Amplicon Sequencing Minimal Information (ASqMI): Quality and Reporting Guidelines for Actionable Calls in Biodefense Applications.

BACKGROUND: Accurate, high-confidence data is critical for assessing potential biothreat incidents. In a biothreat event, false-negative and -positive results have serious consequences. Worst case scenarios can result in unnecessary shutdowns or fatalities at an exorbitant monetary and psychological cost, respectively. Quantitative PCR assays for agents of interest have been successfully used for routine biosurveillance. Recently, there has been increased impetus for adoption of amplicon sequencing (AS) for biosurveillance because it enables discrimination of true positives from near-neighbor false positives, as well as broad, simultaneous detection of many targets in many pathogens in a high-throughput scheme. However, the high sensitivity of AS can lead to false positives. Appropriate controls and workflow reporting can help address these challenges. OBJECTIVES: Data reporting standards are critical to data trustworthiness. The standards presented herein aim to provide a framework for method quality assessment in biodetection. METHODS: We present a set of standards, Amplicon Sequencing Minimal Information (ASqMI), developed under the auspices of the AOAC INTERNATIONAL Stakeholder Program on Agent Detection Assays for making actionable calls in biosurveillance applications. In addition to the first minimum information guidelines for AS, we provide a controls checklist and scoring scheme to assure AS run quality and assess potential sample contamination. RESULTS: Adoption of the ASqMI guidelines will improve data quality, help track workflow performance, and ultimately provide decision makers confidence to trust the results of this new and powerful technology. CONCLUSION: AS workflows can provide robust, confident calls for biodetection; however, due diligence in reporting and controls are needed. The ASqMI guideline is the first AS minimum reporting guidance document that also provides the means for end users to evaluate their workflows to improve confidence. HIGHLIGHTS: Standardized reporting guidance for actionable calls is critical to ensuring trustworthy data.

Long-term outcome of hamstring lengthening versus transfer and the role of biceps femoris lengthening in patients with spastic diplegia and dynamic knee flexion in gait.

Background: Orthopedic treatment of flexed-knee gait consists of hamstring lengthening along with surgery at other levels. Transfer of the semitendinosus (hamstring transfer) was introduced to avoid increase of anterior pelvic tilt as well as reduce risk of recurrence. Methods: We retrospectively assessed children with spastic cerebral palsy and flexed-knee gait pre-operatively, 1 year post-operatively, and at a minimum of 7 years post-operatively. Results: The 39 patients were a mean 9.4 ± 3.4 years at the time of surgery, 20 subjects underwent hamstring transfer, and 19 subjects had hamstring lengthening with mean follow-up 9.1 years. Passive range of motion improved initially, but regressed at long term. Dynamic minimum knee flexion in stance decreased in both groups at the first post-operative study, and was maintained at final follow-up in 64-67% of patients. There was a small increase in anterior pelvic tilt at the 1-year follow-up which subsequently decreased to less than pre-operative in the hamstring lengthening group but remained mildly increased (5°) in the hamstring transfer group at final follow-up. Success in correcting stance knee flexion of the entire group was 69% of the Gross Motor Function Classification System grades I and II and 60% of the Gross Motor Function Classification System grade III subjects. Gait profile Score and sagittal knee Gait Variable Score both showed clinically important improvement after surgery and was mostly maintained long term for both groups. Lateral hamstring lengthening was beneficial in more severe patients, with minimal risk of adverse effects. Conclusion: Hamstring surgery as part of single event multi-level surgery (SEMLS) is effective in correcting flexed-knee gait in 60%-70% of patients with minimal effect on anterior pelvic tilt. There was no added advantage to hamstring transfer. Biceps Femoris lengthening may be beneficial and without significant additional risk. Level of evidence: level III.

A Longitudinal Study of Quantitative Muscle Strength and Functional Motor Ability in Ambulatory Boys with Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder, that is characterized by progressive muscle degeneration and loss of ambulation between 7-13 years of age. Novel pharmacological agents targeting the genetic defects and disease mechanisms are becoming available; however, corticosteroid (CS) therapy remains the standard of care. OBJECTIVE: The purpose of this longitudinal study was to elucidate the effect of CS therapy on the rate of muscle strength and gross motor skill decline in boys with DMD and assess the sensitivity of selected outcome measures. METHODS: Eighty-four ambulatory boys with DMD (49-180 months), 70 on CS, 14 corticosteroid naïve (NCS), participated in this 8-year multi-site study. Outcomes included; isokinetic dynamometry, the Standing (STD) and Walking/Running/jumping (WRJ) dimensions of the Gross Motor Function Measure (GMFM), and Timed Function Tests (TFTs). Nonlinear mixed modeling procedures determined the rate of change with age and the influence of steroids. RESULTS: Despite CS therapy the rate of decline in strength with age was significant in all muscle groups assessed. CS therapy significantly slowed decline in knee extensor strength, as the NCS group declined at 3x the rate of the CS group. Concurrently, WRJ skills declined in the NCS group at twice the rate of the CS group. 4-stair climb and 10 meter walk/run performance was superior in the boys on CS therapy. CONCLUSION: CS therapy slowed the rate of muscle strength decline and afforded longer retention of select gross motor skills in boys on CS compared to boys who were NCS. Isokinetic dynamometry, Walk/Run/Jump skills, and select TFTs may prove informative in assessing the efficacy of new therapeutics in ambulatory boys with DMD.

Longitudinal changes in energy cost during walking in boys with Duchenne Muscular Dystrophy (DMD).

BACKGROUND: In boys with DMD, muscle weakness progresses in a proximal to distal pattern, leading to compensatory gait strategies, including hyperlordosis and equinus, that increase energy cost and accelerate the loss of walking capacity. RESEARCH QUESTION: The purpose of this study was to determine the changes in the energy cost of walking that occur with disease progression and to determine the optimal normalization scheme for the longitudinal assessment of the energy cost of walking in boys with DMD. METHODS: Energy cost was assessed with the COSMED K4b2. Three normalization schemes were examined: gross energy cost (EC), net non-dimensional oxygen cost (NNcost) and speed-matched control energy cost (SMC-EC). Nonlinear mixed modeling procedures determined the rate of change with age. Linear regression was used to asses the relationship between each normalization scheme and age and body height. RESULTS: 74 boys with DMD were assessed for the energy cost of walking. Velocity decreased at a significant rate (-.00245/month, p = .03) across time; (Fig. 2), while gross EC (.003248/month, p = 0.0026), NNcost (.006155/month, p < 0.0001) and SMC-EC (.001690/month, p = 0.03) all increased significantly. Age and height were significantly associated with NNcost and SMC-EC. The sensitivity of NNcost and SMC-EC to age over time were similar, while SMC-EC was less sensitive to changes in height over time than NNcost. SIGNIFICANCE: In contrast to able-bodied peers, boys with DMD decrease their velocity while all walking energy cost measures increased over time. Both SMC-EC and NNcost proved appropriate normalization schemes for boys with DMD. Compared to gross EC, both NNcost and SMC-EC were less sensitive to changes in age over time, while SMC-EC was less sensitive to changes in height than NNcost. Therefore, both NNCost and SMC-EC are suggested normalization schemes for the longitudinal assessment of energy cost in boys with DMD.

Efficacy of corticosteroid in decreasing scoliosis and extending time to loss of ambulation in a single clinic: an effectiveness trial.

PURPOSE: Pharmacologic doses of corticosteroid (CS) have been shown to ameliorate the progression of Duchenne muscular dystrophy (DMD) preserving strength, pulmonary function and ambulation as well as reducing the incidence of scoliosis. However, there are serious side effects of CS, which may impact dose tolerance. The purpose of this study was to compare the magnitude of positive CS effects on patients in our clinic to those reported in the literature. METHODS: We retrospectively reviewed medical records and radiographs of 142 DMD patients who were seen between 1st January 1991 and 31st December 2017. RESULTS: In total, 101 boys met study inclusion criteria. Of these 32 were steroid naïve, 37 took the recommended dose (standard of care, SOC) of Prednisone or Deflazacort, and 32 took a lower dose (LD). Following initiation of CS, both treatment groups showed an increase in weight velocity and decrease in linear growth velocity. Although there was a trend to later loss of ambulation (LOA) in the SOC group relative to the naïve group by one year, this was not significant, however, a small subgroup of boys on Deflazacort showed a 3.4 year later LOA than the naïve group. The incidence of scoliosis was reduced from 69% in the naïve, to 41% in the LD and 47% in the SOC group. CONCLUSIONS: Although there was a reduction in the incidence of scoliosis, it was not as robust as seen elsewhere. Many published studies have inadequate data on scoliosis probably due to the lack of inclusion of orthopaedists in the study group. LEVEL OF EVIDENCE: IV.

Respiratory Management of the Patient With Duchenne Muscular Dystrophy.

In 2010, Care Considerations for Duchenne Muscular Dystrophy, sponsored by the Centers for Disease Control and Prevention, was published in Lancet Neurology, and in 2018, these guidelines were updated. Since the publication of the first set of guidelines, survival of individuals with Duchenne muscular dystrophy has increased. With contemporary medical management, survival often extends into the fourth decade of life and beyond. Effective transition of respiratory care from pediatric to adult medicine is vital to optimize patient safety, prognosis, and quality of life. With genetic and other emerging drug therapies in development, standardization of care is necessary to accurately assess treatment effects in clinical trials. This revision of respiratory recommendations preserves a fundamental strength of the original guidelines: namely, reliance on a limited number of respiratory tests to guide patient assessment and management. A progressive therapeutic strategy is presented that includes lung volume recruitment, assisted coughing, and assisted ventilation (initially nocturnally, with the subsequent addition of daytime ventilation for progressive respiratory failure). This revision also stresses the need for serial monitoring of respiratory muscle strength to characterize an individual's respiratory phenotype of severity as well as provide baseline assessments for clinical trials. Clinical controversies and emerging areas are included.

Longitudinal community walking activity in Duchenne muscular dystrophy.

INTRODUCTION: Natural history studies for Duchenne muscular dystrophy (DMD) have not included measures of community ambulation. METHODS: Step activity (SA) monitors quantified community ambulation in 42 boys (ages 4-16 years) with DMD with serial enrollment up to 5 years by using a repeated-measures mixed model. Additionally, data were compared with 10-meter walk/run (10mWR) speed to determine validity and sensitivity. RESULTS: There were significant declines in average strides/day and percent strides at moderate, high and pediatric high rates as a function of age (P < 0.05). Significant correlations for 10mWR versus high and low stride rates were found at baseline (P < 0.05). SA outcomes were sensitive to change over 1 year, but the direction and parameter differed by age group (younger vs. older). Changes in strides/day and percentages of high frequency and low frequency strides correlated significantly with changes in 10mWR speed (P < 0.05). DISCUSSION: Community ambulation data provide valid and sensitive real-world measures that may inform clinical trials. Muscle Nerve 57: 401-406, 2018.

Hip kinetics during gait are clinically meaningful outcomes in young boys with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked genetic neuromuscular disorder characterized by progressive proximal to distal muscle weakness. The success of randomized clinical trials for novel therapeutics depends on outcome measurements that are sensitive to change. As the development of motor skills may lead to functional improvements in young boys with DMD, their inclusion may potentially confound clinical trials. Three-dimensional gait analysis is an under-utilized approach that can quantify joint moments and powers, which reflect functional muscle strength. In this study, gait kinetics, kinematics, spatial-temporal parameters, and timed functional tests were quantified over a one-year period for 21 boys between 4 and 8 years old who were enrolled in a multisite natural history study. At baseline, hip moments and powers were inadequate. Between the two visits, 12 boys began a corticosteroid regimen (mean duration 10.8±2.4 months) while 9 boys remained steroid-naïve. Significant between-group differences favoring steroid use were found for primary kinetic outcomes (peak hip extensor moments (p=.007), duration of hip extensor moments (p=.007), peak hip power generation (p=.028)), and spatial-temporal parameters (walking speed (p=.016) and cadence (p=.021)). Significant between-group differences were not found for kinematics or timed functional tests with the exception of the 10m walk test (p=.03), which improves in typically developing children within this age range. These results indicate that hip joint kinetics can be used to identify weakness in young boys with DMD and are sensitive to corticosteroid intervention. Inclusion of gait analysis may enhance detection of a treatment effect in clinical trials particularly for young boys with more preserved muscle function.

Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen.

Although biallelic mutations in non-collagen genes account for <10% of individuals with osteogenesis imperfecta, the characterization of these genes has identified new pathways and potential interventions that could benefit even those with mutations in type I collagen genes. We identified mutations in FKBP10, which encodes the 65 kDa prolyl cis-trans isomerase, FKBP65, in 38 members of 21 families with OI. These include 10 families from the Samoan Islands who share a founder mutation. Of the mutations, three are missense; the remainder either introduce premature termination codons or create frameshifts both of which result in mRNA instability. In four families missense mutations result in loss of most of the protein. The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families. The loss of the activity of FKBP65 has several effects: type I procollagen secretion is slightly delayed, the stabilization of the intact trimer is incomplete and there is diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular cross-link formation in bone. The phenotype overlaps with that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the enzyme that hydroxylates the telopeptide lysyl residues. These findings define a set of genes, FKBP10, PLOD2 and SERPINH1, that act during procollagen maturation to contribute to molecular stability and post-translational modification of type I procollagen, without which bone mass and quality are abnormal and fractures and contractures result.

A comparison of the changes in the energy cost of walking between children with cerebral palsy and able-bodied peers over one year.

For ambulatory children with cerebral palsy, the assessment of walking energy efficiency is utilized to determine functional changes following surgical, pharmacologic, or orthotic interventions. While the assessment of energy efficiency is considered a useful outcome tool, minimal information exists about the changes in energy efficiency over one year in children with cerebral palsy at different gross motor function classification system (GMFCS) levels and whether the patterns of change are similar to their able-bodied peers. The purpose of this study was to determine whether energy efficiency variables change similarly over one year in children with cerebral palsy by GMFCS level and whether they differ from their age-matched peers. Forty-five able-bodied children and 34 children with cerebral palsy, GMFCS levels I-III participated in the study. Energy efficiency variables were measured at baseline and at 12 months using a Cosmed K4b2. All subjects walked at their self-selected velocity for testing around a 33 m track. Baseline velocity and net non-dimensional cost (NNcost) differed by GMFCS level and between the able-bodied peers and all GMFCS levels. Children in GMFCS level III had the highest cost and the slowest velocity. When controlling for age and baseline values, significant differences in the magnitude of change were seen in velocity between children in GMFCS level III and children in GMFCS level I and II and their able-bodied peers. In comparison to their able-bodied peers, all GMFCS levels had an increase in NNcost over one year when controlling for age and baseline NNcost, with the difference in magnitude increasing by GMFCS level. Consistent with the literature, children with cerebral palsy had an increase in NNcost over one year in comparison to their able-bodied peers, which increased with GMFCS level. This finding demonstrates that when evaluating the change in walking energy efficiency with maturation and therapeutic intervention, comparisons should be made by GMFCS level.

Single laboratory validation of a microsatellite marker-based method in tomato variety identification.

The objective of this study was to develop a systematic and flexible method for assembling multiplex simple sequence repeat marker panels for high-throughput genome analysis in the tomato, Solanum lycopersicum, for varietal identification and to demonstrate the technical viability of these genetic markers for use in the enforcement of U.S. Department of Agriculture marketing order-based identity preservation programs. GeneMapper, a semiautomated software tool, was used for designing multiplex panels, allele identification, and polymorphism pattern evaluation of diverse tomato cultivars. Semiautomated genotyping was performed on a set of 12 microsatellite markers providing genome-wide coverage of the tomato chromosomes. Microsatellites were detected with fluorescently labeled primers grouped into five multiplex panels, and each primer pair was assessed in replicated trials for reliability of allele size estimates. Allele sizes for each locus were compared, and a database for 34 tomato varieties was developed. The microsatellite marker set identified distinct allelic peaks and unique genetic fingerprints for each of the studied tomato varieties. A "blind testing" exercise with UglyRipe and Vintage Ripe tomato varieties, using the above set of markers and database, further established the usefulness of these microsatellite markers for tomato commodity marketing order enforcement.

Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes.

Recessive mutations in the cartilage-associated protein (CRTAP), leucine proline-enriched proteoglycan 1 (LEPRE1) and peptidyl prolyl cis-trans isomerase B (PPIB) genes result in phenotypes that range from lethal in the perinatal period to severe deforming osteogenesis imperfecta (OI). These genes encode CRTAP (encoded by CRTAP), prolyl 3-hydroxylase 1 (P3H1; encoded by LEPRE1) and cyclophilin B (CYPB; encoded by PPIB), which reside in the rough endoplasmic reticulum (RER) and can form a complex involved in prolyl 3-hydroxylation in type I procollagen. CYPB, a prolyl cis-trans isomerase, has been thought to drive the prolyl-containing peptide bonds to the trans configuration needed for triple helix formation. Here, we describe mutations in PPIB identified in cells from three individuals with OI. Cultured dermal fibroblasts from the most severely affected infant make some overmodified type I procollagen molecules. Proα1(I) chains are slow to assemble into trimers, and abnormal procollagen molecules concentrate in the RER, and bind to protein disulfide isomerase (PDI) and prolyl 4-hydroxylase 1 (P4H1). These findings suggest that although CYPB plays a role in helix formation another effect is on folding of the C-terminal propeptide and trimer formation. The extent of procollagen accumulation and PDI/P4H1 binding differs among cells with mutations in PPIB, CRTAP and LEPRE1 with the greatest amount in PPIB-deficient cells and the least in LEPRE1-deficient cells. These findings suggest that prolyl cis-trans isomerase may be required to effectively fold the proline-rich regions of the C-terminal propeptide to allow proα chain association and suggest an order of action for CRTAP, P3H1 and CYPB in procollagen biosynthesis and pathogenesis of OI.

Clinical and genetic characterization of manifesting carriers of DMD mutations.

Manifesting carriers of DMD gene mutations may present diagnostic challenges, particularly in the absence of a family history of dystrophinopathy. We review the clinical and genetic features in 15 manifesting carriers identified among 860 subjects within the United Dystrophinopathy Project, a large clinical dystrophinopathy cohort whose members undergo comprehensive DMD mutation analysis. We defined manifesting carriers as females with significant weakness, excluding those with only myalgias/cramps. DNA extracted from peripheral blood was used to study X-chromosome inactivation patterns. Among these manifesting carriers, age at symptom onset ranged from 2 to 47 years. Seven had no family history and eight had male relatives with Duchenne muscular dystrophy (DMD). Clinical severity among the manifesting carriers varied from a DMD-like progression to a very mild Becker muscular dystrophy-like phenotype. Eight had exonic deletions or duplications and six had point mutations. One patient had two mutations (an exonic deletion and a splice site mutation), consistent with a heterozygous compound state. The X-chromosome inactivation pattern was skewed toward non-random in four out of seven informative deletions or duplications but was random in all cases with nonsense mutations. We present the results of DMD mutation analysis in this manifesting carrier cohort, including the first example of a presumably compound heterozygous DMD mutation. Our results demonstrate that improved molecular diagnostic methods facilitate the identification of DMD mutations in manifesting carriers, and confirm the heterogeneity of mutational mechanisms as well as the wide spectrum of phenotypes.

Classification of the gait patterns of boys with Duchenne muscular dystrophy and their relationship to function.

Corticosteroids have recently been shown to reduce expected loss of muscle strength in patients with Duchenne muscular dystrophy and extend the time they can walk. We evaluated 43 boys with the condition to determine whether taking corticosteroids is associated with differences in gait pattern, gross motor skills, energy efficiency, and timed motor performance. We used the gait deviation index to quantify the degree of gait pathology and a single measure of gait quality. There were minimal differences in gait pattern, gross motor skills, energy efficiency, or timed motor performance in boys who took corticosteroids compared with those who did not. Clustering by gait deviation index, however, revealed subtle differences between groups in gait patterns, gross motor skills, and energy efficiency. We conclude that, in boys with Duchenne muscular dystrophy, gait pattern deviations are related to function, which can provide further insight into the understanding of disease progression and treatment options to enhance function and maintain ambulation.

Relationship between clinical outcome measures and parent proxy reports of health-related quality of life in ambulatory children with Duchenne muscular dystrophy.

In Duchenne muscular dystrophy, data directly linking changes in clinical outcome measures to patient-perceived well-being are lacking. This study evaluated the relationship between clinical outcome measures used in clinical trials of ambulatory Duchenne muscular dystrophy (Vignos functional grade, quantitative knee extension strength, timed functional performance measures, and gait velocity) and 2 health-related quality of life measures--the Pediatric Outcomes Data Collection Instrument and Pediatric Quality of Life Inventory-in 52 ambulatory Duchenne muscular dystrophy subjects and 36 controls. Those with the disease showed significant decrements in parent proxy-reported health-related quality of life measures versus controls across all domains. The Pediatric Outcomes Data Collection Instrument transfers/basic mobility and sports/ physical function and the Pediatric Quality of Life Inventory physical functioning domains had significant associations with age (and hence disease progression) and traditional clinical outcome measures employed in clinical trials of ambulatory boys with Duchenne muscular dystrophy. Selected domains of the Pediatric Outcomes Data Collection Instrument and generic Pediatric Quality of Life Inventory are potential patient-reported outcome measures for clinical trials in ambulatory individuals with the disease.

Varus derotation osteotomy for the treatment of hip subluxation and dislocation in GMFCS level III to V patients with unilateral hip involvement. Follow-up at skeletal maturity.

PURPOSE: Hip displacement is common in children with cerebral palsy (CP). The risk of hip displacement is related to gross motor function level as graded with the Gross Motor Function Classification System (GMFCS). Most clinicians agree that surgical treatment is indicated for progressive hip subluxation in patients with CP. However, it is unclear whether unilateral bony surgery and musculotenduous release is effective in cases in which the contralateral hip is well seated. The purpose of this study is to describe the fate of the original and the contralateral hip of severely involved patients with CP, GMFCS III to V, with unilateral hip subluxation or dislocation treated by unilateral femoral osteotomy with or without pelvic osteotomy along with unilateral or bilateral soft tissue release when the contralateral hip was well seated followed to skeletal maturity. METHODS: A continuous group of GMFCS III to V CP patients with unilateral hip subluxation or dislocation who underwent soft tissue release (adductor and iliopsoas) and unilateral intertrochanteric varus, rotation and shortening osteotomy with or without pelvic osteotomy are included. All patients were clinically and radiologically followed from the time of presentation until skeletal maturity. RESULTS: Twenty-seven children and adolescents with GMFCS level III, IV, and V met the inclusion criteria. Two patients (7.4%) were GMFCS III, 5 (18.5%) were GMFCS IV and 20 (74.1%) GMFCS V. The male:female ratio was almost 1 (13 boys and 14 girls). At the time of chart and radiograph review, the average age of this patient group was 20.4 years (range: 14 to 25 y). Twelve patients (44%) required subsequent bony surgical management of the contralateral hip for subluxation or dislocation after the index procedure. Initially, in all cases there was pelvic obliquity with the operative side higher, which reversed in cases in which the contralateral hip deteriorated, and did not reverse when the contralateral hip remained stable. Nine of them were treated with femoral varus osteotomy alone and 3 underwent a combination of femoral and pelvic osteotomy. Three of these 12 (25%) patients had revision of the first hip and bony correction of the contralateral hip. Age at surgery did not seem to have a significant effect on maintaining reduction or in preventing the contralateral hip to deteriorate. CONCLUSIONS: The rates of recurrence of the original hip and contralateral hip subluxation and dislocation after unilateral bony surgery in GMFCS III to V spastic patients are higher than those of other earlier series. However, in this series patients were followed until skeletal maturity. It is prudent to warn families of the possibility of long-term subluxation or dislocation of the original hip and development of the hip dysplasia requiring surgery on the contralateral side. Consideration should be given to adductor and iliopsoas release and bony surgery on the contralateral side in a GMFCS level III to V child undergoing surgery for hip displacement, even when the hip seem radiologically normal. If unilateral bony surgery is carried out, close radiological follow-up of both hips is recommended. It also seems that unilateral hip surgery alters the forces maintaining pelvic alignment, which can lead to destabilization of the contralateral hip. LEVEL OF EVIDENCE: Case series. Level IV.

Variability and minimum detectable change for walking energy efficiency variables in children with cerebral palsy.

For individuals with neuromuscular disorders, the assessment of walking energy efficiency is useful as a clinical outcome measure. Issues surrounding data collection methodology, normalization of the data, and variability and clinical utility of energy efficiency data preclude universal application. This study examined the variability and the clinical utility of velocity, energy efficiency index (EEI), gross cost, and net nondimensional cost (NNcost) in children and adolescents with spastic diplegic cerebral palsy (CP) in Gross Motor Function Classification System (GMFCS) levels I to III. The energy efficiency of walking was evaluated in 23 children and adolescents (12 males, 11 females, mean age 11y 3mo [SD 3y 5mo]; range 7-17y). Day-to-day variability was similar for all energy efficiency variables, with no significant differences in magnitude of variability between GMFCS levels. Correlations between EEI and gross cost and EEI and NNcost were fairly good (r=0.65, p<0.001, and r=0.74, p<0.001 respectively). However, only gross cost and NNcost discriminated between GMFCS levels in children with CP. Gross cost required the greatest amount of change to be considered clinically significant, whereas NNcost and EEI required a similar amount of change. For cohorts of children with CP who are evaluated over time, NNcost is the best normalization method as it reduces the variability between participants of different ages, height, and weight while evaluating only the amount of energy used to ambulate.