Pediatr Radiol (2014) 44:1573–1587 DOI 10.1007/s00247-014-3041-x
ORIGINAL ARTICLE
Evidence-based outcomes on diagnostic accuracy of quantitative ultrasound for assessment of pediatric osteoporosis — a systematic review Kuan Chung Wang & Kuan Chieh Wang & Afsaneh Amirabadi & Edward Cheung & Elizabeth Uleryk & Rahim Moineddin & Andrea S. Doria
Received: 8 October 2013 / Revised: 3 March 2014 / Accepted: 12 May 2014 / Published online: 25 June 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background Dual-energy absorptiometry (DXA) is the current reference standard for assessing pediatric osteoporosis; however due to its areal nature, it has limitations. Thus, quantitative ultrasound (QUS), a modality free of ionizing radiation, has been proposed as a potential surrogate for DXA. Objective To semi-quantitatively assess the diagnostic accuracy of QUS for evaluating pediatric osteoporosis according to the U.S. Preventive Services Task Force guidelines. Materials and methods We retrieved articles on the diagnostic accuracy of quantitative US for assessing abnormal bone quality or quantity in patients of mean age ≤19 years from MEDLINE, EMBASE and Cochrane Library CCTR databases. Evidences were analyzed for reliability, construct and criterion validity, and responsiveness of quantitative US, according to the following questions: (1) How reliable is the acquisition of QUS measurements? (2) Is QUS diagnostically
Electronic supplementary material The online version of this article (doi:10.1007/s00247-014-3041-x) contains supplementary material, which is available to authorized users. K. C. Wang : K. C. Wang : A. Amirabadi : E. Cheung : A. S. Doria (*) Department of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, 555 University Ave., Toronto M5G 1X8, Canada e-mail: [email protected] E. Uleryk Library Services, The Hospital for Sick Children, Toronto, Canada R. Moineddin Department of Family and Community Medicine, University of Toronto, Toronto, Canada
accurate to characterize bone strength and quality in osteoporotic children? (3) Is QUS sensitive to detect changes in bone status over time? (4) Is QUS able to predict future skeletal fractures/degeneration? Three reviewers independently evaluated the quality of reporting and methodological quality using the Standards for Reporting of Diagnostic Accuracy (STARD) and the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tools. Results Out of 262 retrieved references (215 unique), we included 28 studies (1,963 patients; 807 reported boys and 761 girls, others unspecified; reported mean age, 0–19 years). The mean quality of reporting score was “excellent”in 24/28 (86%) studies; 11/28 (39%) studies had “adequate” research design quality. Conclusion There is no evidence of the diagnostic value of QUS at the present time despite the overall excellent and adequate research design quality of primary studies. Although QUS can produce reliable measurements, insufficient evidence has been reported to support other clinimetric properties of this technique. Keywords Osteoporosis . Child . Quantitative ultrasound . Speed of sound . Standard for Reporting of Diagnostic Accuracy (STARD) . Quality Assessment of Diagnostic Accuracy Studies (QUADAS)
Introduction Osteoporosis is a metabolic disease characterized by the general decrease in bone strength and density, which can lead to increased susceptibility to fractures, limited mobility and other life-hindering disabilities. In children osteoporosis is often diagnosed as a complication of
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primary diseases, or is induced by administered treatments for primary diseases [1–8]. With recent advances in treatments for osteoporosisinducing diseases in children and adolescents, the patient survival rate has increased significantly. As a consequence, there has been an increased awareness of the long-term effects of treatment on the quality of life of patients [1, 3, 5, 9]. Thus it becomes vital that clinicians can count on a valid and reliable diagnostic tool for assessment of early osteoporosis in the pediatric population. Dual energy absorptiometry (DXA) is a widely accepted reference standard for detecting osteoporosis in adults [10, 11]. Advantages of DXA over other imaging modalities in adults include high reproducibility, low radiation dose, short scanning time, and availability of well-established normative values [1–3, 5, 12]. Nevertheless in the pediatric population, in addition to concerns about radiation exposure, normative values are not well-established and the influence of puberty, weight and height on bone mineral density makes DXA data interpretation difficult in children [12, 13]. Furthermore, given the fact that bone mineral density is size-dependent and many osteoporotic children and adolescents who suffer from chronic disorders are small-for-age, DXA might be incompetent for measuring true bone density [14–16]. Quantitative ultrasound (QUS) has been developed to serve as a potential surrogate for DXA. It is free of ionizing radiation, and portable, making it easier to establish normative values for pediatric patients without the concern of radiation exposure [17–24]. Moreover, the parameters of QUS (speed of sound, broadband ultrasound attenuation, stiffness factor, and bone transmission time) are capable of measuring bone properties other than bone mineral density, such as elasticity, micro-architecture and thickness [25–31]. Although the U.S. Food and Drug Administration has approved QUS for osteoporosis screening in adults based on the fact that it is a good predictor of fracture risk in postmenopausal women [16, 29, 32], no systematic review has been undertaken to summarize the evidence on the diagnostic accuracy of this technique in the pediatric population. The objectives of this systematic review concerning the use of QUS for assessment of osteoporosis in children and adolescents were to investigate: (1) the intra- and/or interoperator reliability of acquisition of QUS measurements; (2) the diagnostic accuracy of this technique; (3) its responsiveness to osteoporosis treatment aimed at improving bone quality or interval observational changes; (4) its ability to predict skeletal fractures or degeneration. The analytic framework of the study objectives with regard to bodies of evidence to be investigated is in Fig. 1. Definitions of clinimetric properties of QUS evaluated in this review are in Appendix 1. Note that all appendices are provided online as supplemental material.
Pediatr Radiol (2014) 44:1573–1587
Materials and methods The research ethics board of our institution waived approval for this review. Study selection This review included studies that met the following inclusion criteria: (1) evaluation of bone strength and/or quality by QUS; (2) application of at least one of the parameters of QUS, namely speed of sound and broadband ultrasound attenuation; (3) mean age of subjects ≤19 years; (4) minimum sample size of >10 subjects, (5) subjects with osteoporosis or abnormal bone quality regardless of having or not having a baseline disease. Reviews, case reports and studies written in languages other than English, French, German, Spanish, Italian, Portuguese and Chinese were excluded. Search and data collection strategies The electronic search of studies was performed by two investigators, one student (K.C.W.1) and one experienced librarian (E.U.), who searched MEDLINE, EMBASE, and EBM Reviews (CCTR) using the OvidSP interface updated to May 27, 2013. Search terms were adapted to the individual database vocabularies and free text words for: (bone density OR bone and bones OR bone diseases, metabolic OR osteoporosis OR osteopenia) AND (quantitative ultrasound OR ultrasound OR quantitative ultrasonography). Results were limited to age group (0 to 18 years) and evidence-based study design methodology filters for therapy, diagnosis and prognosis. The complete search strategies are listened in Appendix 2. Titles and abstracts were systematically screened by three investigators (A.A., K.C.W.1, K.C.W.2) to determine eligibility for this systematic review. Full-text articles were then retrieved and reviewed by these three investigators. References of selected papers were also screened for eligibility for this review. Data appraisal — assessment of quality of reporting and methodology Quality of reporting and methodology were assessed semiquantitatively using the Standard for Reporting of Diagnostic Accuracy (STARD) and the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tools, respectively [33, 34]. Studies were appraised by three reviewers (A.A., K.C.W.1, K.C.W.2), where two reviewers (A.A., K.C.W.1) used both STARD and QUADAS-2 and one reviewer (K.C.W.2) used only the STARD tool. For each item of the STARD checklist, "1" was given for full completeness of reporting, "0.5" for partial completeness, and "0" for absent or insufficient reporting. If the item was not applicable for the
Pediatr Radiol (2014) 44:1573–1587 Fig. 1 Diagram shows the analytical framework for the use of quantitative US as a diagnostic tool of osteoporosis in children. Dashed tracing indicates topics not available in this review. DXA dual-energy absorptiometry, QUS quantitative ultrasonography
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Persons at risk
Screening
Early detection of target condition
Final outcome (reduced morbidity and/or mortality)
Intermediate outcome Assessment with DXA / QUS
Assessment with QUS
Patients with osteoporosis (mean age 19)
1
Reliability
2
Validity
3 Responsiveness
Quantification of bony trabeculae Peripheral skeleton
Treatment
Reliability Validity Evidence of vertebral (axial skeleton) or extremity (peripheral skeleton) fractures
3 Responsiveness Association Treatment
Improved morphologic appearance of vertebrae or extremities (X-ray scoring system) or clinical outcome
4 Prediction Validity
study design, "N/A" was indicated. For each domain (patient selection, index test, reference standard, and flow and timing) of the two aspects (risk of bias, applicability concern) of the QUADAS-2 tool "low risk" or "high risk" was given for studies that were deemed to have low or high risk of bias or applicability concern, respectively, and "unclear" was given for studies deemed to have unclear risk of bias or applicability concern. "N/A" was given for domains or items that did not apply to the study design. Disagreements between reviewers were solved by a different reader (A.S.D.) who acted as a tiebreaker. Detailed criteria for STARD and QUADAS-2 items are available in appendices 3 and 4.
(USPSTF) for hierarchy of research design (Appendix 5) [39]. Levels of recommendation were assigned according to USPSTF guidelines with regard to different clinimetric properties of studies (Appendix 6). Inter-rater agreement of overall scores of STARD (two reviewers) and QUADAS-2 (two reviewers) was demonstrated by intraclass correlation for the sum of all items using similar cutoffs as those applied for r-values and by weighted kappa for each individual item [36].
Results Data analysis Search and data collection For each study, STARD scores ≥60% corresponded to excellent, scores ≥40 and
ORIGINAL ARTICLE
Evidence-based outcomes on diagnostic accuracy of quantitative ultrasound for assessment of pediatric osteoporosis — a systematic review Kuan Chung Wang & Kuan Chieh Wang & Afsaneh Amirabadi & Edward Cheung & Elizabeth Uleryk & Rahim Moineddin & Andrea S. Doria
Received: 8 October 2013 / Revised: 3 March 2014 / Accepted: 12 May 2014 / Published online: 25 June 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background Dual-energy absorptiometry (DXA) is the current reference standard for assessing pediatric osteoporosis; however due to its areal nature, it has limitations. Thus, quantitative ultrasound (QUS), a modality free of ionizing radiation, has been proposed as a potential surrogate for DXA. Objective To semi-quantitatively assess the diagnostic accuracy of QUS for evaluating pediatric osteoporosis according to the U.S. Preventive Services Task Force guidelines. Materials and methods We retrieved articles on the diagnostic accuracy of quantitative US for assessing abnormal bone quality or quantity in patients of mean age ≤19 years from MEDLINE, EMBASE and Cochrane Library CCTR databases. Evidences were analyzed for reliability, construct and criterion validity, and responsiveness of quantitative US, according to the following questions: (1) How reliable is the acquisition of QUS measurements? (2) Is QUS diagnostically
Electronic supplementary material The online version of this article (doi:10.1007/s00247-014-3041-x) contains supplementary material, which is available to authorized users. K. C. Wang : K. C. Wang : A. Amirabadi : E. Cheung : A. S. Doria (*) Department of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, 555 University Ave., Toronto M5G 1X8, Canada e-mail: [email protected] E. Uleryk Library Services, The Hospital for Sick Children, Toronto, Canada R. Moineddin Department of Family and Community Medicine, University of Toronto, Toronto, Canada
accurate to characterize bone strength and quality in osteoporotic children? (3) Is QUS sensitive to detect changes in bone status over time? (4) Is QUS able to predict future skeletal fractures/degeneration? Three reviewers independently evaluated the quality of reporting and methodological quality using the Standards for Reporting of Diagnostic Accuracy (STARD) and the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tools. Results Out of 262 retrieved references (215 unique), we included 28 studies (1,963 patients; 807 reported boys and 761 girls, others unspecified; reported mean age, 0–19 years). The mean quality of reporting score was “excellent”in 24/28 (86%) studies; 11/28 (39%) studies had “adequate” research design quality. Conclusion There is no evidence of the diagnostic value of QUS at the present time despite the overall excellent and adequate research design quality of primary studies. Although QUS can produce reliable measurements, insufficient evidence has been reported to support other clinimetric properties of this technique. Keywords Osteoporosis . Child . Quantitative ultrasound . Speed of sound . Standard for Reporting of Diagnostic Accuracy (STARD) . Quality Assessment of Diagnostic Accuracy Studies (QUADAS)
Introduction Osteoporosis is a metabolic disease characterized by the general decrease in bone strength and density, which can lead to increased susceptibility to fractures, limited mobility and other life-hindering disabilities. In children osteoporosis is often diagnosed as a complication of
1574
primary diseases, or is induced by administered treatments for primary diseases [1–8]. With recent advances in treatments for osteoporosisinducing diseases in children and adolescents, the patient survival rate has increased significantly. As a consequence, there has been an increased awareness of the long-term effects of treatment on the quality of life of patients [1, 3, 5, 9]. Thus it becomes vital that clinicians can count on a valid and reliable diagnostic tool for assessment of early osteoporosis in the pediatric population. Dual energy absorptiometry (DXA) is a widely accepted reference standard for detecting osteoporosis in adults [10, 11]. Advantages of DXA over other imaging modalities in adults include high reproducibility, low radiation dose, short scanning time, and availability of well-established normative values [1–3, 5, 12]. Nevertheless in the pediatric population, in addition to concerns about radiation exposure, normative values are not well-established and the influence of puberty, weight and height on bone mineral density makes DXA data interpretation difficult in children [12, 13]. Furthermore, given the fact that bone mineral density is size-dependent and many osteoporotic children and adolescents who suffer from chronic disorders are small-for-age, DXA might be incompetent for measuring true bone density [14–16]. Quantitative ultrasound (QUS) has been developed to serve as a potential surrogate for DXA. It is free of ionizing radiation, and portable, making it easier to establish normative values for pediatric patients without the concern of radiation exposure [17–24]. Moreover, the parameters of QUS (speed of sound, broadband ultrasound attenuation, stiffness factor, and bone transmission time) are capable of measuring bone properties other than bone mineral density, such as elasticity, micro-architecture and thickness [25–31]. Although the U.S. Food and Drug Administration has approved QUS for osteoporosis screening in adults based on the fact that it is a good predictor of fracture risk in postmenopausal women [16, 29, 32], no systematic review has been undertaken to summarize the evidence on the diagnostic accuracy of this technique in the pediatric population. The objectives of this systematic review concerning the use of QUS for assessment of osteoporosis in children and adolescents were to investigate: (1) the intra- and/or interoperator reliability of acquisition of QUS measurements; (2) the diagnostic accuracy of this technique; (3) its responsiveness to osteoporosis treatment aimed at improving bone quality or interval observational changes; (4) its ability to predict skeletal fractures or degeneration. The analytic framework of the study objectives with regard to bodies of evidence to be investigated is in Fig. 1. Definitions of clinimetric properties of QUS evaluated in this review are in Appendix 1. Note that all appendices are provided online as supplemental material.
Pediatr Radiol (2014) 44:1573–1587
Materials and methods The research ethics board of our institution waived approval for this review. Study selection This review included studies that met the following inclusion criteria: (1) evaluation of bone strength and/or quality by QUS; (2) application of at least one of the parameters of QUS, namely speed of sound and broadband ultrasound attenuation; (3) mean age of subjects ≤19 years; (4) minimum sample size of >10 subjects, (5) subjects with osteoporosis or abnormal bone quality regardless of having or not having a baseline disease. Reviews, case reports and studies written in languages other than English, French, German, Spanish, Italian, Portuguese and Chinese were excluded. Search and data collection strategies The electronic search of studies was performed by two investigators, one student (K.C.W.1) and one experienced librarian (E.U.), who searched MEDLINE, EMBASE, and EBM Reviews (CCTR) using the OvidSP interface updated to May 27, 2013. Search terms were adapted to the individual database vocabularies and free text words for: (bone density OR bone and bones OR bone diseases, metabolic OR osteoporosis OR osteopenia) AND (quantitative ultrasound OR ultrasound OR quantitative ultrasonography). Results were limited to age group (0 to 18 years) and evidence-based study design methodology filters for therapy, diagnosis and prognosis. The complete search strategies are listened in Appendix 2. Titles and abstracts were systematically screened by three investigators (A.A., K.C.W.1, K.C.W.2) to determine eligibility for this systematic review. Full-text articles were then retrieved and reviewed by these three investigators. References of selected papers were also screened for eligibility for this review. Data appraisal — assessment of quality of reporting and methodology Quality of reporting and methodology were assessed semiquantitatively using the Standard for Reporting of Diagnostic Accuracy (STARD) and the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tools, respectively [33, 34]. Studies were appraised by three reviewers (A.A., K.C.W.1, K.C.W.2), where two reviewers (A.A., K.C.W.1) used both STARD and QUADAS-2 and one reviewer (K.C.W.2) used only the STARD tool. For each item of the STARD checklist, "1" was given for full completeness of reporting, "0.5" for partial completeness, and "0" for absent or insufficient reporting. If the item was not applicable for the
Pediatr Radiol (2014) 44:1573–1587 Fig. 1 Diagram shows the analytical framework for the use of quantitative US as a diagnostic tool of osteoporosis in children. Dashed tracing indicates topics not available in this review. DXA dual-energy absorptiometry, QUS quantitative ultrasonography
1575
Persons at risk
Screening
Early detection of target condition
Final outcome (reduced morbidity and/or mortality)
Intermediate outcome Assessment with DXA / QUS
Assessment with QUS
Patients with osteoporosis (mean age 19)
1
Reliability
2
Validity
3 Responsiveness
Quantification of bony trabeculae Peripheral skeleton
Treatment
Reliability Validity Evidence of vertebral (axial skeleton) or extremity (peripheral skeleton) fractures
3 Responsiveness Association Treatment
Improved morphologic appearance of vertebrae or extremities (X-ray scoring system) or clinical outcome
4 Prediction Validity
study design, "N/A" was indicated. For each domain (patient selection, index test, reference standard, and flow and timing) of the two aspects (risk of bias, applicability concern) of the QUADAS-2 tool "low risk" or "high risk" was given for studies that were deemed to have low or high risk of bias or applicability concern, respectively, and "unclear" was given for studies deemed to have unclear risk of bias or applicability concern. "N/A" was given for domains or items that did not apply to the study design. Disagreements between reviewers were solved by a different reader (A.S.D.) who acted as a tiebreaker. Detailed criteria for STARD and QUADAS-2 items are available in appendices 3 and 4.
(USPSTF) for hierarchy of research design (Appendix 5) [39]. Levels of recommendation were assigned according to USPSTF guidelines with regard to different clinimetric properties of studies (Appendix 6). Inter-rater agreement of overall scores of STARD (two reviewers) and QUADAS-2 (two reviewers) was demonstrated by intraclass correlation for the sum of all items using similar cutoffs as those applied for r-values and by weighted kappa for each individual item [36].
Results Data analysis Search and data collection For each study, STARD scores ≥60% corresponded to excellent, scores ≥40 and
