Influence of age on gadoxetic acid disodium-induced transient respiratory motion artifacts in pediatric liver MRI.

PURPOSE: Gd-EOB-DTPA-enhanced liver MRI is frequently compromised by transient severe motion artifacts (TSM) in the arterial phase, which limits image interpretation for the detection and differentiation of focal liver lesions and for the recognition of the arterial vasculature before and after liver transplantation. The purpose of this study was to investigate which patient factors affect TSM in children who undergo Gd-EOB-DTPA-enhanced liver MRI and whether younger children are affected as much as adolescents.
METHODS: One hundred and forty-eight patients (65 female, 83 male, 0.1-18.9 years old), who underwent 226 Gd-EOB-DTPA-enhanced MRIs were included retrospectively in this single-center study. The occurrence of TSM was assessed by three readers using a four-point Likert scale. The relation to age, gender, body mass index, indication for MRI, requirement for sedation, and MR repetition was investigated using uni- and multivariate logistic regression analysis.
RESULTS: In Gd-EOB-DTPA-enhanced MRIs, TSM occurred in 24 examinations (10.6%). Patients with TSM were significantly older than patients without TSM (median 14.3 years; range 10.1-18.1 vs. 12.4 years; range 0.1-18.9, p<0.001). TSM never appeared under sedation. Thirty of 50 scans in patients younger than 10 years were without sedation. TSM were not observed in non-sedated patients younger than 10 years of age (p = 0.028). In a logistic regression analysis, age remained the only cofactor independently associated with the occurrence of TSM (hazard ratio 9.152, p = 0.049).
CONCLUSION: TSM in Gd-EOB-DTPA-enhanced liver MRI do not appear in children under the age of 10 years.

Introduction

MRI is the preferred imaging modality for the assessment of liver pathologies in daily clinical practice, both for adults, and also, increasingly, for pediatric patients [1, 2]. Gadoxetate disodium (Gd-EOB-DTPA, Primovist® or Eovist®) has improved liver magnetic resonance imaging due to its superior performance in diffuse and focal liver diseases [3-8], with the benefit of not only superior lesion detection and characterization, but also the possibility to perform an assessment of liver function [3, 9], which is also applicable in children [7, 10, 11]. For the detection and differentiation of focal liver lesions, the image quality of the arterial phase in Gd-EOB-DTPA-enhanced liver MRI is essential [12-14], and proper assessment of the arterial vasculature is also required for patients before and after liver transplantation [15-17]. However, the image quality of Gd-EOB-DTPA-enhanced liver MRI is sometimes limited by transient severe motion (TSM) artifacts in the arterial phase, which are the result of acute transient dyspnea and reduced breath-holding capacity [18-20]. Probable causes and suggested solutions have been discussed controversially over the last several years in adult patients, but have been less thoroughly studied in children [3, 20–26]. Thus far, it is known from pediatric patients that sedation appears to have a protective effect against TSM, yet other confounders, such as age, have not been studied in detail as yet [27, 28].

The purpose of this study was to investigate which patient factors affect TSM after the administration of Gd-EOB-DPTA in pediatric patients, and whether younger children are affected as much as adolescents.

Materials and methods

Patients and clinical data

The Institutional Review Board of Medical University of Vienna (IRB No. 1296/2017) approved this retrospective, single-center study, and written, informed consent was waived for the data analysis. All procedures performed in the study that involved human participants were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki declaration and its later amendments.

All pediatric Gd-EOB-DTPA-enhanced liver MRI scans performed at our tertiary referral center between July 2012 and March 2017 were included in this study.

Inclusion criteria were patient age younger than 19 years and examination performed on a single MRI scanner (1.5 Tesla Magnetom AERA®, Siemens Healthineers, Siemens Healthcare GmbH), with adherence to the standard liver MRI-examination protocol using Gd-EOB-DTPA (Primovist®, Eovist®, Bayer Vital GmbH) as a contrast agent.

Exclusion criteria were a protocol deviation from the standard liver MRI protocol, the application of a different GBCA other than Gd-EOB-DTPA, and overall non-diagnostic image quality. The selection process is illustrated in Fig 1.

Fig 1

Flowchart of the included MRIs.

The following clinical data were retrieved from the hospital information system and/or scan documentation: patient age; gender; indication for liver MRI; height; weight; body mass index; and requirement for sedation.

MRI examination protocols

The liver MRI examination protocol is described in S1 Table. Contrast administration was performed based on the clinical indication. For the administration of contrast agent, dedicated, informed consent was obtained from the referring physician and the patients’ legal guardian.

Need for sedation was decided by the treating radiologist together with a pediatric anesthesiologist. Children were not intubated, but breathed freely with an oxygen mask. All non-sedated children performed breath-hold-commands exercises with our radiology technologists before they went into the MR-scanner.

Gd-EOB-DTPA was applied at a standard dose of 0.025 mmol/kg body weight and was slowly administered manually as an intravenous bolus injection.

The dynamic images were obtained with the same parameters used for the unenhanced sequence with a sequential k-space ordering. The acquisition times were 3 times à 16 seconds, beginning at the time to aortic peak (arterial) and 48 seconds (portal venous), and 300 seconds (equilibrium) (S1 Table).

Image assessment and interpretation

Three radiologists, including a pediatric radiologist and two abdominal radiologists, with 15, 10, and six years of experience, respectively, in the interpretation of abdominal MRI, read the studies, which were viewed on a PACS (Picture Archiving and Communication System, Agfa) workstation. The readers were blinded to the clinical course of the patient.

Image quality was determined using a four-point Likert scale, modified according to Polanec et al. [3]:

“0” for severe motion artifacts, non-diagnostic image quality;

“1” for marked motion artifacts, reduced diagnostic image quality, but acceptable;

“2” for minimal motion artifacts, good diagnostic image quality; and

“3” for no motion artifacts, excellent diagnostic image quality.

For the arterial phase, the decision criterion was the visibility of the common hepatic artery and the proper hepatic artery, and, for the portal-venous phase and the transitional phases, the decision criterion was the visibility of the intra- and extrahepatic parts of the hepatic portal vein, as well as the liver parenchyma. The hepatobiliary phase was not assessed for the purpose of this study. The mean value of image quality for all three readers was used for further calculations after inter-reader variability was confirmed to be comparable to other studies in this field [28].

The presence of transient severe motion artifacts (TSM) was defined as a decrease of image quality by at least one point in the arterial phase compared to the unenhanced scan, which returned to baseline values until the transitional phase. Patients with non-diagnostic images in all exam phases and/or missing variables (n = 1) were not included in the TSM analysis.

Statistical analysis

The statistical analysis was performed using the software package SPSS, Version 25.0 (IBM, Armonk, NY). Demographic data were analyzed as absolute numbers, and distributions were presented as median and range, or mean +/- standard deviation, where applicable. Variables were compared using a parametric (Student´s t-test) or non-parametric test (Mann-Whitney U), or the Chi-square test, where applicable.

Inter-reader agreement among the three readers was assessed using κ coefficients.

Logistic regression analysis by age, gender, weight, body mass index (BMI), and sedation, with regard to the occurrence of TSM, was performed. Results are presented as hazard ratios (HR) and 95% confidence intervals (CI). All variables used in the univariate analysis (except BMI due to the collinearity with weight) were included into a multivariate regression model with stepwise backward elimination. Results with a p value <0.05 were considered significant.

Results

Patients

A total of 148 patients with 226 Gd-EOB-DTPA-enhanced liver MRI examinations (65 female, 83 male, 0.1–18.9 years old) met the inclusion criteria. The indications for performing a liver MRI were quite variable; however, four general indication groups were identified (transplantation, liver mass, pancreaticobiliary disorders, and hepatobiliary functional liver diseases, Table 1, and S2 Table).

Table 1

Demographics.

Characteristics	No. of Gd-EOB-DTPA MRIs
No. Patients (%)	148
• Females (%)	65 (43.9)
Examinations	226
Patients with a single MRI	111
Patients with repeated MRIs (%)	37 (25)
• Repeated MRIs per patients	2 (2–12)
Sedation (%)	27 (11.9)
Median age (all patients, y)	12.6 (0.1–18.9)
• With sedation	4.3 (0.1–16.8)
• Without sedation	13.4 (0.6–18.9)
Median weight (all patients, kg)	45 (2.5–147)
BMI (all patients, kg/m2)	19.2 (8.2–44.1)
Indication for liver MRI
• Transplantation	23 (10.2)
• Masses	71 (31.4)
• Pancreaticobiliary disorders	49 (21.7)
• Hepatobiliary functional disorders	83 (36.7)

Data presented are absolute numbers or median and range in parentheses, when applicable. Percentages apply to the respective groups, or to the entire cohort

Assessment of image artifacts—inter-reader agreement

The overall inter-reader agreement was substantial (intraclass correlation coefficient: 0.608–0.699); therefore, a mean score for image quality was used, as described above.

Image quality in the dynamic contrast phases

The mean image quality in the unenhanced, arterial, portal venous, and transitional phases was 2.05±0.70, 1.98±0.65, 2.12±0.66, and 2.18±0.65, respectively, with the quality of the arterial phase significantly lower than that of the portal and transitional phases, if TSM were present (p<0.001). This is illustrated in Fig 2A and 2B.

Fig 2

The image quality in the unenhanced, arterial, portal venous, and transitional phases.

An image quality score of 3 indicated no artifacts, while 0 indicated non-diagnostic images due to artifacts. (2A) The image quality of the study collective and (2B) the image quality of the non-sedated patients with TSM.

Assessment of TSM in relation to age and sedation

TSM in the arterial phase occurred in 24 examinations (10.6%) in 23 patients after Gd-EOB-DTPA. Patients with TSM were significantly older compared to patients without TSM (median 14.3 years [10.1–18.1] vs. 12.4 years [0.1–18.9], p<0.001). TSM were not observed in patients below the age of 10 years, Fig 3. Weight and BMI was not different between patients with or without TSM (p = 0.062 and 0.393).

Fig 3

Relation of age and transient severe motion artifacts in patients with and without sedation.

Of 226 liver MRIs performed with Gd-EOB-DTPA, 27 (12%) examinations required sedation. No TSM were noted in patients who had MRI under sedation (p = 0.039 vs. exams without sedation). Patients who required sedation were younger (median age 4.3 years [0.1–16.8] vs. 13.4 years [0.6–18.9], p<0.001) and of lower median weight and BMI compared to those without sedation (weight 17.0 kg [4.0–75.0] vs. 47.0 kg [2.5–147.0], p<0.001; BMI 16.1 [8.1–24.0] vs. 19.5 [11.3–44.1] kg/m2, p<0.001), Table 1.

Although patients who required sedation were generally younger (Table 1), there was also a considerable number of patients younger than 10 years who did not require sedation. Of the 50 studies in patients younger than 10 years, 30 (60.0%) did not require sedation, while 169 of 176 (96.0%) studies in patients older than 10 years were performed without sedation. The rate of TSM events in the older, non-sedated group was 14.2% (24 of 169 studies), while it was 0.0% (0 of 30 studies) in the younger, non-sedated group (p = 0.028). This is also illustrated in Fig 3, with age as a continuous variable. Fig 4 presents an example of TSM.

Fig 4

Example of TSM.

A 16-year-old girl with an alveolar soft-tissue sarcoma of the left thigh who underwent Gd-EOB-DTPA-enhanced liver MRI for a suspected liver metastasis. There were no respiratory artifacts in the unenhanced phase (4A, IQ 3). TSM in the arterial phase (4B, IQ 1). There were still mild motion artifacts in the portal-venous phase (4C, IQ 2), and again, excellent IQ in the transitional phase (4D, IQ 3).

Assessment of TSM in patients undergoing repeated examinations

Of 37 patients who had repeated Gd-EOB-DTPA-enhanced MRIs, 28 patients did not develop a TSM, and nine patients had at least one TSM event (S3 Table). Five of nine patients with repeated Gd-EOB-DTPA-enhanced MRI had at least one uneventful subsequent Gd-EOB-DTPA-enhanced MRI, after a TSM event. Fourteen patients of 23 patients with TSM events had only a single Gd-EOB-DTPA-enhanced MRI. Only one patient with six Gd-EOB-DTPA-enhanced MRIs had two events, at the first and at the third scan. In this case, there were also no TSM observed in the subsequent MRIs (S3 Table).

Regression analysis of factors that influence TSM

To identify the impact of various, independent effects of factors on TSM, a uni- and multivariate regression analysis was performed (Table 2). While age, gender and weight tended to be associated to TSM in the univariate analysis, age remained as the only factor positively associated with TSM in the multivariate analysis (hazard ratio 9.152, p = 0.049). In order to address the multiplicity of MRIs in 9 patients with TSM, we included this parameter in the regression analysis, but it did not show an association in the univariate analysis (hazard ratio 0.66, p = n.s.).

Table 2

Logistic regression analysis of factors associated with transient severe motion artifacts in the arterial phase.

	Univariate					Multivariate
	B	p value	HR	95% CI		B	p value	HR	95% CI
Age (≤ 10 years vs. > 10 years)	2.609	0.011	13.583	1.798	102.633	2.214	0.049	9.152	1.009	82.98
Gender (male vs. female)	0.912	0.041	2.490	1.040	5.960
Sedation (non-sedated vs. sedated)	19.216	0.998	n.a.	n.a.	n.a.
BMI (kg/m2)	0.047	0.230	1.049	0.970	1.133
Weight (kilogram)	0.017	0.062	1.017	0.999	1.035
MR repetition (single vs. multiple)	-0.416	0.342	0.660	0.280	1.555

B = unstandardized beta, HR = hazard ratios, CI = confidence interval, n.a., not applicable

Discussion

In this retrospective single-center study, we observed, for the first time, that transient respiratory motion artifacts in children who underwent Gd-EOB-DTPA-enhanced liver MRI, only occurred after the age of 10 years. After correcting for weight, BMI, sedation, and gender, age remained the only factor associated with TSM. Interestingly, patients under 10 years of age never exhibited signs of TSM, regardless of sedation.

TSM appear as frequently in children as in adults, with a rate of 10.6% in our series, compared to a rate of 10.7–39% in adult patients [3, 18, 19, 21, 29]. TSM can limit the image quality of Gd-EOB-DTPA-enhanced liver MRI in the arterial phase [18-20], which is essential for the differential diagnosis of focal liver lesions [12-14] and for the assessment of the arterial vasculature before and after liver transplantation [15-17]. Due to the increased number of indications for pediatric liver MRI [7, 10, 11, 16], it is crucial to demonstrate that these examinations can be performed with adequate image quality, even in small children.

Two studies have, to date, investigated TSM in pediatric patients. Gilligan et al. reported the experience with Gd-EOB-DTPA-induced TSM in 130 children and compared the presence and severity of TSM in children who were imaged awake versus under general anesthesia [27]. They observed a significantly higher rate of TSM in awake children compared to children under general anesthesia, probably due to a suppression of TSM [27]. In their study cohort, there were significantly heavier (p = 0.0033) and older (p = 0.0066) children in their awake patient group compared to the patients who received anesthesia. Lanier et al. also found TSM in only eight of 102 children (7.84%) without sedation and no TSM in children under sedation, and also discussed the probably protective effect of anesthesia against TSM [28]. These findings were confirmed in our study, with no observed TSM in any of the examinations performed under sedation. Neither of those other studies, however, found any age effect on the occurrence of TSM in non-sedated patients [27, 28], probably because the number of non-sedated patients was too low to draw firm conclusions (63 and 102 patients, respectively). Our study cohort, with 226 cases—199 (88.1%) of them without sedation—is currently the largest cohort to deal with image quality with regard to Gd-EOB-DTPA-induced TSM in pediatric patients, which can only properly be assessed in awake patients. Although there was a clear “protective” trend of sedation towards TSM that was observed in the crude data analysis, there was no association of TSM and sedation using a Fisher´s exact test, p = 0.088, data not shown. Still, we included sedation in the multivariate regression analysis, however it was removed during the first step of the backward elimination process and thus is not independently associated to TSM in our cohort.

The reason for the appearance of TSM only after the age of 10 years is unknown. Due to the off-label use of Gd-EOB-DTPA in pediatric patients, there is little evidence about the nature and occurrence of TSM in this patient population [27, 28]. In adults, pulmonary, cardiac, kidney and liver diseases, gender, body mass index, and history of previous GBCA reactions have been discussed controversially as possible reasons for TSM [20, 21]. A Gd-EOB-DTPA-associated decrease in peripheral capillary oxygen saturation (SpO2) and heart rate have also been discussed [22], as well as breath-hold failure, as the cause of TSM [24].

McQueen et al. described, in 1989, the concept of transient severe hyperventilation upon drug application and concluded that the rapid transient hyperventilation was due to the immediate activation of peripheral chemoreceptors in the carotid body and aortic arch [30]. Polanec et al. speculated that the transiently high concentration of Gd-EOB-DTPA in the initial distribution phase causes a threshold effect that triggers the chemoreceptors centrally, either at the brain stem or carotid artery [3]. If TSM is the result of an activation of chemoreceptors, the reason for the absence of TSM in children younger than 10 years of age could likely be the different regulation or later development of those chemoreceptors in younger children. This was also suggested by Springer et al., who suspected that the maturation of the peripheral chemoreceptors is not complete in childhood, but rather in early adulthood [31].

Limitations

Our study has several limitations. First, it is a retrospective analysis of a very heterogeneous cohort of pediatric patients who underwent liver MRIs for a variety of reasons. The study cohort included both basically healthy adolescents with, e.g., an incidental benign lesion detected on ultrasound, as well as critically ill children after a liver transplantation, all of which pose different challenges. However, this reflects the clinical reality in a tertiary referral center.

Second, the influence of TSM on the detection of focal liver lesions was not evaluated, and thus, limits the extension of these findings for this part of a liver evaluation. This was due to the fact that many patients did not undergo liver MRI for the assessment of liver lesions, but for hepatobiliary functional or pancreaticobiliary indications, where no focal lesions were present.

Third, the manual injection that was performed in every patient limited the optimal timing of the arterial phase, which would usually not be an issue in adult patients assessed with bolus tracking.

Fourth, the fact that we included several patients, who had repeated MRIs could have led to a clustering effect. There was only one patient, who developed TSM twice within six MRI examinations, and the remaining eight patients had TSM only once, even though up to six examinations were performed. Five of nine patients with repeated MRI, had uneventful subsequent Gd-EOB-DTPA-enhanced MRIs after a TSM event. The rate of TSM in patients with repeated examinations (10 TSM/115 repeated MRIs = 8.7%) was lower than that of the overall cohort (24TSM/226 MRIs = 10.6%); therefore, we think that a clustering bias can be excluded. Furthermore, we included single vs. repeat MR as a covariate in the logistic regression analysis, where it did not prove to be a factor associated to TSM.

Conclusion

In conclusion, we demonstrated, for the first time, that TSM in the arterial phase of Gd-EOB-DTPA-enhanced liver MRI exclusively appears after the age of 10 years. We speculate that this might be the result of the different respiratory regulation by chemoreceptors between older and younger children. We could also confirm that sedation has a protective effect against the occurrence of TSM, which has been shown previously.

Liver MR scan protocol with Gd-EOB-DTPA.

(DOCX)

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Indications for liver MRI.

(DOCX)

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Patients with TSM events after i.v. application of Gd-EOB-DTPA-MRI.

(DOCX)

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22 Oct 2021

16 Nov 2021

Reviewer #1:

General comments:

This paper is well written, and the results are clearly presented.

Query #1. It's better to avoid the title that makes assertions.

Response:

Thank you for your suggestion. We propose to change the manuscript’s title as follows:

Influence of age on Gadoxetic acid disodium-induced transient respiratory motion artifacts in pediatric liver MRI

Query #2. Were these MR examinations performed with breath-hold technique? Could young children (e.g. a 0.6-year-old child) hold their breath without sedation?

Response:

In our institution, all non-sedated children do breath-hold-commands exercises with our radiology technologists before they go in the MR-scanner. Therefore, the following of breath-hold-commands depend on the mental development of the child. The sedated children breathe freely during sedation using an oxygen mask, and they are not intubated for MRI, so they generally do not hold their breath. As is already suggested by the nature of this question, many young children are not able to hold breath voluntarily. Thus, we assessed the change in image quality relative to the unenhanced series, which take the individual breathing artifacts into account.

We added an appropriate explanation about our breath-hold-commands during the MR-examination in the section “Patients and clinical data”

Need for sedation was decided by the treating radiologist together with a pediatric anesthesiologist. Children were not intubated, but breathed freely with an oxygen mask. All non-sedated children performed breath-hold-commands exercises with our radiology technologists before they went into the MR-scanner.

Query #3. Please show the timing of arterial, portal-venous, and transitional phases.

Response:

The dynamic images were obtained with the same parameters used for the unenhanced sequence with a sequential k-space ordering. The acquisition times were 3 times à 16 seconds, beginning at the time to aortic peak (arterial) and 48 seconds (portal venous), and 300 seconds (equilibrium) (Supporting S1-Table).

We added appropriate details in the Materials and Methods section under “MRI examination protocols”:

The dynamic images were obtained with the same parameters used for the unenhanced sequence with a sequential k-space ordering. The acquisition times were 3 times à 16 seconds, beginning at the time to aortic peak (arterial) and 48 seconds (portal venous), and 300 seconds (equilibrium) (Supporting S1-Table).

Query #4. How was the normal distribution tested?

Response:

A Levene´s test for similarity of variances was performed and based on the result, either a non-parametric test or a parametric test was used. Levene´s test is an appropriate method to compare distribution between two groups, however, data can still be non-normally distributed despite similarity of variance. Hence, a Mann-Whitney U test was used in case that a normal distribution was not clearly assessable.

Query #5. I think Mann-Whitney U test is commonly used for non-normal distributions. Why the authors used non-parametric t-test?

Response:

A Mann-Whitney U test was used for non-parametric distributions, e.g. body weight. For normal distributions, a Student´s t-test was used. This was included in the METHODS section:

Variables were compared using a parametric (Student´s t-test) or non-parametric t-test (Mann-Whitney U), or the Chi-square test, where applicable.

Reviewer #2:

In the manuscript "Gadoxetic acid disodium-induced transient respiratory motion artifacts do not appear in children under the age of 10 years", the authors performed retrospective study on several factors that are potentially associated with transient severe motion. My major concern is the validity of the statistical analysis applied in the study.

Query #1: As stated in line 199-200: "no TSM were noted in patients who had MRI under sedation", this statement seems to be strongly indicating that the factor of sedation status (non-sedated vs. sedated) may be a very important factor in differentiating the groups with and without TSM. However, such a potentially important factor was discarded in later model selections, and according to the authors' explanation, this is due to the unavailability of hazard ratio in a logistic regression analysis. Such an argument is not quite convincing -- in fact, the absence of TSM events under sedation does not pose any issue to statistical analysis, if more appropriate statistical methods for categorical variables had been employed, such as Fisher's exact test. With such a potentially important factor discarded in the first place, the later analyses become very questionable.

Response:

Thank you for this very important comment. We want to apologize for the unclear formulation, and the misinterpretation this might have caused. Indeed, TSM WAS included in the multivariate analysis. We used a binary logistic regression analysis with backwise elimination using likelihood ratios. In this method, all variables assessed in the univariate analysis are entered into the model and based on the -log2 likelihood ratio when a term is removed, the model continuously removes variables until only variables remain, which exhibit a significant association to the dependent variable. Possible issues with this method would be entering a plethora of variables (leading to an accumulation of random effects, or cross effects) or entering variables with a high degree of collinearity, e.g. weight and BMI. We therefore have included the variables age, gender, sedation, BMI and MR repetition into the model. “Sedation” was removed in the first step of the multivariate backwise elimination model by the software. After running through 3 more steps, “Age” remained as the only covariate associated to TSM. This does not mean that other variables, which are significant in the univariate analysis do not play any role in relation to TSM; it just means, that age is obviously the only variable INDEPENDENTLY associated to TSM, when various other factors are taken into account.

Regarding the “n.a.” in the univariate analysis of sedation in relation to TSM, the true number that was given by SPSS for the HR was 221550852, which seemed unrealistic to us. We asked our statistician and this could well be due to the fact that zero events were recorded in the sedated subgroup and hence the regression method might be prone to this error (see below). It might also be due to the fact that only about 10% of patients required sedation and that this subgroup was too small to put this observation into the context of the regression analysis.

Therefore, we also performed a crosstable examination, where the Fisher´s exact test yielded a two-sided p of 0.088, which is not shown in the results (please see below, apologies for our german-language version of SPSS).

Therefore, we feel that after this analysis, the way of interpreting the observation of the multivariate model is appropriate and that TSM and sedation might be related, but not independently. We have added the following paragraph for clarification (methods):

All variables used in the univariate analysis (except BMI due to the collinearity with weight) were included into a multivariate regression model with stepwise backward elimination.

and (Discussion)

Although there was a clear “protective” trend of sedation towards TSM that was observed in the crude data analysis, there was no association of TSM and sedation using a Fisher´s exact test, p=0.088, data not shown. Still, we included sedation in the multivariate regression analysis, however it was removed during the first step of the backward elimination process and thus is not independently associated to TSM in our cohort.

Query #2: Furthermore, it has come to my attention that the statistical conclusion on the effect of age is only very much marginally significant with p value 0.049, given the multiple other factors and the questionable discarding of the sedation factor, such a weak evidence for two-level factor of age is not likely to yield sufficiently useful and reliable information for future studies.

Response:

We agree with the reviewer, that a p value of marginally below 0.05 is close to showing a significance. However, this value results after using a multivariate model with heterogeneous input variables in a population with 24 events of the dependent variable. This p-value would be lower, if fewer confounding variables were included in the multivariate analysis, however, we wanted to give a realistic correction for possible confounders. The hazard ratio, however, indicates, that the weighted effect of “age>10 years” on the occurrence on TSM is in fact 13.5 and 9.1 in the uni- and multivariate analysis, respectively. This means, that the older age group has a 9.1-fold increased likelihood of developing TSM, which we do think is clinically relevant.

Reviewer #3: In this manuscript, Azadeh Hojreh et al demonstrated that patients with TSM were significantly older than patients without TSM and TSM were not observed in patients under the age of 10. This result provides us an important speculation that age may have a protective effect against TSM. I think authors well prepared this paper and did steady work. Statistical methods were valid and correctly applied. Interpretation for their results seems appropriate. The references covered the relevant literature.

This manuscript may be accepted for publication.

Response: Thank you very much for your comments.

Submitted filename: Response to Reviewers.docx

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3 Feb 2022

Influence of age on Gadoxetic acid disodium-induced transient respiratory motion artifacts in pediatric liver MRI

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Reviewer #1: The authors have responded to most of the reviewer's concerns and the manuscript has been greatly improved.

> Query #5. I think Mann-Whitney U test is commonly used for non-normal distributions.

> Why the authors used non-parametric t-test?

> Response:

> A Mann-Whitney U test was used for non-parametric distributions, e.g. body weight.

> For normal distributions, a Student’s t-test was used. This was included in the METHODS section:

> Variables were compared using a parametric (Student’s t-test) or non-parametric t-test (Mann-Whitney U), or > the Chi-square test, where applicable.

I've never heard of a “non-parametric t-test”, I think it's a “non-parametric test”.

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Reviewer #1: No

21 Feb 2022

PONE-D-21-16470R1

Influence of age on Gadoxetic acid disodium-induced transient respiratory motion artifacts in pediatric liver MRI

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