Radiographic Evaluation of Pediatric Patients with Patellofemoral Instability

Abstract

Purpose of Review

The purpose of this review is to highlight the radiographic assessments of utility in the evaluation of a pediatric patient with patellofemoral instability to facilitate a thorough work-up. Understanding of these measures is useful in understanding evolving research in this field, providing accurate patient risk assessment, and appropriately directing surgical decision-making.

Recent Findings

Recent literature has broadened the radiographic characterization of the pediatric patellar instability and its anatomic risk factors. Knee MRI can inform the assessment of skeletal maturity and novel axial alignment measurements may enhance our identification of patients at increased risk of recurrent instability. Additional improvements have been made in the objective measurement and classification of trochlear dysplasia.

Summary

Knee MRI-based skeletal age assessments may obviate the need for hand bone age assessments in growing children with patellofemoral instability. Novel objective measures exist in the evaluation of pediatric patellar instability both in the assessment of axial alignment and trochlear dysplasia. Future work should focus on how these measures can aid in guiding surgical decision-making.

Introduction

Lateral patellar dislocation (LPD) or recurrent patellofemoral instability (PFI) is a common condition affecting pediatric patients. The estimated annual incidence across all populations ranges from 2.29 to 77.4 per 100,000 person-years, but has been shown to be as high as 100 to 150 per 100,000 among late adolescent female cohorts [1–10]. Recent work suggests that the incidence may be slowly rising, resulting in increased rates of surgical intervention for stabilization [11–13]. The vast majority of primary instability events are known to occur as the result of sport participation [1, 4, 14, 15]; however, a variety of contact and non-contact mechanisms of injury have been described.

Numerous anatomic, demographic, and radiographic factors have been identified demonstrating increased risk of recurrent patellar instability [14–17]. Radiographic assessments including the presence of open regional physes, trochlear dysplasia, patella alta, and axial malalignment assessments (e.g., tibial tubercle-trochlear groove, or TT-TG, distance) are among the strongest and most consistent across studies of these risk factors. Recurrent ipsilateral patellar dislocation occurs in 15% to 54% of pediatric patients following primary dislocation [1, 7, 15, 16, 18–21], while contralateral dislocation is estimated to occur in 10–11% of pediatric patients [1, 7, 18]. Recurrence peaks during adolescence with most episodes occurring within 5 years of the first dislocation [15, 18]. Prior work has found that two-thirds of patients with both open regional physes of the knee and trochlear dysplasia at the time of their first dislocation sustained recurrent episodes of instability, carrying a 3-fold increased risk of recurrent instability events as compared to skeletally mature patients without dysplasia [15]. As such, the radiographic assessment of these patients plays a critical role in the counseling of patients and their families regarding recurrence and in directing surgical decision-making.

This article will provide a review of radiographic measures relevant to the evaluation of pediatric patients with PFI. The purpose is to equip the orthopedic clinician with an up-to-date and detailed review of a “complete” radiographic assessment for patients with patellar instability. While all of the described assessments are not necessary at every phase of clinical care, we feel that a global understanding will enable providers to better tailor their patient counseling and treatment plans. We will highlight measures and classifications to objectively describe and categorize skeletal age, axial and coronal deformity, and trochlear dysplasia, focusing on those that have been described or evaluated in pediatric cohorts and those that have been cited frequently in the orthopedic literature to help guide surgical intervention decisions. While surgical interventions will be mentioned as they relate to these measures, detailed discussion of these procedures, their indications, and their outcomes are beyond the intended scope of this review.

Skeletal Age Assessments

Skeletal age, or “bone age”, assessments provide significant value in the management of many orthopedic conditions. In the setting of PFI, they are critical both in the counseling of patients and families regarding the risk of recurrence, but also in determining the indications for and safety of various procedural interventions which may or may not be appropriate for patients with considerable remaining growth. The Greulisch and Pyle (G&P) atlas [22] estimates of bone age using left hand radiographs and remains the most widely utilized tool for estimating skeletal maturation. Patients with considerable growth remaining are contraindicated for some surgical interventions (e.g., tibial tubercle osteotomy) due to the risk of physeal arrest and may require physeal-respecting technical modifications to other orthopedic interventions for patellar instability. However, open physes also allow for the utilization of growth guidance techniques to address coronal limb deformities which can play a major role in PFI. The G&P method can help to estimate remaining years of growth and the anticipated timing of knee physeal closure. This, however, has the obvious limitation in that it requires imaging outside of the anatomic region undergoing evaluation (i.e., the knee) and is therefore not routinely or immediately available for review for all patients being evaluated for PFI. As such, efforts have been made to develop novel systems for bone age evaluation using knee magnetic resonance imaging (MRI), which is often obtained in the work-up of a patient with PFI.

To avoid the need for additional imaging, bone age systems based on MRI imaging of the knee have been developed. The initial system developed by Pennock et al. [23] identified a series of stepwise changes that occur as the skeleton matures and found excellent correlation with chronological age (r = 0.978, p ≤ 0.001), outperforming the Greulisch and Pyle (G&P) derived bone age (r = 0.865, p ≤ 0.001). Intra- and interrater reliability using knee MRI for bone age assessment were also excellent, similar to that of the G&P atlas. Meza et al. [24••] subsequently developed a “shorthand” knee MRI bone age assessment (Fig. 1). This work also demonstrated a strong correlation with G&P-derived bone age and had good to excellent interrater reliability. Key skeletal maturity timepoints include (1) complete ossification of the tibial apophysis typically occurring at 12 in females and 15 in males, and (2) the start of physeal closure about the knee occurring first centrally about the tibia most commonly at 14 in females and 16 in males. Clinically, this indicates that patients with complete ossification of the tibial apophysis are 1–2 years away from the beginning of physeal closure and may be at lower risk for major growth disturbances from surgical interventions occurring near the physis. Further work is necessary to validate these findings in other cohorts, but both of these studies offer a reliable and reproducible means of skeletal age assessment that obviate the need for additional hand radiographs.

Fig. 1.

Reproducible regional physeal changes of the knee visualized on sagittal intermediate-weighted non-fat saturated images in males and females aged 10 to 17 years old. *Crack represents incomplete fusion and should cross entire apophysis. Figure adapted from Meza et al. [24••]

Coronal Limb Alignment

Coronal limb alignment is a critical component in the evaluation of pediatric patients with patellofemoral instability. Genu valgum, which can be physiologic in many pre-adolescents, contributes to an increased functional Q-angle and results in a laterally directed vector imposed by the extensor mechanism on the patella during knee motion thereby increasing the risk of lateral patellar dislocation events. Correction of genu valgum alone can improve patellofemoral tracking and effectively reduce the risk of patellar instability events [25–29]. While clinical evaluation of limb alignment on examination provides initial screening, subtle deformities can be missed or hidden due to body habitus or ligamentous laxity. The standing orthoroentgenogram [30], a composite, often weight-bearing, lower extremity radiographic image, compliments the clinical limb alignment assessment, allowing a more precise determination of the anatomic and mechanical axes of the lower extremity [25, 27, 31–34].

Limb alignment assessment on orthoroentgenogram begins with determination of the limb mechanical axis (drawn from the center of the femoral head to the center of the ankle joint) and the degree or zone of mechanical axis deviation (MAD), which is classified into zones (1–3, Fig. 2a), with Zone 0 being in the intercondylar notch, zone 1 being in the inner half of the hemijoint, zone 2 in the outer half of the hemijoint, and zone 3 outside of the weightbearing zone. If significant coronal deformity is present, evaluation should next consider what local deformities are contributing to the overall malalignment. Assessment of the anatomic and mechanical lateral distal femoral angle (mLDFA) and medial proximal tibial angle (MPTA) help identify whether the distal femur, proximal tibia, or a combination of the two is most contributing to the patient’s coronal plane malalignment (Fig. 2b) [29, 31, 33]. While normative values have been established for all of these angles in adolescent and adult patients, previous work [33] has shown that children under 7 years of age should use separate standards as normal given that physiologic changes in coronal limb alignment occur during growth in this age group that can correct without intervention. In addition to characterizing the severity of a patient’s coronal plane deformity at presentation, these angles are also utilized in follow-up to monitor the angular deformity correction following surgical intervention or with growth.

Fig. 2.

Measures for assessment of coronal plane angular deformity using standing alignment film. a Illustrates the mechanical axis, mechanical axis deviation (MAD), and anatomic axes of the femur and tibia. b Illustrates angles of interest relative to the mechanical and anatomical axes: lateral distal femoral angle (LDFA) and medial proximal tibial angle (MPTA)

Excessive genu valgum with MAD can serve as an indication for surgical intervention in PFI patients, as soft tissue procedures alone (e.g., MPFL) may be at greater risk of failure [29••]. Correction can be achieved via “guided growth,” using hemiepiphysiodesis for skeletally immature patients, and opening- or closing-wedge osteotomy for the skeletally mature [27, 29, 31, 35, 36]. The anatomic location of these interventions is based on the primary source of the underlying coronal deformity (tibia, femur, or both).

Lower Extremity Version Assessments

Excessive femoral anteversion and external tibial torsion impact rotational limb alignment, resulting in internal rotation of the distal femoral trochlea and external rotation of the distal attachment of the extensor mechanism. Together, these rotational abnormalities have been referred to as “miserable malalignment” and may increase the risk of patellar instability in addition to causing patellofemoral pain [37–40]. This is due to the maladaptive forces on the knee leading to greater tension on the MPFL and increased lateral patellofemoral tracking resulting in asymmetric tracking of the patella, subluxation or dislocation [41–43].

Evaluation of the rotation profile begins on clinical exam with evaluation of the thigh-foot axis (tibial version) and hip rotation (femoral version). When a pathologic degree of version is suspected, cross-sectional imaging can be used to more precisely quantify the rotational profile, which has traditionally utilized osseous data from computed tomography (CT) scanning [41–44]. Notably, MRI may also be used and may be a more desirable approach in adolescents due to the decreased levels of radiation exposure compared to CT scanning. A variety of measurement techniques have been described using different key axial slices of the femur and tibia [40, 45–47]; however, regardless of technique, the normal version of the femur is approximately 22° in children (range 0–65) as compared to roughly 15° (range 10–20) in adults [48–51]. In children, the average version of the tibia is 20° (range 0–45) [52].

It is important to consider these imaging results in the context of the patient, as many young children have physiologic degrees of femoral anteversion and/or tibial torsion that tends to spontaneously resolve [41, 42]. Additionally, some ligamentously lax patients with significant femoral anteversion are still capable of “normal” mobility and may not require surgical intervention [43•]. While many cases of pediatric femoral anteversion and/or tibial torsion may not require surgical intervention, those pediatric patients dealing with symptomatic PFI in the setting of significant rotation deformity may be considered candidates from femoral or tibial derotational osteotomies [40, 41, 43]. However, it is important to continue to monitor coronal plane alignment post-operatively, as rotational osteotomies have been shown to impact coronal alignment [41, 43] (Fig. 3).

Fig. 3.

CT version study with 3D reconstruction of the right (a) and left (b) legs in a patient with patellar instability and femoral anteversion. Versional assessment is determined by finding the angle made by the femoral neck (dashed line) and the posterior condylar axis of the femur (solid line). In this patient, femoral anteversion was 36 degrees in the right femur and 35 degrees in the left femur

Patellar Height

Patella alta is a well-established risk factor for PFI as this results in late engagement of the bony stability of the patellofemoral articulation during knee flexion [14, 16, 17]. Several methods have been described to quantify patellar height on radiograph including the Caton-Deschamps Index [53], the Insall-Salvati index (ISI) [54, 55], the Koshino index (KI) [56], and the Blackburne-Peel (BP) ratio [57] (Fig. 4). Some of these, however, have limited utility in the pediatric population due to complex measurement technique or measurement reliability impacted by ossification changes occurring during growth. Thévenin-Lemoine et al. found the Caton Deschamps index (CDI) to be both simple and reliable, representing the preferred measure of patellar height on radiographs in children and adolescents [58]. Their study findings also indicated that patellar height appears to decrease with age, reaching adult normative values by 12 years old.

Fig. 4.

Measurement techniques for sagittal alignment ratios of ISI, CDI, and PTI. *PTI measured on the midline sagittal section MRI through the patella with the thickest articular cartilage and maximal length of the patella

While all of the aforementioned techniques were first described using lateral radiographs as a basis for measurement, MRI-based comparisons have been made with evidence indicating acceptable correlation between radiographs and 3-dimensional imaging (CT and/or MRI) for both ISI and CDI in largely adult cohorts [59–61]. In skeletally immature patients, ISI has demonstrated comparable radiograph and MRI measurements [60•], but no study has evaluated radiograph- and MRI-derived CDI measures exclusively in this age group. Subtle differences between these modalities are likely the result of the discrepancy between articular cartilage geometry and subchondral osseous structures seen on radiograph which is accentuated in the skeletally-immature patient.

The patellotrochlear index (PTI) is another patellar height assessment described by Biedert et al. that uses sagittal MRI to evaluate the overlap of articular surfaces on the patella and trochlea [62], which authors argue is the important anatomic factor of patellar height in PFI. Benefits of this measure include the evaluation of true patellotrochlear articular congruence, immunity from changes posed by osseous variations or previous surgeries, high reliability, and measurement in full extension limiting variation imposed by knee flexion angles required by other measures [59, 62–64]. Despite these purported benefits, there is limited evidence validating this measure as a PFI risk factor in skeletally immature patients or a measure to specifically guide surgical decision-making. Therefore, based on the available evidence, the preferred method of measuring patellar height in pediatric patients is uncertain, but limited evidence suggests that CDI is the preferred method on radiographs, while ISI may be more appropriate with MRI. The PTI also shows promise as its measure is uniquely relevant to the anatomic basis of PFI.

Treatment options described for the PFI patient with excessive patella alta include distalizing tibial tubercle osteotomy in skeletally mature patients [65] or patellar tendon advancement/imbrication in those who are skeletally immature [66–68]. While clinically significant cutoffs exist for patella alta, indications for and necessity of correction remains unclear, particularly when other surgical interventions are already being implemented [69, 70].

Axial Alignment Assessments

The axial alignment of the extensor mechanism refers to the relative translational position of the patella, patellar tendon, trochlea, and tibial tubercle on axial imaging in addition to the rotational relationship of the distal femoral and proximal tibia. A more lateral distal attachment of the patellar tendon increases the lateral forces imposed on the patella and extensor mechanism during knee flexion [71]. Lateralization of the tibial tubercle relative to the distal femoral trochlea is quantified using the tibial tubercle-trochlear groove (TT-TG) distance which is one of the most frequently cited modifiable risk factors for recurrent PFI [17, 18, 72–78]. Normative data in adults suggests that TT-TG distances below 15 mm are considered normal while values over 20 mm may indicate surgical correction in symptomatic patients [78]. However, like many radiographic measures, values in adult populations are not directly applicable to pediatric patients. Dickens et al. validated TT-TG using MRI in skeletally immature patients showing that this measure gradually increased with age reaching adult-based normative values by approximately 15 years of age [79]. The mean TT-TG of in pediatric patients (9 months to 15 years old) with and without instability was 8.5 mm and 12.1 mm, respectively. A percentile-based growth curve was generated for TT-TG distance in the skeletally immature patient [79].

Although CT is the gold standard for visualizing bony structures, such as TT-TG, MRI is becoming the preferred comprehensive advanced imaging modality of choice in the imaging work-up of these patients as it also provides information regarding cartilaginous trochlear morphology, integrity of the regional ligaments, and tendons without the use of ionizing radiation. However, the measured TT-TG distance may differ between CT and MRI due to the use of different anatomic landmarks. While the initial published paper found no significant difference in TT-TG distances between CT and MRI with excellent interrater and intrarater [72]. More recent work has demonstrated differences with CT measuring approximately 2 mm greater than MRI. This difference increased with greater TT-TG measures (i.e., over 20 mm). Similarly, new studies focusing on the skeletally immature population have also shown that CT produced relatively greater measurements when compared to MRI, with a mean difference of 4 mm and 2 mm using bony and cartilaginous landmarks, respectively [80].

Two newer measures have been described exploring the concept of containment of the extensor mechanism by the trochlear groove. Mistovich et al. examined the axial width of the patellar tendon beyond the lateral trochlear ridge (PT-LTR) and compared this to the TT-TG in addition to numerous other axial alignment measures in pediatric patients with and without patellar instability [81•]. The authors found the PT-LTR distance to be reliable and discriminative for patellofemoral instability in addition to showing similar sensitivity but higher specificity for this condition than TT-TG. Building on this patellofemoral containment logic, Weltsch et al. explored the tibial tubercle to lateral trochlear ridge (TT-LTR) distance and found that the localization of the tibial tubercle outside of the lateral trochlear ridge was the only axial MRI measure predictive of recurrent patellar instability in their multivariate logistic regression analysis [82••]. While neither study has examined the surgical implications of these measures, their findings together suggest that our understanding of the axial alignment in pediatric patient with PFI extends beyond just the TT-TG distance, with localization of the tibial tubercle outside of the lateral trochlear ridge being more important than any one threshold TT-TG value.

Pathologic axial malalignment is both a risk factor for recurrent instability, and for failure of surgical stabilization with soft tissue reconstruction (i.e., MPFL) alone [83]. Therefore, in the setting of elevated axial alignment measures, consideration may be made for realignment procedures. In skeletally mature patients, this can be done with tibial tubercle medialization or anteromedialization [84, 85] to better centralize the extensor mechanism within the trochlear groove during knee motion. Due to the proximity to the proximal tibial growth plate and the risk of physeal arrest, this procedure is contraindicated in skeletally immature patients in whom deferred surgical treatment or soft tissue transfers (e.g., Roux-Goldwaithe) may be considered [86–88].

Trochlear Dysplasia

Trochlear dysplasia, defined as flattening or even convexity of the femoral trochlear groove, has been identified as a significant risk factor for recurrent patellar instability [14, 15, 37, 89–91]. Distal femur morphology including the trochlear groove is established early in life, with dysplasia likely having both congenital and developmental factors resulting from aberrant forces applied to the patellofemoral joint during growth due to lateral tracking and/or recurrent instability [92, 93]. A dysplastic trochlea decreases the bony stability of the patellofemoral joint resulting in reduced restraint to lateral translation of the patella with increased stress placed upon the MPFL (Fig. 5).

Fig. 5.

Measurement techniques for axial alignment assessments including TT-TG, PT-LTR, and LTR-TT are described and presented with representative drawings

Traditionally, trochlear dysplasia assessments in the literature have been largely based on the classification system described by Dejour et al. [37]. This system, which uses a true lateral radiograph of the knee, categorizes patients into four types (A through D) based on the presence of radiographic findings. The hallmark finding of a Dejour A trochlea is the crossing sign which indicates a shallow trochlear groove (sulcus angle > 145°). Dejour B trochleae have both the crossing sign and a supratrochlear spur which correlates with a flat or convex trochlea. Dejour C findings include a crossing sign and a double contour sign manifested by asymmetry of the trochlear facets while Dejour D having all of these radiographic changes. Given the limitations and reproducibility of true lateral radiographs, some have described MRI adaptations of this classification by evaluating the contour of the proximal trochlea [94••]. However, despite this system being widely utilized clinically and within the literature, there has been controversy regarding its utility as it is notably sensitive to the quality of radiographs, has low intra- and interrater reliability, and does not provide distinct guidance for surgical decision-making [89, 94, 95]. More recently, the MRI-based Oswestry-Bristol classification (OBC) was developed in part to address some of these limitations and provide a more reliable system for categorizing the severity of trochlear dysplasia [96•]. The OBC grades dysplasia as normal, mild, moderate, or severe (corresponding to a normal, shallow, flat, or convex proximal trochlea, respectively). Though early in its use and not yet validated in skeletally immature patients, this system has demonstrated greater reliability than the Dejour classification [97, 98]. The Dejour and Oswestry-Bristol classifications and their characteristic findings are depicted in Figs. 6 and 7, respectively.

Fig. 6.

The Dejour classification of trochlear dysplasia is described along with representative figures depicting expected findings on axial MRI (MRI Dejour [94•]) at the proximal-most aspect of the trochlear cartilage for each subtype are presented

Fig. 7.

The Oswestry-Bristol classification of trochlear dysplasia is described and presented along with representative axial MRI findings at the proximal-most aspect of the trochlear cartilage

In addition to categorical classification systems like Dejour and OBC, a number of quantitative measures of trochlear morphology have also been described including the sulcus angle (SA), lateral trochlear inclination (LTI) angle [99, 100], trochlear depth index (TDI) [101], and medial condyle trochlear offset (MCTO) [94••]. While sulcus angle was one of the earliest objective measures of dysplasia prescribed on merchant radiographs of the knee, its reliability is impacted by knee flexion angle, age of the patient, and precise selection of location along the groove for measurements [92, 93, 102, 103]. Sulcus angle has been adapted to measure trochlear morphology on axial CT and MRI images using bone and cartilage landmarks, but variability exists in the literature regarding the location of measurement on axial imaging (proximal-most visible trochlear cartilage, full articular cartilage across both trochlear facets, or at the level of measurement of the posterior condylar axis) [104, 105]. Additional work has further demonstrated the limitations of bony assessments of trochlear morphology in the pediatric population [106, 107]. In skeletally immature patients (7–16 years old), Stephanovich et al. found that pediatric-modified LTI, TDI, and MCTO measures demonstrated better reliability and improved detection of patients with patellar instability when compared to radiographic or MRI-based Dejour classification. LTI, TDI, and MCTO critical cutoffs of 17°, 3 mm, and 1 mm, respectively, were identified [94••]. Further work is needed to determine the clinical implications of these more objective assessments, but their diagnostic power, reliability, and accuracy may facilitate enhanced understanding of trochlear dysplasia in the pediatric patient. Objective trochlear dysplasia measures are compared in Fig. 8.

Fig. 8.

Objective trochlear measurements to identify and characterize trochlear dysplasia on axial MRI of the knee are presented. Measurement techniques for SA, LTI, TDI, and MCTO are described with representative drawings

Currently, trochleoplasty is the only described surgical procedure that directly addresses the dysplastic trochlea. A variety of techniques for trochleoplasty have been described [108–110], but the general principles of the procedure are to increase the concavity and lateralize the trochlear groove to both enhance patellofemoral bony stability during knee flexion and reduce axial malalignment. Controversy exists [111–116] regarding the indications for use of trochleoplasty and the preferred surgical approach for patients with recurrent PFI and severe trochlear dysplasia when alternative interventions to address complex instability (namely tibial tubercle osteotomy) are available. While a growing body of evidence has demonstrated highly successful patellofemoral stabilization using trochleoplasty in pediatric [117–119] and adult [120, 121] patients with severe trochlear dysplasia, improved evidence is needed to clarify the indications for this procedure in patients with PFI as considerable variation in the rate of reported complications exists in the published literature [122, 123].

Conclusions

Due to the complex anatomic considerations impacting patellofemoral instability and the changes that can occur during skeletal maturity, providers caring for this condition should be aware of the numerous tools and measures that exist to appropriately evaluate skeletal maturity, coronal alignment, lower extremity limb version, patellar height, axial extensor mechanism alignment, and trochlear morphology in the pediatric PFI patient. This study provides an in-depth review of the most up-to-date literature regarding the evolution of imaging assessments most relevant to children and adolescents.

While all of these assessments described are not necessary to evaluate at every stage of clinical care, familiarity with each enables providers to comprehensively evaluate, counsel, and treat this unique patient population. The authors’ preferred approach to the radiographic assessment of pediatric patients with patellar instability is as follows:

1. Skeletal age assessment with knee MRI can be safely and reliably utilized in lieu of hand radiographs in risk counseling and surgical decision-making.

2. Clinically apparent valgus should be explored radiographically with standing alignment imaging. Treatment implications of this study depend on the severity of MAD, other concomitant risk factors, and remaining growth.

3. Clinically significant version abnormalities can be further assessed with rotational MRI or CT studies; however, the indications for versional correction remain controversial.

4. Patellar height is assessed with radiographs and knee MRI using CDI. Values > 1.3 are considered abnormal and correction is considered if surgery has been indicated.

5. Axial alignment is assessed on Knee MRI using TT-TG, PT-LTR, and LTR-TT measures. Abnormal TT-TG is used primarily to indicate surgical correction; however, the other measures may influence decision-making in otherwise borderline cases.

6. Trochlear morphology is assessed both subjectively and objectively for the diagnosis and characterization of trochlear dysplasia, but at this time their impact on surgical decision-making in pediatric patients is not clear and varies by provider. The measures and classifications described in this review are actively being utilized in ongoing research to further our understanding of the femoral trochlea and the appropriate indications for correction in this patient population.

Author Contribution

This manuscript has not been published previously. All authors made significant contributions to multiple aspects of the study as described in the ICMJE authorship criteria recommendations, detailed here:

• Kevin J. Orellana: substantial contributions to data acquisition, data interpretation, manuscript drafting, critical revision, and final approval of the version to be published.

• Morgan G. Batley: substantial contributions to data acquisition, data interpretation, manuscript drafting, critical revision, and final approval of the version to be published.

• J. Todd R. Lawrence: substantial contributions to concept and design, data interpretation, critical revision, and final approval of the version to be published.

• Jie C. Nguyen: substantial contributions to concept and design, data interpretation, critical revision, and final approval of the version to be published.

• Brendan A. Williams: substantial contributions to conception and design, data acquisition, data interpretation, manuscript drafting, critical revision, and final approval of the version to be published.

Declarations

Conflict of Interest

Kevin J. Orellana, Morgan G. Batley, Jie C. Nguyen, and Brendan A. Williams declare that they have no conflict of interest. J. Todd R. Lawrence is a board or committee member of the American Academy of Pediatrics and has received IP royalties from Sawbones/Pacific Research Laboratories.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.