the attenuation – the decay
rate of a wave as it propagates through bone. We use the distance between transmitter and
receiver as an ‘Attenuation factor - ATN’.
In the current study, the new technique was compared with manual reading by the GP method
and with automated reading using both PG and TW3 methods. The latter gave the best regression
against BA by SB; as much as 82% of the total variation in BA, is explained by ATN and SOS.
For all three methods, the ATN showed important contribution to the regression, yet, in all three
the SOS was important and significant predictor for bone age above and beyond the ATN.
Thus, the measurements of SB device are all hand-area inclusive (W, MC, P), objective, and of
physiological agreement to the goal of bone maturation assessment (SOS, ATN), offering a
possible alternative to the present radiation based mostly subjective GP, and TW3 methods. As
BA is an essential measurement procedure for pediatric Endocrinology physicians and quite
often must be repeated over time, the SonicBone offers an important advantage over the current
methods, with no side effects and with objective readings by a system accessible at the clinician
office. The current report does not provide reference or standard for BA by chronological age for
the QUS method. This is currently under development using a normal population distribution for
all ages according to gender.
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In summary, the radiation-free assessment of BA by the SonicBone device in pediatric
population attending endocrinology clinics was found to be highly reproducible and comparable
to the BA assessed by hand X-rays based methods, both subjective and objective methods.
Author Contribution:
MR, LN, KMA, AL, NKM, TB and ZH, made substantial contributions to conception and
design, or acquisition of data, or analysis and interpretation of data, took part in drafting the
article or revising it critically for important intellectual content, and gave their final approval of
the version to be published.
MR, ZB, LN, NKM and ZH take responsibility for the integrity of the work as a whole, from
inception to published article.
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Res Paediatr 76, 1-9.
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(2009) Clinical application of automated Greulich-Pyle bone age determination in
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Table 1: Demographic, clinical and body composition parameters of study population, randomly
divided into the analysis and the validation groups
All ‘Analysis
Group’
‘Validation
Group’
P
value
Number 150 100 50
Gender (f) 74 51 (51%) 23 (46%) 0.34
Pre-puberty* 46 39 (39%) 17 (34%) 0.33
BMI SDS 0.21.4 0.31.3 -0.11.5 0.09
Age (years) 10.63.3 10.53.2 10.93.4 0. 85
Mean BA by GP - W (years) 10.03.4 10.13.2 10.03.8 0.20
Mean BA by GP - CMC (years) 10.13.5 10.13.3 10.03.8 0.26
Mean BA by GP - P (years) 10.33.4 10.33.2 10.33.7 0.47
Mean BA by GP (all sites ) 10.1 3.3 10.1 3.1 9.9 3.6 0.77
*Data is based on n=148, FTT- failure to thrive, GHD – growth hormone deficiency.
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Table 2: The regression coefficients, used in the conversion equation from the Analaysis Group
Site
Parameter
Coef.b
SE
Beta
t
P value
R2
BA-Manual GP
Constant -28.68 4.87 -5.88 <0.001
0.80
Gender 0.187 0.310 0.030 0.602 0.548
SOS *(cm/sec) 1.09 0.293 0.230 3.73 <0.001
ATN **(mm) 0.330 0.029 0.724 11.39 <0.001
BA-Automated GP
Constant -30.77 4.88 -6.30 <0.001
0.81
Gender 0.345 0.31 0.053 1.11 0.268
SOS *(cm/sec) 1.160 0.293 0.236 3.96 <0.001
ATN **(mm) 0.341 0.029 0.722 11.75 <0.001
BA- Automated TW3
Constant -29.55 4.55 -6.49 <0.001
0.82
Gender 0.411 0.289 0.067 1.42 0.159
SOS *(cm/sec) 1.133 0.274 0.241 4.14 <0.001
ATN **(mm) 0.323 0.027 0.718 11.94 <0.001
SE= standard error, t=statistics value. *SOS- speed of sound, measurements ranges from 1,604
m/sec to 2,647 m/sec. ***ATN- attenuation, measurements ranges from 29.5 mm to 82.7 mm.
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Table3: Comparison of BA by SonicBone to the BA by the three X-ray methods (in the
validation group of subjects).
Mean
difference
S.E.
95% C.I.
P
SB - manual GP
-0.034
0.237
-0.51-0.44
0.887
SB - automated GP
0.036
0.207
-0.38-0.45
0.861
SB -automated TW3
0.219
0.198
-0.18-0.62
0.274
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Figure legends:
Figure 1: Bone age assessment by SonicBone bone sonometer at the third proximal phalange
(A), the metacarpal (B) and the wrist (C). The device measures two parameters (D): the speed of
propagation of inaudible high frequency waves of a short ultrasound pulse through bone; and the
Attenuation/distance between a transmitter probe (T) and a receiver probe (R), located at the
edges of the measured bone area for assessment of the attenuation factor.
Figure 2: Quartiles distribution of SonicBone parameters of SOS and ATN according to the
measured areas of the left hand, wrist (W), carpal (MC) and phalanx (P), in the whole study
population (n=150). 1a. Speed of sound in m/sec (SOS). 1b. Attenuation/distance in mm (ATN).
Lines within boxes indicate median; limits of boxes indicate 25th and 75th percentiles; circles
represent outliers.
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Figure 1
A
A
B
B
C
C
D
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Figure 2a Figure 2b