Beyond Confounders: Addressing Source of Measurement Variability and Error in Shear Wave Elastography
Phase: NA
Conditions: Liver Fibrosis, Liver Diseases
Sponsor: Massachusetts General Hospital

Study Protocol and Statistical Analysis Plan 
 
Study Title: Beyond Confounders: Addressing Source of Measurement Variability and Error in 
Shear Wave Elastography 
 
NCT number: NCT03342560 
 
Document date: 08/20/2019 
 
HYPOTHESIS:  We hypothesize that variation using ultrasound elastography (UE) for the 
estimation of stage of liver fibrosis in patients with diffuse liver disease exists due to different 
methods of measurements, and/or different systems.  
 
BACKGROUND: Liver disease and cirrhosis are important causes of morbidity and mortality in 
the United States and are a major public health problem with 40,000 deaths and more than 1.4 
billion dollars spent on medical services. Hepatic fibrosis is the final common pathway for many 
different liver insults and is known to be a dynamic process, which is  reversible if diagnosed 
early and treated. If untreated, fibrosis eventually progresses to cirrhosis, which is irreversible. 
The diagnosis of fibrosis relies on liver biopsy (the gold standard) however, is an invasive 
procedure with risks and sampling errors. Indirect biomarkers of fibrogenesis can measure 
some of these components to determine categories of fibrosis, with a sensitivity and specificity 
of 47% and 90% respectively.It is shown in the literature that, fat content of liver is related with 
fibrosis development. Biopsy is accepted as the most accurate technique to assess liver fat and 
fibrosis amount. Fibrotic livers demonstrate increased stiffness, a property that can be 
measured using technology named Ultrasound Elastography or sonoelastography (SWE). SWE 
is performed by insonating the patient with a low energy, amplitude, and frequency shear wave 
created by a vibrating probe.  The propagated wave travels faster with increasing fibrosis: the 
stiffer the tissue, the faster the shear wave propagates. A pulse-echo ultrasound acquisition 
allows measurement of the wave velocity and the results are presented as kilopascals (kPa). 
Prior reports have described sensitivity and specificity for liver fibrosis detection of 80% and 
97% respectively for SWE. The benefits of SWE are that it is inexpensive, reproducible, 
painless, rapid (< 10 min), easy to perform, and can be used for diagnosis, prognosis and 
monitoring disease progression. 
 
SPECIFIC AIMS: 
-Compare shear wave elastography (SWE) measurements from different ultrasound systems; 
using histopathology as reference standards. 
-Assess intra-operator and inter-operator reliability by measuring variability in elastography 
values by two operators on a single system. 
-Determine the effect of deviations from guidelines (less number of measurements and 
measurements during active breath) 
 
The proposed investigation is a cross-sectional study using ultrasound elastography and fat 
quantification modalities. We enrolled 30 subjects 18 years old and older in whom diffuse liver 
disease was suspected, and who had undergone non-focal liver biopsy in the past 6 months or 
are scheduled to undergo biopsy within 3 months of enrollment, as part of their routine clinical 
care.  
 
Inclusion criteria: 
- 
Adult patients (age 18 or older) 
- 
Men or women  

-    Suspected diffuse liver disease and have had a liver biopsy within the last 6 months 
or are scheduled for a liver biopsy in the next 3 months. 
- 
Consent to participate in the study  
 
Exclusion criteria: 
-    Pregnancy  
- 
Acute illness/cognitive impairment resulting in inability to cooperate with ultrasound 
- 
Patients that do not consent to ultrasound examination. 
 
All subjects came for 2 study visits within 60 days of each other. In addition, subjects needed to 
fast for at least 4 hours prior to study visits. Sonoelastography was performed using four FDA-
approved ultrasound units. 2 sonographers performed; 
• 
Median Elastograpy (10 measurements) on regular and variable map at a depth(in the 
area between 2cm from capsule and 6.5cm from skin) 
• 
Median SWE value with active/free breath(10measurements) 
• 
Median SWE value with less number of acquisitions(3measurements) 
 
 
STATISTICAL ANALYSIS PLAN: 
Statistical analysis software to use: SPSS (Release 24, IBM, NY, USA) software.  
Intra-operator agreement between each operators’ median measurement was calculated using 
ICC (Intraclass correlation coefficient). 95% confidence intervals were computed for parameter 
estimates. All p-values were two sided. p values less than 0.05 were considered statistically 
significant.