Radiol Oncol 2022; 56(4): 471-478. doi: 10.2478/raon-2022-0040 471 research article Reliability of haemophilia early arthropathy detection with ultrasound (HEAD-US) in children: a comparative magnetic resonance imaging (MRI) study Domen Plut1,2, Barbara Faganel Kotnik3, Luka Pusnik2, Peter Slak1,2, Ziga Snoj1,2, Vladka Salapura1,2 1 Clinical Radiology Institute, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Department of Haematology and Oncology, Children’s Hospital, University Medical Centre Ljubljana, Slovenia Radiol Oncol 2022; 56(4): 471-478. Received 23 August 2022 Accepted 4 September 2022 Correspondence to: Assist. Prof. Domen Plut, M.D., Ph.D., Clinical Radiology Institute, University Medical Centre Ljubljana, Zaloška cesta 7, SI-1000 Ljubljana, Slovenia. E-mail: plut.domen@gmail.com Disclosure: No conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Ultrasound (US) has been proven to be reliable in the assessment of early haemophilic arthropathy in the adult haemophilic population, however few studies so far focused on the reliability of US specifically in the pae- diatric haemophilic population. We were interested if the changing appearance of the growing bone hinders the ultrasonographic evaluation of the pathologic processes caused by haemophilic arthropathy. The aim of the study was to assess the reliability of US for evaluation of haemophilic arthropathy in children in comparison to magnetic resonance imaging (MRI). Patients and methods. The study included all children aged 6 years or more with severe haemophilia in the country (n = 10). We assessed their elbows, knees, and ankles bilaterally by US and compared the results to the MRI as the reference standard. Pearson correlation coefficient (r) was used to analyse correlation. Results. The correlation with MRI for the US for the total score was excellent for all joints (r = 0.849 for the elbows, r = 1 for knees, r = 0.842 for ankles). The correlation of scores for specific joint components showed fair, moderate, or excellent correlation for all joint components in all joints. The correlation was the lowest for the evaluation of cartilage and bone in the ankles (r = 0.546 and r = 0.478) and bone in the elbows (r = 0.499). Conclusions. Our study proved that US using the HEAD-US method performed by paediatric radiologists is a reliable tool for detection and quantification of haemophilic arthropathy in children in comparison to MRI. Key words: haemophilia; children; haemophilic arthropathy; HEAD-US; ultrasound; magnetic resonance imaging Introduction Haemophilic arthropathy (HA) is caused by recur- rent bleeding into joints and is characterized by synovial hypertrophy with hemosiderin deposi- tion, cartilage destruction, and structural changes of subchondral bone. Long-term repeated hemar- throses lead to joint destruction and severe func- tional impairment.1 As the development of HA ordinarily begins during childhood, albeit with minimal changes, early detection is indispensable. Early recognition of subclinical arthropathy based on the imaging modalities is fundamental as it en- ables appropriate prophylactic treatment modifi- cation and prevents further disease progression.2,3 Among the imaging tools, magnetic resonance Radiol Oncol 2022; 56(4): 471-478. Plut D et al. / Haemophilic arthropathy detection with ultrasound in children472 imaging (MRI) with its high spatial and contrast resolution is superior to the other modalities and enables the most precise assessment of early ar- thropathic changes.4 As MRI is a time-consuming modality with limited availability, a high cost, and requires sedation in young children, routine as- sessment of multiple joints with it is not feasible. Ultrasound (US) has been proven to be highly reli- able in the assessment of early inflammatory and destructive joint changes in the adult haemophilic population5-7, however very few studies so far focused on the reliability of US in the paediatric haemophilic population. The US has even more advantages in the paediatric population: it is a safe technique without radiation, it enables a quick as- sessment of multiple joints, and sedation is not re- quired even in young children. Thus, with possible detection of joint effusions, synovial hypertrophy, cartilage changes, and subchondral bone erosions it may be an invaluable tool for recognition of sub- clinical HA in children.8,9 We were interested if the changing appearance of the growing bone hinders the ultrasonographic evaluation of the pathologic processes caused by HA. Hitherto, a paucity of data has been published regarding US measurements of hyaline cartilage thickness in healthy children in comparison to MRI measurements. Consequently, published values are not standardised and require further research to distinguish unaffected growing bone from the pathologic processes caused by HA.10–14 The aim of our study was to assess the reliability of the US for evaluation of haemophilic arthropathy in children in comparison to the MRI. Patients and methods Board approval The study was approved by the National Medical Ethics Committee (reference number 0120- 523/2015-8). The participants in this study were children, therefore informed consent for the par- ticipants was signed by their parents. The par- ticipants, however, gave their informed assent to the study. Research was conducted following the Helsinki Declaration. Patients The study included all children with severe hae- mophilia A in the country. The patients were re- cruited at the Slovenian National Haemophilia Comprehensive Care Centre at the University Medical Centre Ljubljana. The inclusion criteria were: diagnosis of severe haemophilia A, prophy- lactic treatment with factor concentrates, and age between 6 and 18 years. The age of 6 years as the low cut-off was chosen to avoid the need for an- aesthesia for the MRI. The exclusion criteria were non-cooperation and contraindications for the MRI. Patient history (history of joint bleeds, hae- mophilia joint health score (HJHS), prophylaxis information) was retrieved from their medical re- cords. Ultrasonography A ProSound F75 US scanner with a 13–5 MHz electronic linear-array transducer (Hitachi Aloka Medical, Ltd. Tokyo, Japan) was used to perform the US examinations. US was performed by an ex- perienced paediatric radiologist (7 years of subspe- cialty experience). The assessment of each joint was made using the HEAD-US protocol and scoring method. This standardised method includes bi- lateral systematic evaluation of the elbows, knees, and ankles in defined positions for the detection of hypertrophied synovium and osteochondral dam- age. The results for each joint are expressed on a 9-point scale (0–8; 0 corresponds to the best joint condition, while 8 corresponds to the worst joint condition).8 The total scanning time per patient for all joints combined was approximately 20 minutes. A series of images and clips from all examinations for each patient were additionally independently reviewed and scored by another paediatric radiol- ogist (2 years of subspecialty experience) to deter- mine the inter-rater reliability. Both US reviewers were blinded to the results of MRI examinations. Magnetic resonance imaging MRI was performed on a 3T Achieva unit (Philips Healthcare, Eindhoven, The Netherlands). Phased array coils were used for the imaging of each joint. The protocol included 3D T2*-weighted water selec- tive gradient echo sequence (FOV, 160×160×108mm; voxel size, 0.58×0.58×0.50mm; flip angle: 15°; TE 9.2/6.1ms; TR 26ms), and 3D proton density (PD) weighted turbo spin echo sequence (FOV, 160×160×161mm; voxel size: 0.52×0.52×0.52mm; TE 33ms; TR 1000ms). The total scanning time for each joint was approximately 15 minutes. In each patient, all joints were scanned in a single session for a total examination time around 1.5 hours. The MRI examinations were scored according to the International Prophylaxis Study Group (IPSG) Radiol Oncol 2022; 56(4): 471-478. Plut D et al. / Haemophilic arthropathy detection with ultrasound in children 473 MRI scale. The IPSG score includes evaluation of joint effusion, hypertrophied synovium with he- mosiderin deposition, and osteochondral dam- age. The IPSG score uses an 18-point scale (0–17; 0 corresponds to the best joint condition with no disease present, while 17 corresponds to the worst joint condition with progressive arthropathy).15 The presence of HA was defined as IPSG score > 0. The scoring was performed independently by two experienced musculoskeletal radiologists (19 and 4 years of subspecialty experience) who were blind- ed regarding the results of the US examinations. Statistical analysis Descriptive statistics were obtained to describe the characteristics of the study group. Pearson correlation coefficient (r) was used to analyse the correlation between US and MRI examinations. Correlation was considered poor if r was < 0.3, fair if r was < 0.6, substantial if r was < 0.8, and excel- lent if r was > 0.8.16 The correlation results were graphically illustrated. The inter-rater reliability of HEAD-US and IPSG MRI scoring system for the total scores was made with Lin’s concordance cor- relation coefficient (CCC) and for all the sub-scores using Cohen’s kappa statistics (with quadratic weights). The results of US were referenced to the results of MRI in order to obtain measures of di- agnostic accuracy (specificity, sensitivity, positive predictive value, and negative predictive value). Statistical analysis was performed using IBM SPSS Statistics for Windows software, version 25 (IBM Corp.). A two-tailed P value < 0.05 was considered to indicate statistical significance. Results Patient and joint characteristics The study group included a total of 10 patients (age range 6 to 17 years, mean age 11.5 years). In each patient, six joints (elbows, knees, and ankles bilat- erally) were systematically examined first using the US, followed by MRI, according to the proto- cols. Altogether in the study we assessed 60 joints: 20 elbows, 20 knees, and 20 ankles. All the patients included in the study have been receiving prophylactic treatment with clot- ting factor concentrates. The type of prophylaxis for the patients was primary or secondary. The patients were on three times per weekly regimen. A proportion of patients were on individual pro- phylactic regimens according to population-based pharmacokinetic tools. Two patients developed in- hibitors to prophylactic treatment. In one patient the inhibitors were successfully eradicated by im- mune tolerance induction. Details on treatment and joint-bleeds history are shown in Table 1 along with other study group baseline characteristics. Results of US and MRI Descriptive statistics for US and MRI results are gathered in Table 2. MRI results were used as a reference standard for joint status. The results of the correlation be- tween US and MRI for detection and evaluation of HA in children are summarized in Table 3. The correlation with MRI for each joint type is graphi- cally depicted in Figure 1. The correlation with MRI for US for the total score was excellent for all TABLE 1. Characteristics of subjects included in the study Age: mean; range (years) 11.5; 6–17 Age at the start of prophylaxis: mean; range (years) Primary prophylaxis – 5 patients: Secondary prophylaxis – 5 patients: 3; 0.8–6.6 2.2; 0.8–3.8 3.8; 2.5–6.6 Duration of prophylaxis: mean; range (years) 9.1; 3.2–14.7 Haemophilia Joint Health Score (HJHS): mean; range 0.9; 0–7 Number of previous joint bleeds per patient: mean; range 16.2; 0–83 Number of previous joint bleeds per joint: mean; range 2.5; 0–71 Number of previous joint bleeds: Elbows Knees Ankles Overall 0 (number of joints) 14 7 9 30 1–4 (number of joints) 5 12 8 25 > 5 (number of joints) 1 1 3 5 Radiol Oncol 2022; 56(4): 471-478. Plut D et al. / Haemophilic arthropathy detection with ultrasound in children474 joints (r = 0.849 for the elbows, r = 1 for knees, r = 0.842 for ankles). The correlation of scores for spe- cific joint components showed fair, moderate, or excellent correlation for all joint components in all joints. The correlation was the lowest for the evalu- ation of cartilage and bone in the ankles (r = 0.546 and r = 0.478) and bone in the elbows (r = 0.499). Figures 2-5 show images from the study. The inter-rater reliability of interpretation was excellent for the US examinations of all joints. The Lin’s CCC values for the total scores ranged from 0.986 to 1.000. The inter-rater reliability for the MRI was also excellent for all joints with the CCC val- ues for the total scores ranging from 0.957 to 0.993. Measures of diagnostic accuracy Our study included 49 joints (15 elbows, 20 knees, and 14 ankles) with no signs of HA on MRI (IPSG scores were 0) and 11 joints with HA (5 elbows and 6 ankles). The IPSG MRI score of joints with HA ranged from 1 to 8, mean was 4.8. Two joints that showed signs of HA on MRI (two elbows in the same patient with IPSG MRI scores 4 and 1) were scored 0 on the US. There was one false positive on the US, an ankle with a score of 1. The calculated measures of diagnostic accuracy for HEAD-US are presented in Table 4. Discussion Our study aimed to evaluate the reliability of US (HEAD-US scanning protocol and scoring meth- od) for the detection and evaluation of haemophil- ic arthropathy in children in comparison to MRI (ISPG MRI scoring scale). We evaluated the three most commonly affected joints (ankles, knees, and elbows) in all children with severe haemophilia A in our country (n = 10). Overall, we evaluated 60 joints. The results of the correlation analysis showed a very high correlation for the evaluation of haemophilic arthropathy between the US and TABLE 2. Descriptive statistics for US and MRI assessment scores Joints Statistic US MRI Elbows % of zeros Median Mean SD 85 0 0.35 0.93 75 0 1.05 2.82 Knees % of zeros Median Mean SD 100 0 0 0 100 0 0 0 Ankles % of zeros Median Mean SD 65 0 0.8 1.2 70 0 1.6 2.2 Overall % of zeros Median Mean SD 83.3 0 0.38 0.92 81.7 0 0.88 2.16 TABLE 3. The results of the correlation analysis US vs MRI Pearson’s correlation coefficient (r) Elbows Knees Ankles Total score 0.849 1 0.842 Synovium 0.841 1 0.722 Cartilage 0.829 1 0.546 Bone 0.499 1 0.478 Note: all the reported correlations are statistically significant (p < 0.05). FIGURE 1. Concordance plot for depicting agreement between US and MRI scores for all three joints. Equal size of the fields denotes perfect agreement. The plots demonstrate overall an excellent agreement between the methods. It can also be observed, that in most cases of discordance, US slightly undervalued the progression of the joint disease. TABLE 4. Measures of diagnostic accuracy for detection of haemophilic arthropathy by US (HEAD-US) in comparison to MRI (IPSG MRI score) as the reference standard Specificity 81.8% Sensitivity 98% Positive predictive value 90% Negative predictive value 96% Radiol Oncol 2022; 56(4): 471-478. Plut D et al. / Haemophilic arthropathy detection with ultrasound in children 475 MRI for all the joints (r = 0.849 for elbows; r = 1 for knees; r = 0.842 for ankles). Excellent inter-rater reliability for both the US and MRI in our study further supports the validity of both methods for haemophilia imaging in children. These results show that the HEAD-US method is reliable in comparison to MRI for the detection and quantification of HA in children. High speci- ficity and sensitivity (81.8% and 98%) confirm the method as a dependable tool for the recognition of the presence of HA, whereas high correlation proves the method is also reliable in the quanti- fication of the disease progression. Our results indicate that US is reliably applicable for all evalu- ated joints (elbows, knees, and ankles), however the detailed analysis of the joint components (syn- ovium, cartilage, bone) showed some important differences. The correlation between the methods was the lowest for the evaluation of the cartilage and bone changes of the ankles (r = 0.546 and 0.478) and bone changes of the elbows (r = 0.499) in com- parison to other joint components (r > 0.7). The FIGURE 2. Anterior transverse US images over the distal humeral epiphysis in a 7-years and 16-years old healthy boys. A wavy osteochondral surface consisting of the convex capitellum and the concave trochlea is shown. Note the age-dependent anatomic differences: subchondral bony surface in the younger child (A) shows physiological irregularities (thick arrow); the articular cartilage, which appears as a uniform hypoechoic band overlying the subchondral bone (thin arrows), is thinner in the older child (B). A B FIGURE 3. PD weighted MRI of ankles in sagittal plane. Image (A) shows an ankle with no signs of haemophilic arthropathy in an 11-years old boy, while image (B) shows a severely affected ankle in a 17-years old boy. The thin arrow marks a talar osteochondral defect, while the thick arrow marks synovial hypertrophy with hemosiderin deposition. A B Radiol Oncol 2022; 56(4): 471-478. Plut D et al. / Haemophilic arthropathy detection with ultrasound in children476 lower correlation for the evaluation of osteochon- dral changes in the ankles was due to the limited visualization of the central weight-bearing part of the osteochondral surface of the ankle joint by US, which is a more commonly affected area of the joint. Comparable results were observed in our previously performed study in the adult popula- tion.17 Similarly, the lower correlation for the bone changes in the elbows was due to inability of the US to detect centrally located subchondral cysts. Nevertheless, as noted above, the overall correla- tion between both methods for all the joint com- ponents for all the joints was still substantial. In our study in the adult population, we observed a lower correlation between the US and MRI for the detection and evaluation of synovial hypertrophy in the ankles (r = 0.561). In this study in the paedi- atric population however, this was not the case (r = 0.722). We believe this can be attributed to a gener- ally better ability of US to differentiate soft tissues in children due to a higher tissue water content. As synovial hypertrophy is the earliest sign of HA, high reliability to evaluate this finding in all joints in children is important for the clinical application of the method. In the published literature, the comparisons of the joint assessment between the US and MRI within the paediatric haemophilic population are scant. Only three studies included exclusively chil- dren within their study group. Doria et al. evalu- ated ankles and knees in children with haemo- philia and von Willebrand disease and reported that if performed by experienced radiologists US is highly reliable for assessing soft-tissue abnormali- ties and substantially to highly reliable for assess- ing osteochondral changes in these joints. These results are concordant with the findings of our study. However, it is worthy to note that in their study the US interpreters were unblinded to the MRI results.6 Prasetyo et al. evaluated knees in 27 children with haemophilia, employing a complex US examination including Doppler evaluation and evaluation of hemosiderin deposits, and reported moderate correlation between the US and MRI scores.18 In another study that evaluated ankles in A B FIGURE 4. An example of good concordance between HEAD-US and MRI in a 7-years old child. US image of the femoral trochlea in the transverse plane is shown (A). T2* weighted MR image in the transverse plane (B) of the same knee is shown for comparison of the corresponding structures. The smooth bone surface and normal thickness trochlear joint cartilage with homogenous structure are shown (white arrow); the corresponding intact structures are shown on MR image. On MRI, there were also no additional arthropathic changes in the parts of the joint not visualized by the US. The images show a perfect concordance between US and MRI findings in this knee with no signs of haemophilic arthropathy. FIGURE 5. An example of a lesion causing a discordance between the US and MRI. A T2* weighted MR image of an ankle of a 16-years old boy in the sagittal plane is shown. A small subchondral cyst covered with intact cortical bone and articular cartilage (white arrow) is shown. MRI demonstrates a defect which cannot be visualized by US. Radiol Oncol 2022; 56(4): 471-478. Plut D et al. / Haemophilic arthropathy detection with ultrasound in children 477 11 boys with haemophilia, Prasetyo et al. evaluated only the ability of US to detect hemosiderin depos- its within the joint and determined that the asso- ciation between the US and MRI for detection of hemosiderin deposits was weak.19 Additional two studies included children as a part of their study group. Sierra Aisa et al. included patients with HA between the age of 4-82 years and reported sen- sitivity, specificity, positive predictive value, and negative predictive value for diagnosing HA with- in the same interval as presented in our study.5 Acharya et al. evaluated the use of US with Power Doppler in comparison to contrast-enhanced MRI to detect haemophilic synovitis in subjects be- tween the ages of 6-60 years and concluded that the correlation between the methods is good.20 All of the aforementioned studies already showed great potential for the use of US in the diagnostics of HA in children, however, each study had some limitations, such as different and complex US pro- tocols or evaluation limited to specific joints or joint components. Therefore, in our study we used a simplified standardized US protocol (HEAD-US) for the joint evaluation, which allows quick exami- nation with great repeatability, we systematically evaluated all three most commonly involved joints in haemophilia, and made sure the US evaluators were blinded to the results of the MRI examina- tion. The findings of the currently presented study and our previously published study in the adult population17 made us reconsider our clinical prac- tice. Due to the good availability of US machines and reliability of the US to detect even early HA in clinically asymptomatic joints, we incorporated the US into our regular clinical yearly follow-up of paediatric patients with haemophilia. All the chil- dren with severe haemophilia in our country have been included in the screening program, even chil- dren younger than 6 years old. During this time, we found early HA in clinically asymptomatic joints with no previously recorded bleeds in two children and consequently modified their prophy- lactic treatment regimen. The study had some research design limitations. Although our study group included all children with severe haemophilia A in the country, due to the rarity of the disease, the overall number of pa- tients was relatively low (n = 10). Furthermore, we couldn’t include the youngest children with hae- mophilia aged under 6 years due to the require- ment of general anaesthesia to perform MRI in this group of children. Most joints we evaluated in our study were either healthy or had only early HA. This is because HA is a progressive chronic disease and all of the included patients had pro- phylactic treatment since the early youth, therefore more progressive disease forms were prevented. However, extensive studies evaluating the value of US in comparison with MRI in patients with pro- gressive HA have been already performed in the adult population and, moreover, diagnosing early HA remains the challenge for today’s medicine. Conclusions Our study proved that US using the HEAD-US method performed by paediatric radiologists is a reliable tool for detection and quantification of haemophilic arthropathy in children in compari- son to MRI. Due to its simplicity, availability, and reliability, HEAD-US is an invaluable tool in di- agnostics and regular follow-up of children with haemophilia and can be safely included into the regular screening protocols of children with se- vere haemophilia where possible. Further stud- ies are needed to answer some important ques- tions regarding the use of HEAD-US in children with haemophilia: what is the ideal start age for the screening? How often should the screening be performed during the childhood, and who should perform the scanning (radiologist, clinician, physi- otherapist)? Acknowledgments This study was funded by Pfizer Inc., USA. The au- thors have no competing interests. We would like to thank Anja Silič, Marko Gabrijelčič, Damjana Ključevšek, and Lidija Kitanovski for their contri- bution to the study. References 1. Gualtierotti R, Solimeno LP, Peyvandi F. Hemophilic arthropathy: current knowledge and future perspectives. J Thromb Haemost 2021; 19: 2112-21. doi: 10.1111/jth.15444 2. Plut D, Faganel Kotnik B, Preložnik Zupan I, Ključevšek D, Vidmar G, Snoj Ž, et al. Detection and evaluation of haemophilic arthropathy: which tools may be considered more reliable. Haemophilia 2021; 27: 156-63. doi: 10.1111/ hae.14153 3. Pergantou H, Platokouki H, Matsinos G, Papakonstantinou O, Papadopoulos A, Xafaki P, et al. Assessment of the progression of haemophilic ar- thropathy in children. Haemophilia 2010; 16: 124-9. doi: 10.1111/j.1365- 2516.2009.02109.x 4. Kilcoyne RF, Nuss R. Radiological assessment of haemophilic arthropa- thy with emphasis on MRI findings. Haemophilia 2003; 9: 57-64. doi: 10.1046/j.1365-2516.9.s1.11.x Radiol Oncol 2022; 56(4): 471-478. Plut D et al. / Haemophilic arthropathy detection with ultrasound in children478 5. Sierra Aisa C, Lucía Cuesta JF, Rubio Martínez A, Fernández Mosteirín N, Iborra Muñoz A, Abío Calvete M, et al. Comparison of ultrasound and magnetic resonance imaging for diagnosis and follow-up of joint lesions in patients with haemophilia. Haemophilia 2014; 20: e51-7. doi: 10.1111/ hae.12268 6. Doria AS, Keshava SN, Mohanta A, Jarrin J, Blanchette V, Srivastava A, et al. Diagnostic accuracy of ultrasound for assessment of hemophilic arthropa- thy: MRI correlation. Am J Roentgenol 2015; 204: W336-47. doi: 10.2214/ AJR.14.12501 7. De la Corte-Rodriguez H, Rodriguez-Merchan EC, Jimenez-Yuste V. Point-of- care ultrasonography in orthopedic management of hemophilia: multiple uses of an effective tool. HSS J 2018; 14: 307-13. doi: 10.1007/s11420-018- 9604-x 8. Martinoli C, Casa Alberighi O Della, Di Minno G, Graziano E, Claudio Molinari A, Pasta G, et al. Development and definition of a simplified scanning proce- dure and scoring method for haemophilia early arthropathy detection with ultrasound (HEAD-US). Thromb Haemost 2013; 109: 1170-9. doi: 10.1160/ TH12-11-0874 9. Di Minno MND, Iervolino S, Soscia E, Tosetto A, Coppola A, Schiavulli M, et al. Magnetic resonance imaging and ultrasound evaluation of “healthy” joints in young subjects with severe haemophilia A. Haemophilia 2013; 19: e167-73. doi: 10.1111/hae.12107 10. Keshava SN, Gibikote SV, Mohanta A, Poonnoose P, Rayner T, Hilliard P, et al. Ultrasound and magnetic resonance imaging of healthy paediatric ankles and knees: a baseline for comparison with haemophilic joints. Haemophilia 2015; 21: e210-22. doi: 10.1111/hae.12614 11. Soliman M, Daruge P, Dertkigil SSJ, De Avila Fernandes E, Negrao JR, de Aguiar Vilela Mitraud S, et al. Imaging of haemophilic arthropathy in grow- ing joints: pitfalls in ultrasound and MRI. Haemophilia 2017; 23: 660-72. doi: 10.1111/hae.13249 12. Samanta M, Mitra S, Samui PP, Mondal RK, Hazra A, Sabui TK. Evaluation of joint cartilage thickness in healthy children by ultrasound: an experi- ence from a developing nation. Int J Rheum Dis 2018; 21: 2089-94. doi: 10.1111/1756-185X.13374 13. Spannow A, Stenboeg E, Pfeiffer-Jensen M, Fiirgaard B, Haislund M, Ostergaard M, et al. Ultrasound and MRI measurements of joint cartilage in healthy children: a validation study. Ultraschall Med 2010; 32(Suppl 1): S110-6. doi: 10.1055/s-0029-1245374 14. Sidharthan S, Yau A, Almeida BA, Shea KG, Greditzer HG, Jones KJ, et al. Patterns of articular cartilage thickness in pediatric and adolescent knees: a magnetic resonance imaging–based study. Arthrosc Sport Med Rehabil 2021; 3: e381-90. doi: 10.1016/j.asmr.2020.09.029 15. Lundin B, Manco-Johnson ML, Ignas DM, Moineddin R, Blanchette VS, Dunn AL, et al. An MRI scale for assessment of haemophilic arthropathy from the International Prophylaxis Study Group. Haemophilia 2012; 18: 962-70. doi: 10.1111/j.1365-2516.2012.02883.x 16. Chan YH. Biostatistics 104: correlational analysis. Singapore Med J 2005; 46: 153-60. 17. Plut D, Kotnik BF, Zupan IP, Kljucevsek D, Vidmar G, Snoj Z, et al. Diagnostic accuracy of haemophilia early arthropathy detection with ultrasound (HEAD-US): a comparative magnetic resonance imaging (MRI) study. Radiol Oncol 2019; 53: 178-86. doi: 10.2478/raon-2019-0027 18. Prasetyo M, Gatot D, Tulaar A, Pandelaki J, Bardosono S, Sukrisman L, et al. Association between US and MRI scores and correlations with urinary C-terminal telopeptide Type II collagen levels for early detection of hemo- philic arthropathy of the knee. J Phys Conf Ser 2018; 1073: 042022. doi: 10.1088/1742-6596/1073/4/042022 19. Prasetyo M, Mongan AE, Chozie NA, Prihartono J, Setiawan SI. Hemosiderin deposition evaluation in hemophilic ankle joints: association between US finding and gradient-recalled echo MR imaging sequence. Insights Imaging 2021; 12: 1-7. doi: 10.1186/s13244-021-01050-1 20. Acharya SS, Schloss R, Dyke JP, Mintz DN, Christos P, Dimichele DM, et al. Power Doppler sonography in the diagnosis of hemophilic synovitis - a promising tool. J Thromb Haemost 2008; 6: 2055-61. doi: 10.1111/j.1538- 7836.2008.03160.x