Measuring Developmental Delays: Comparison of Parent Report and Direct Testing.

PURPOSE: Developmental assessment is part of a comprehensive autism evaluation. During in-person evaluations, developmental assessment is completed via direct testing by an examiner. In telehealth evaluations, developmental assessment relies on caregiver-report instruments. This study examined correspondence between caregiver report and direct testing of developmental skills. METHODS: Participants were 93 children, aged 18-42 months, undergoing evaluation for possible autism spectrum disorder (ASD). Caregivers were interviewed with the Developmental Profile, 4th edition (DP-4) via telehealth platform and children were tested in person 2-4 weeks later using the Mullen Scales of Early Learning (MSEL). RESULTS: Correlations between the DP-4 and MSEL were high (ranging from 0.50 to 0.82) across standard scores, age equivalents, and functional categories, as well as across individual subtests and overall composite scores. CONCLUSION: The high convergent validity found in this study suggests that the DP-4 provides a suitable proxy for direct developmental testing using the MSEL in the context of telehealth evaluations for ASD in young children, delivering a good estimate of both developmental functioning and presence of delays. TRIAL REGISTRATION: Data were obtained from registered clinical trial NCT05047224, date of registration 2021-09-07.

Case report: Transient symptoms of autism spectrum disorder in a 2-year-old boy.

Though early ASD diagnosis is highly stable, this case report describes a rare situation in which symptoms resolved without intervention over a 4 month period. We do not recommend delaying diagnosis in symptomatic children who meet criteria but when major behavioral changes are reported after diagnosis, reevaluation may be beneficial.

Factors related to retention in a longitudinal study of infants at familial risk for autism.

Background: Reporting retention data is critical to determining the soundness of a study's conclusions (internal validity) and broader generalizability (external validity). Although selective attrition can lead to overestimates of effects, biased conclusions, or overly expansive generalizations, retention rates are not reported in many longitudinal studies. Methods: We examined multiple child- and family-level factors potentially associated with retention in a longitudinal study of younger siblings of children with autism spectrum disorder (ASD; n = 304) or typical development (n = 163). The sample was followed from the first year of life to 36 months of age, for up to 7 visits. Results: Of the 467 infant siblings who were consented and participated in at least one research visit, 397 (85.0%) were retained to study completion at 36 months. Retention rates did not differ by familial risk group (ASD-risk vs. Low-risk), sex, race, ethnicity, age at enrollment, number of children in the family, maternal employment, marital status, or parent concerns about the child at enrollment. A stepwise regression model identified 4 variables that, together, provided the most parsimonious predictive model of study retention: maternal education, maternal age at child's birth, travel distance to the study site, and diagnostic outcome classification at the final study visit. Conclusions: The retained and not-retained groups did not differ on most demographic and clinical variables, suggesting few threats to internal and external validity. The significantly higher rate of retention of children diagnosed with ASD (95%) than typically developing children (83%) may, however, present biases when studying recurrence risk. We conclude by describing engagement and tracking methods that can be used to maximize retention in longitudinal studies of children at risk of ASD.

The National Conference on Health Disparities Student Research Forum.

The annual National Conference on Health Disparities (NCHD) was launched in 2000. It unites health professionals, researchers, community leaders, and government officials, and is a catalyzing force in developing policies, research interventions, and programs that address prevention, social determinants, health disparities, and health equity. The NCHD Student Research Forum (SRF) was established in 2011 at the Medical University of South Carolina to build high-quality biomedical research presentation capacity in primarily underrepresented undergraduate and graduate/professional students. This paper describes the unique research training and professional development aspects of the NCHD SRF. These include guidance in abstract development, a webinar on presentation techniques and methods, a vibrant student-centric conference, and professional development workshops on finding a mentor and locating scholarship/fellowship funding, networking, and strategies for handling ethical issues in research with mentors. Between 2011 and 2018, 400 undergraduate and graduate/professional students participated in the NCHD SRF. Most students were women (80.5%). Approximately half were African American or black (52.3%), 18.0% were white, and 21.3% were of Hispanic/Latinx ethnicity. The NCHD SRF is unique in several ways. First, it provides detailed instructions on developing a scientific abstract, including content area examples. Second, it establishes a mandatory pre-conference training webinar demonstrating how to prepare a scientific poster. Third, it works with the research mentors, faculty advisors, department chairs, and deans to help identify potential sources of travel funding for students with accepted abstracts. These features make the NCHD SRF different from many other conferences focused on students' scientific presentations.

Measuring social-communication difficulties in school-age siblings of children with autism spectrum disorder: Standardized versus naturalistic assessment.

Younger siblings of children with autism spectrum disorder (ASD; high-risk siblings) are at elevated risk for developing the broader autism phenotype (BAP), which consists of subclinical features of ASD. We examined conversational skills in a naturalistic context and standardized assessments of pragmatic language and communication skills in high-risk and low-risk school-age children with BAP (n = 22) and ASD (n = 18) outcomes, as well as comparison children without ASD or BAP (n = 135). Children with BAP characteristics exhibited lower conversational skills than comparison children, but did not differ on any of three standardized measures. Only the conversational ratings significantly predicted membership in the BAP versus Comparison group. This suggests that naturalistic tasks are crucial when assessing social-communication difficulties in children with a family history of ASD. LAY SUMMARY: The broader autism phenotype (BAP) consists of subclinical features of autism spectrum disorder (ASD) and is more common among family members of those with ASD. School-age children with BAP characteristics exhibited lower conversational skills than comparison children, but did not differ on standardized language measures tapping similar abilities. This suggests that naturalistic tasks may be more sensitive to the social-communication difficulties seen in some children with a family history of ASD than the standardized language tests used in most evaluations.

Can Familial Risk for ADHD Be Detected in the First Two Years of Life?

Objective: We evaluated trajectories of attention-deficit/hyperactivity (ADHD)-relevant behaviors in a sample of infants at high and low familial risk for ADHD who were prospectively evaluated at 12, 18, and 24 months of age.Method: Participants included 43 infants at risk for ADHD based on family history (i.e., diagnosed first-degree relative) and 40 low-risk infants (i.e., no family history of ADHD). Instances of inattention, out-of-seat, and grabbing behavior were coded from video; analogous constructs were rated by examiners unaware of familial risk status after completing structured standardized assessments with the infants/toddlers. At the end of each study visit, examiners solicited parents' concerns about their child's behavior. Differences in ADHD-related behaviors and parent concerns were examined between 12 and 24 months of age.Results: Infants with an older sibling or parent diagnosed with ADHD were distinguishable from infants with no family history of ADHD as early as 12 months of age based on directly observed and examiner reports of behavior, particularly with respect to hyperactive-impulsive behavior. Parents of infants at familial risk for ADHD also reported significantly more behavior/temperament concerns as early as 12 months of age compared to parents of infants at low risk for ADHD.Conclusions: These findings highlight the ability to detect genetic liability for ADHD by the end of the first year of life, suggesting that well-designed family risk studies of ADHD are feasible and may be clinically valuable. They also suggest the potential for earlier detection of risk for ADHD than has previously been possible.

Screen time in 36-month-olds at increased likelihood for ASD and ADHD.

We examined the relationship between video-based media viewing (screen time), behavioral outcomes, and language development in 120 36-month-old children with a family history of Autism Spectrum Disorder (ASD) or Attention-Deficit/Hyperactivity Disorder (ADHD) or no family history of either condition. Participants were classified into one of three diagnostic groups: ASD (n = 20), ADHD Concerns (children with elevated ADHD symptoms; n = 14), or Comparison (n = 86). Children in the ADHD Concerns group spent more time viewing screen media than Comparison children. Increased screen time was associated with lower receptive and expressive language scores across groups. Future longitudinal studies are needed to determine the direction of effects and causality.

A video-based measure to identify autism risk in infancy.

BACKGROUND: Signs of autism are present in the first 2 years of life, but the average age of diagnosis lags far behind. Instruments that improve detection of autism risk in infancy are needed. This study developed and tested the psychometric properties of a novel video-based approach to detecting ASD in infancy. METHODS: A prospective longitudinal study of children at elevated or lower risk for autism spectrum disorder was conducted. Participants were 76 infants with an older sibling with ASD and 37 infants with no known family history of autism. The Video-referenced Infant Rating System for Autism (VIRSA) is a web-based application that presents pairs of videos of parents and infants playing together and requires forced-choice judgments of which video is most similar to the child being rated. Parents rated participants on the VIRSA at 6, 9, 12, and 18 months of age. We examined split-half and test-retest reliability; convergent and discriminant validity; and sensitivity, specificity, and negative and positive predictive value for concurrent and 36-month ASD diagnoses. RESULTS: The VIRSA demonstrated satisfactory reliability and convergent and discriminant validity. VIRSA ratings were significantly lower for children ultimately diagnosed with ASD than children with typical development by 12 months of age. VIRSA scores at 18 months identified all children diagnosed with ASD at that age, as well as 78% of children diagnosed at 36 months. CONCLUSIONS: This study represents an initial step in the development of a novel video-based approach to detection of ASD in infancy. The VIRSA's psychometric properties were promising when used by parents with an older affected child, but still must be tested in community samples with no family history of ASD. If results are replicated, then the VIRSA's low-burden, web-based format has the potential to reduce disparities in communities with limited access to screening.

Onset patterns in autism: Variation across informants, methods, and timing.

While previous studies suggested that regressive forms of onset were not common in autism spectrum disorder (ASD), more recent investigations suggest that the rates are quite high and may be under-reported using certain methods. The current study undertook a systematic investigation of how rates of regression differed by measurement method. Infants with (n = 147) and without a family history of ASD (n = 83) were seen prospectively for up to 7 visits in the first three years of life. Reports of symptom onset were collected using four measures that systematically varied the informant (examiner vs. parent), the decision type (categorical [regression absent or present] vs. dimensional [frequency of social behaviors]), and the timing of the assessment (retrospective vs. prospective). Latent class growth models were used to classify individual trajectories to see whether regressive onset patterns were infrequent or widespread within the ASD group. A majority of the sample was classified as having a regressive onset using either examiner (88%) or parent (69%) prospective dimensional ratings. Rates of regression were much lower using retrospective or categorical measures (from 29 to 47%). Agreement among different measurement methods was low. Declining trajectories of development, consistent with a regressive onset pattern, are common in children with ASD and may be more the rule than the exception. The accuracy of widely used methods of measuring onset is questionable and the present findings argue against their widespread use. Autism Res 2018, 11: 788-797. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study examines different ways of measuring the onset of symptoms in autism spectrum disorder (ASD). The present findings suggest that declining developmental skills, consistent with a regressive onset pattern, are common in children with ASD and may be more the rule than the exception. The results question the accuracy of widely used methods of measuring symptom onset and argue against their widespread use.

Early Detection of ADHD: Insights From Infant Siblings of Children With Autism.

Converging evidence suggests shared genetic underpinnings of attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Studies of infants at risk for ASD have proliferated over the past decade; the few studies that have followed these infants beyond age 3 report a range of difficulties facing a subset of these infants as they reach school age, including elevated levels of attention problems and externalizing behavior. Given this, we aimed to identify early predictors of school-age ADHD outcomes in a sample of infant siblings at risk for ASD. This study reports on a sample of 59 infants at high and low risk for ASD who had been followed for more than a decade, collecting data at regular intervals from 3 to 36 months and then determining diagnostic outcome at 8-10 years of age. Seventeen participants were diagnosed with Diagnostic and Statistical Manual of Mental Disorders (5th ed.) ADHD at school age (n = 14 high risk, 3 low risk). As infants, the ADHD outcome group demonstrated atypical longitudinal patterns of sustained visual attention. A significantly larger proportion of their parents reported behavior/temperament problems at 36 months of age, and examiners noted the presence of inattentive, hyperactive, and/or impulsive behaviors in this group by 18 months of age. These data suggest that behavioral indicators of risk for later ADHD may be present early in development, which may improve earlier detection and treatment of the disorder.

Response to Name in Infants Developing Autism Spectrum Disorder: A Prospective Study.

OBJECTIVE: To examine longitudinal patterns of response to name from 6-24 months of age in infants at high and low risk for autism spectrum disorder (ASD). STUDY DESIGN: A response to name task was tested at 6, 9, 12, 15, 18, and 24 months of age in 156 infant siblings of children with ASD (high-risk) or typical development (low-risk). At 36 months of age, participants were classified into 1 of 3 outcome groups: group with ASD (n = 20), high-risk group without ASD (n = 76), or low-risk group without ASD (n = 60). Differences in longitudinal performance were assessed using generalized estimating equations, and sensitivity and specificity for identifying ASD were calculated. Differences in age 36-month functioning were examined between infants who developed ASD and repeatedly vs infrequently failed to respond to name. RESULTS: At 9 months of age, infants developing ASD were more likely to fail to orient to their names, persisting through 24 months. Sensitivity/specificity for identifying ASD based on at least 1 failure between 12 and 24 months were estimated at .70 in this sample. One-half of the infants who developed ASD had repeated failures in this timeframe, and demonstrated lower age 36-month receptive language, and earlier diagnosis of ASD than infants with ASD who had infrequent failures. CONCLUSIONS: In addition to recommended routine broad-based and ASD-specific screening, response to name should be regularly monitored in infants at risk for ASD. Infants who consistently fail to respond to their names in the second year of life may be at risk not only for ASD but also for greater impairment by age 3 years.

School-age outcomes of infants at risk for autism spectrum disorder.

Studies of infants at risk for autism spectrum disorder (ASD) have proliferated, but few of these samples have been followed longer-term. We conducted a follow-up study, at age 5.5-9 years, of younger siblings of children with ASD (high-risk group, n = 79) or typical development (low-risk group, n = 60), originally recruited as infants. Children with ASD were excluded because of the focus on understanding the range of non-ASD outcomes among high-risk siblings. Using examiner ratings, parent ratings, and standardized assessments, we evaluated differences in clinical outcomes, psychopathology symptoms, autism symptoms, language skills, and nonverbal cognitive abilities. After adjusting for covariates, the high-risk group had increased odds of any clinically elevated/impaired score across measures relative to the low-risk group (43% vs. 12%, respectively). The high-risk group also had increased odds of examiner-rated Clinical Concerns (CC) outcomes (e.g., ADHD concerns, broader autism phenotype, speech-language difficulties, anxiety/mood problems, learning problems) relative to the low-risk group (38% vs. 13%, respectively). The high-risk group with CC outcomes had higher parent-reported psychopathology and autism symptoms, and lower directly-assessed language skills, than the Low-Risk Typically Developing (TD) and High-Risk TD groups, which did not differ. There were no differences in nonverbal cognitive skills. For some in the high-risk group, clinical concerns persisted from early childhood, whereas for others clinical concerns were first evident at school-age. Results suggest continued vulnerability in at least a subgroup of school-age children with a family history of ASD and suggest that this population may benefit from continued screening and monitoring into the school-age years. Autism Res 2016, 9: 632-642. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

The broader autism phenotype in infancy: when does it emerge?

OBJECTIVE: This study had 3 goals, which were to examine the following: the frequency of atypical development, consistent with the broader autism phenotype, in high-risk infant siblings of children with autism spectrum disorder (ASD); the age at which atypical development is first evident; and which developmental domains are affected. METHOD: A prospective longitudinal design was used to compare 294 high-risk infants and 116 low-risk infants. Participants were tested at 6, 12, 18, 24, and 36 months of age. At the final visit, outcome was classified as ASD, Typical Development (TD), or Non-TD (defined as elevated Autism Diagnostic Observation Schedule [ADOS] score, low Mullen Scale scores, or both). RESULTS: Of the high-risk group, 28% were classified as Non-TD at 36 months of age. Growth curve models demonstrated that the Non-TD group could not be distinguished from the other groups at 6 months of age, but differed significantly from the Low-Risk TD group by 12 months on multiple measures. The Non-TD group demonstrated atypical development in cognitive, motor, language, and social domains, with differences particularly prominent in the social-communication domain. CONCLUSIONS: These results demonstrate that features of atypical development, consistent with the broader autism phenotype, are detectable by the first birthday and affect development in multiple domains. This highlights the necessity for close developmental surveillance of infant siblings of children with ASD, along with implementation of appropriate interventions as needed.

A prospective study of the emergence of early behavioral signs of autism.

OBJECTIVE: To examine prospectively the emergence of behavioral signs of autism in the first years of life in infants at low and high risk for autism. METHOD: A prospective longitudinal design was used to compare 25 infants later diagnosed with an autism spectrum disorder (ASD) with 25 gender-matched low-risk children later determined to have typical development. Participants were evaluated at 6, 12, 18, 24, and 36 months of age. Frequencies of gaze to faces, social smiles, and directed vocalizations were coded from video and rated by examiners. RESULTS: The frequency of gaze to faces, shared smiles, and vocalizations to others were highly comparable between groups at 6 months of age, but significantly declining trajectories over time were apparent in the group later diagnosed with ASD. Group differences were significant by 12 months of age on most variables. Although repeated evaluation documented loss of skills in most infants with ASD, most parents did not report a regression in their child's development. CONCLUSIONS: These results suggest that behavioral signs of autism are not present at birth, as once suggested by Kanner, but emerge over time through a process of diminishment of key social communication behaviors. More children may present with a regressive course than previously thought, but parent report methods do not capture this phenomenon well. Implications for onset classification systems and clinical screening are also discussed.

How early do parent concerns predict later autism diagnosis?

OBJECTIVE: To study the relationship between parent concerns about development in the first year and a half of life and later autism diagnostic outcomes. METHOD: Parent concerns about development were collected for infants at high and low risk for autism, using a prospective, longitudinal design. Parents were asked about developmental concerns at study intake and when their infant was 6, 12, and 18 months. Infants were then followed up until 36 months, when diagnostic status was determined. RESULTS: By the time their child was 12 months, parents who have an older child with autism reported significantly more concerns in autism spectrum disorders-related areas than parents of children with typical outcomes. These concerns were significantly related to independent measures of developmental status and autism symptoms and helped predict which infants would later be diagnosed with autism or autism spectrum disorders. At 6 months, however, the concerns of parents who have an older child with autism do not predict outcome well. CONCLUSION: Explicitly probing for parent concerns about development is useful for identifying children in need of closer monitoring and surveillance, as recommended by the American Academy of Pediatrics.

Home-based, peer-led chronic illness self-management training: findings from a 1-year randomized controlled trial.

PURPOSE: Studies suggest peer-led self-management training improves chronic illness outcomes by enhancing illness management self-efficacy. Limitations of most studies, however, include use of multiple outcome measures without predesignated primary outcomes and lack of randomized follow-up beyond 6 months. We conducted a 1-year randomized controlled trial of Homing in on Health (HIOH), a Chronic Disease Self-Management Program variant, addressing these limitations. METHODS: We randomized outpatients (N = 415) aged 40 years and older and who had 1 or more of 6 common chronic illnesses, plus functional impairment, to HIOH delivered in homes or by telephone for 6 weeks or to usual care. Primary outcomes were the Medical Outcomes Study 36-ltem short-form health survey's physical component (PCS-36) and mental component (MCS-36) summary scores. Secondary outcomes included the EuroQol EQ-5D and visual analog scale (EQ VAS), hospitalizations, and health care expenditures. RESULTS: Compared with usual care, HIOH delivered in the home led to significantly higher illness management self-efficacy at 6 weeks (effect size = 0.27; 95% CI, 0.10-0.43) and at 6 months (0.17; 95% CI, 0.01-0.33), but not at 1 year. In-home HIOH had no significant effects on PCS-36 or MCS-36 scores and led to improvement in only 1 secondary outcome, the EQ VAS (1-year effect size = 0.40; CI, 0.14-0.66). HIOH delivered by telephone had no significant effects on any outcomes. CONCLUSIONS: Despite leading to improvements in self-efficacy comparable to those in other CDSMP studies, in-home HIOH had a limited sustained effect on only 1 secondary health status measure and no effect on utilization. These findings question the cost-effectiveness of peer-led illness self-management training from the health system perspective.

Self-report adherence measures in chronic illness: retest reliability and predictive validity.

BACKGROUND: Patient self-report is a practical method for measuring adherence, but little is known about its optimal use. OBJECTIVES: To examine the retest reliability and predictive validity of 3 different types of self-report adherence measures among patients with common chronic illnesses. RESEARCH DESIGN: Correlation and regression analyses of data from an ongoing randomized controlled trial. SUBJECTS: Patients (N = 415) aged >or=40 years recruited from a primary care network with arthritis, asthma, chronic lung disease, congestive heart failure, depression, and/or diabetes mellitus, plus impairment in >or=1 basic activity and/or a score of >or=4 on the 10-item Center for Epidemiologic Studies Depression Scale. MEASURES: : Self-report adherence (administered variously at baseline, 2, 4, and 6 weeks, and 6 months): number of pills taken/number of pills prescribed (PT/PP), using 1-7 days recall, and global reports of medication adherence and overall adherence tendencies. Six-month functional outcomes: Health Assessment Questionnaire (HAQ) and Short Form-36 (SF-36). RESULTS: Correlation coefficients among contemporaneously administered 1-7 days PT/PP measures were >or=0.78. Correlations among PT/PP measures and global adherence measures, and among PT/PP measures at 2 and 4 weeks, ranged from 0.11 to 0.54. PT/PP measures using >or=3-4 days recall significantly predicted adjusted 6-month HAQ but not SF-36 score. CONCLUSIONS: Self-report PT/PP and general medication adherence measures tap different behavioral constructs. Self-reported PT/PP at a given point in time is not necessarily representative of medication adherence over time. Among chronically ill patients, 3-4 days recall of PT/PP yield adherence estimates, which are practically as reliable and valid as longer intervals and which predict functional outcomes.

Depressive symptoms moderated the effect of chronic illness self-management training on self-efficacy.

BACKGROUND: Identifying moderators of the effects of self-efficacy enhancing interventions could facilitate their refinement and more targeted, cost-effective delivery. Current theories and data concerning the potential moderating effect of depressive symptoms on interventions to enhance patient chronic illness self-management self-efficacy are conflicting. OBJECTIVES: To explore the moderating effect of depressive symptoms on the effect of an intervention to enhance patient self-efficacy for self-managing chronic illness. RESEARCH DESIGN: Regression analyses using baseline and postintervention (6 weeks) data from an ongoing randomized controlled trial. SUBJECTS: Patients (N = 415) aged >or=40 years recruited from a primary care network in Northern California with arthritis, asthma, chronic obstructive pulmonary disease, congestive heart failure, depression, and/or diabetes mellitus, plus impairment in >or=1 basic activity, and/or a score of >or=4 on the 10-item Center for Epidemiologic Studies Depression Scale (CES-D). MEASURES: Stanford self-efficacy scale, self-reported depression, CES-D, and Medical Outcomes Study Short Form health status questionnaire (SF-36) Mental Component Summary score. RESULTS: Regression analyses revealed the intervention was effective primarily in those with self-reported depression (interaction effect F = 8.24, P = 0.0003), highest CES-D score category (F = 5.68, P = 0.0037), and lowest (most depressed) Mental Component Summary-36 tercile (F = 4.36, P = 0.0135). CONCLUSIONS: Individuals with more depressive symptoms seem more likely to experience self-efficacy gains from chronic illness self-management training than individuals with less depressive symptoms. Future self-management training studies should stratify subjects within study groups by depressive symptom level to further explore its potential moderating effect.

Communicating evidence in clinical documentation.

BACKGROUND/AIM: The purpose of this study was to examine occupational therapy practitioners' and stakeholders' opinions, perceptions, and attitudes towards communicating evidence in patient documentation. Moreover, it sought to establish relationships between factors that affect the use of evidence in documentation. METHODS: A mixed method design was used and two distinct surveys were created by the researchers in order to collect the data. In the first survey, occupational therapy practitioners in the Midwestern region of the USA completed an electronic survey. The second, a Delphi survey, was sent to other stakeholders such as case managers, rehabilitation supervisors, and payers. RESULTS: There were 126 surveys returned and analysed (29% response rate). Data revealed that 63.5% of practitioners believed in communicating evidence in documentation. Clinicians of all education levels agree that practitioners should communicate the evidence when funding is at stake (χ(2) (6, N = 110) = 15.97, P = 0.014). Participants also agreed that evidence should be communicated when dictated by their department (χ(2) (2, N = 110) = 6.25, P = 0.012).

Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1.

PURPOSE: To assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of mapatumumab (HGS-ETR1, TRM-1), a fully human agonist monoclonal antibody directed to the tumor necrosis factor-related apoptosis-inducing ligand receptor-1 (TRAIL-R1). PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of mapatumumab intravenously (IV) administered over 30 to 120 minutes, initially as a single dose and then repetitively. Plasma mapatumumab concentrations were measured and serum was assayed to detect human antimapatumumab antibody formation. Archival tumor specimens were collected to detect the presence of TRAIL-R1 by immunohistochemistry. RESULTS: Forty-nine patients received 158 courses at doses ranging from 0.01 to 10 mg/kg IV. Initially, patients received mapatumumab as a single dose, then every 28 days repetitively, and then 10 mg/kg every 14 days. Mild (grade 1 or 2) fatigue, fever, and myalgia were the most frequently reported nonhematologic adverse events related to mapatumumab, whereas hematologic toxicity was not clinically significant. The mean (+/- standard deviation) clearance and terminal elimination half-life values for mapatumumab at 10 mg/kg every 14 days were 3.7 mL/d/kg (+/- 1.5 mL/d/kg) and 18.8 days (+/- 10.1 days), respectively. TRAIL-R1 was documented in 68% of patients' tumors assayed. Nineteen patients had stable disease, with two lasting 9 months. CONCLUSION: Mapatumumab can be administered safely and feasibly at 10 mg/kg IV every 14 days. The absence of severe toxicities and the attainment of plasma mapatumumab concentrations that are active in preclinical models warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.