Scaling of the surface vasculature on the human placenta.

The networks of veins and arteries on the chorionic plate of the human placenta are analyzed in terms of Voronoi cells derived from these networks. Two groups of placentas from the United States are studied: a population cohort with no prescreening, and a cohort from newborns with an elevated risk of developing autistic spectrum disorder. Scaled distributions of the Voronoi cell areas in the two cohorts collapse onto a single distribution, indicating common mechanisms for the formation of the complete vasculatures, but which have different levels of activity in the two cohorts.

Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation.

Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.

The Kaiser Permanente Northern California research program on genes, environment, and health (RPGEH) pregnancy cohort: study design, methodology and baseline characteristics.

BACKGROUND: Exposures during the prenatal period may have lasting effects on maternal and child health outcomes. To better understand the effects of the in utero environment on children's short- and long-term health, large representative pregnancy cohorts with comprehensive information on a broad range of environmental influences (including biological and behavioral) and the ability to link to prenatal, child and maternal health outcomes are needed. The Research Program on Genes, Environment and Health (RPGEH) pregnancy cohort at Kaiser Permanente Northern California (KPNC) was established to create a resource for conducting research to better understand factors influencing women's and children's health. Recruitment is integrated into routine clinical prenatal care at KPNC, an integrated health care delivery system. We detail the study design, data collection, and methodologies for establishing this cohort. We also describe the baseline characteristics and the cohort's representativeness of the underlying pregnant population in KPNC. METHODS: While recruitment is ongoing, as of October 2014, the RPGEH pregnancy cohort included 16,977 pregnancies (53 % from racial and ethnic minorities). RPGEH pregnancy cohort participants consented to have blood samples obtained in the first trimester (mean gestational age 9.1 weeks ± 4.2 SD) and second trimester (mean gestational age 18.1 weeks ± 5.5 SD) to be stored for future use. Women were invited to complete a questionnaire on health history and lifestyle. Information on women's clinical and health assessments before, during and after pregnancy and women and children's health outcomes are available in the health system's electronic health records, which also allows long-term follow-up. DISCUSSION: This large, racially- and ethnically-diverse cohort of pregnancies with prenatal biospecimens and clinical data is a valuable resource for future studies on in utero environmental exposures and maternal and child perinatal and long term health outcomes. The baseline characteristics of RPGEH Pregnancy Cohort demonstrate that it is highly representative of the underlying population living in the broader community in Northern California.

Maternal mid-pregnancy C-reactive protein and risk of autism spectrum disorders: the early markers for autism study.

Maternal pregnancy levels of the inflammatory marker C-reactive protein (CRP) has been previously associated with autism spectrum disorder (ASD) in the offspring. We conducted a population-based nested case-control study with 500 children with ASD, 235 with developmental delay (DD) and 580 general population (GP) controls to further investigate whether elevated CRP during pregnancy increases the risk of ASD. Maternal CRP concentration was measured in archived serum collected during 15-19 weeks of pregnancy and genome-wide single-nucleotide polymorphism (SNP) data were generated. The levels of CRP were compared between ASD vs GP and DD vs GP. The genetic associations with CRP were assessed via linear regression. Maternal CRP levels in mid-pregnancy were lower in mothers of ASD compared with controls. The maternal CRP levels in the upper third and fourth quartiles were associated with a 45 and 44% decreased risk of ASD, respectively. Two SNPs at the CRP locus showed strong association with CRP levels but they were not associated with ASD. No difference was found between maternal CRP levels of DD and controls. The reasons for the lower levels of CRP in mothers of ASD are not known with certainty but may be related to alterations in the immune response to infectious agents. The biological mechanisms underlying this association remain to be clarified.

Increased female autosomal burden of rare copy number variants in human populations and in autism families.

Autosomal genetic variation is presumed equivalent in males and females and makes a major contribution to disease risk. We set out to identify whether maternal copy number variants (CNVs) contribute to autism spectrum disorders (ASDs). Surprisingly, we observed a higher autosomal burden of large, rare CNVs in females in the population, reflected in, but not unique to, ASD families. Meta-analysis across control data sets confirms female excess in CNV number (P=2.1 × 10(-5)) and gene content (P=4.1 × 10(-3)). We additionally observed CNV enrichment in ASD mothers compared with control mothers (P=0.03). We speculate that tolerance for CNV burden contributes to decreased female fetal loss in the population and that ASD-specific maternal CNV burden may contribute to high sibling recurrence. These data emphasize the need for study of familial CNV risk factors in ASDs and the requirement of sex-matched comparisons.

Determining source strength of semivolatile organic compounds using measured concentrations in indoor dust.

UNLABELLED: Consumer products and building materials emit a number of semivolatile organic compounds (SVOCs) in the indoor environment. Because indoor SVOCs accumulate in dust, we explore the use of dust to determine source strength and report here on analysis of dust samples collected in 30 US homes for six phthalates, four personal care product ingredients, and five flame retardants. We then use a fugacity-based indoor mass balance model to estimate the whole-house emission rates of SVOCs that would account for the measured dust concentrations. Di-2-ethylhexyl phthalate (DEHP) and di-iso-nonyl phthalate (DiNP) were the most abundant compounds in these dust samples. On the other hand, the estimated emission rate of diethyl phthalate is the largest among phthalates, although its dust concentration is over two orders of magnitude smaller than DEHP and DiNP. The magnitude of the estimated emission rate that corresponds to the measured dust concentration is found to be inversely correlated with the vapor pressure of the compound, indicating that dust concentrations alone cannot be used to determine which compounds have the greatest emission rates. The combined dust-assay modeling approach shows promise for estimating indoor emission rates for SVOCs. PRACTICAL IMPLICATIONS: The combined dust-assay modeling approach in this study can be used to predict the source strength of indoor released compounds, integrating emissions from consumer products, building materials, and other home furnishings. Our findings show that estimated emission rates are closely related to not only the level of compounds on dust, but also the vapor pressure of the compound. Thus, a fugacity-based indoor mass balance model and measured dust concentrations can be used to estimate the whole-house emission rates from all sources in actual indoor settings, when individual sources of emissions are unknown.

Congenital abnormalities among children with cerebral palsy: More evidence for prenatal antecedents.

OBJECTIVES: To investigate the association between cerebral palsy (CP) and congenital abnormalities among children with very low, low, and normal birth weight. STUDY DESIGN: A population-based, case-control study among the cohort of 155,636 live births delivered between 1983 and 1985 in 4 California counties. Children with moderate or severe congenital CP (n = 192) diagnosed by age 3 were identified from 2 California State service agencies, and 551 control children were randomly sampled from birth certificate files. Information on congenital abnormalities diagnosed by the age of 1 year was obtained from the California Birth Defects Monitoring Program registry. Odds ratios (OR) and 95% CIs were calculated to estimate risk for CP associated with congenital abnormalities. RESULTS: Among singletons, congenital abnormalities were present in 33 (19.2%) children with CP and 21 (4.3%) control children (OR = 5.2, 95% CI 2.8-9.7). For each birth weight group, the percent of children with congenital abnormalities among children with CP exceeded that among control children. Structural abnormalities of the central nervous system were more common among children with CP (OR = 16.2, 95% CI 5.8-49.3) than control children. In contrast, the percent of children with non-central nervous system abnormalities only was similar between case patients and control subjects. CONCLUSION: These findings provide further evidence that factors operating in the prenatal period contribute significantly to the etiology of CP.

The epidemiology of mental retardation of unknown cause.

OBJECTIVE: To describe selected infant and maternal characteristics for children with mild and severe mental retardation (MR) of unknown cause. STUDY DESIGN: Children with MR of unknown cause born in California between 1987 and 1994 were identified through service agency records and compared with the total population of California live births for selected characteristics recorded on the birth certificate. RESULTS: For both children with mild and severe MR, risk was increased among males, low birth weight children, and children born to women of black race, older age at delivery, and lower level of education. Increased risk for mild MR was found for multiple births, second or later-born children, and children whose mothers were born outside of California. Increased risk for severe MR was observed among children born to Hispanic mothers; children born to Asian mothers also had increased risk for severe MR but decreased risk for mild MR. CONCLUSIONS: These results provide clues for understanding the underlying causes of MR and suggest that both biological and social factors are important.

Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation.

There has been little exploration of major biologic regulators of cerebral development in autism. In archived neonatal blood of children with autistic spectrum disorders (n = 69), mental retardation without autism (n = 60), or cerebral palsy (CP, n = 63) and of control children (n = 54), we used recycling immunoaffinity chromatography to measure the neuropeptides substance P (SP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP), and the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4/5 (NT4/5). Neonatal concentrations of VIP, CGRP, BDNF, and NT4/5 were higher (ANOVA, all p values < 0.0001 by Scheffe test for pairwise differences) in children in the autistic spectrum and in those with mental retardation without autism than in control children. In 99% of children with autism and 97% with mental retardation, levels of at least one of these substances exceeded those of all control children. Concentrations were similar in subgroups of the autistic spectrum (core syndrome with or without mental retardation, other autistic spectrum disorders with or without mental retardation) and in the presence or absence of a history of regression. Among children with mental retardation, concentrations did not differ by severity or known cause (n = 11, including 4 with Down syndrome). Concentrations of measured substances were similar in children with CP as compared with control subjects. SP, PACAP, NGF, and NT3 were not different by diagnostic group. No measured analyte distinguished children with autism from children with mental retardation alone. In autism and in a heterogeneous group of disorders of cognitive function, overexpression of certain neuropeptides and neurotrophins was observed in peripheral blood drawn in the first days of life.

Maternal exposure to nitrate from drinking water and diet and risk for neural tube defects.

In this population-based case-control study conducted in California between June 1989 and May 1991, the authors investigated the association between maternal periconceptional exposure to nitrate from drinking water and diet and risk for neural tube defects. The mothers of 538 cases and 539 nonmalformed controls were interviewed regarding residential history, consumption of tap water at home, and dietary intake during the periconceptional period. Dietary nitrate exposure was not associated with increased risk for neural tube defects. Exposure to nitrate in drinking water at concentrations above the 45 mg/liter maximum contaminant level was associated with increased risk for anencephaly (odds ratio (OR) = 4.0, 95% confidence interval (CI): 1.0, 15.4), but not for spina bifida. Increased risks for anencephaly were observed at nitrate levels below the maximum contaminant level among groundwater drinkers only (OR = 2.1, 95% CI: 1.1,4.1 for 5-15 mg/liter; OR = 2.3, 95% CI: 1.1, 4.5 for 16-35 mg/liter; and OR = 6.9, 95% CI: 1.9, 24.9 for 36-67 mg/liter compared with <5 mg/liter). Adjustment for identified risk factors for anencephaly did not substantially alter these associations, nor did control for maternal dietary nitrate, total vitamin C intake, and quantity of tap water consumed. The lack of an observed elevation in risk for anencephaly in association with exposure to mixed water containing nitrate at levels comparable with the concentration in groundwater may indicate that something other than nitrate accounts for these findings.

Periconceptional intake of vitamin supplements and risk of multiple congenital anomalies.

Numerous studies have reported reduced risks for a variety of single congenital anomaly phenotypes associated with maternal periconceptional use of vitamin supplements containing folic acid. Here we investigated whether periconceptional use of vitamin supplements containing folic acid by women altered their risk for delivering infants with multiple congenital anomalies (MCAs). Data were derived from a case-control study representing deliveries (fetal deaths and infants) from 2 California counties between January 1993 and July 1996. MCAs were defined as 2 or more congenital anomalies affecting more than one organ system or a major anomaly in combination with 2 minor anomalies. Controls were randomly selected from nonmalformed live-born infants. Telephone interviews were conducted with 112 (73.7% of eligible) case and 195 (78.0% of eligible) control mothers. Compared to women who did not use multivitamin supplements containing folic acid in the period 3 months before through 3 months after conception, women who used in this time period were observed to have an elevated risk to deliver fetuses or infants with MCAs, odds ratio = 2.6 (95% confidence interval 1.1-6.2). This elevated risk was not substantially altered (adjusted odds ratio = 2.9 [0.8-10.3]) by adjusting for maternal race/ethnicity, education, gravidity, body mass index, alcohol consumption, and cigarette smoking. No particular organ system seemed to be uniquely represented among the MCA fetuses and infants whose mothers used vitamin supplements. The observed elevated risk associated with maternal vitamin use is considered to be preliminary and needs to be replicated in other populations.

Holoprosencephaly: molecular study of a California population.

Holoprosencephaly (HPE) is a common developmental anomaly of the forebrain and midface in which the cerebral hemispheres fail to separate into distinct left and right halves. HPE is extremely heterogeneous. In addition to teratogenic agents, several genes are implicated in the cause of HPE. Using samples from a population-based birth defects registry in California, we performed a mutational analysis of the known HPE genes Sonic Hedgehog (SHH), ZIC2, and SIX3, in addition to two HPE candidate genes, TG-interacting factor (TGIF), and Patched (PTC), on a group of sporadic HPE patients. This is the first molecular study of HPE in a population-based sample of patients. Among these patients, a deletion in the homeodomain of SIX3 and several polymorphisms in SIX3 and TGIF were identified. No sequence changes were detected in SHH, ZIC2, and PTC. Our results suggest that mutations in the currently recognized HPE genes may explain <5% of all sporadic HPE cases.

Risk factors for cytogenetically normal holoprosencephaly in California: a population-based case-control study.

Holoprosencephaly is a developmental field defect manifested by a spectrum of abnormalities of the forebrain and midface. Approximately 50% of holoprosencephaly cases are associated with a cytogenetic abnormality or a monogenic syndrome. Suggested risk factors for the remaining 50% of cases have been described in case reports, but have not been confirmed in systematically conducted studies. We report the results of a population-based case-control study of holoprosencephaly. Live births, fetal deaths, and terminations with a diagnosis of cytogenetically normal holoprosencephaly were identified by the California Birth Defects Monitoring Program. Telephone interviews were conducted with the mothers of 58 cases and 107 live born, nonmalformed controls. Women were questioned about their health and reproductive histories, family demographics, and exposures occurring during their pregnancies. Among nonsyndromic cases, increased risks were observed for females (OR=1.8, 95% C.I. 0.9-3.9), foreign-born vs. U.S. or Mexico-born women (OR=3.1, 95% C.I. 1.1-8.6), and women with early menarche (OR=2.3, 95% C.I. 0.9-5.7). Maternal periconceptional exposures associated with increased risks for nonsyndromic holoprosencephaly included alcohol consumption (OR=2.0, 95% C.I. 0.9-4.5), cigarette smoking (OR=4.1, 95% C.I. 1.4-12.0), and combined alcohol and smoking (OR=5.4, 95% C.I. 1.4-20.0), insulin-dependent diabetes (OR=10.2, 95% C.I. 1.9-39.4), medications for respiratory illnesses (OR=2.3, 95% C.I. 0.9-6.0), and salicylate-containing medications (OR=2.5, 95% C.I. 0.8-7.9). These findings are consistent with risk factors identified in some previous reports, and identify several new potential risk factors that require confirmation in future studies.

Racial and ethnic variations in the prevalence of orofacial clefts in California, 1983-1992.

To investigate variations in the prevalence of oral cleft anomalies according to parental race and ethnicity and maternal country of birth, the authors analyzed a cohort of 2,221,755 live births and fetal deaths delivered between 1983 and 1992 to residents of California. A total of 2,329 cleft lip with or without cleft palate (CL +/- P) cases and 1,475 cleft palate alone (CP) cases were identified by the California Birth Defects Monitoring Program, a population-based registry. Compared to Whites, the prevalence of CL +/- P was lower among African Americans (prevalence ratio (PR) = 0.56, 95% confidence interval (CI) = 0.45-0.69), higher among Native Americans (PR = 1.81, CI = 1.20-2.69), and the same among the Japanese (PR = 1.07, CI = 0.62-1.82) and Chinese (PR = 0.96, CI = 0.71-1.29). The risk of CL +/- P was slightly lower among the offspring of foreign-born Chinese women relative to U.S.-born Chinese women (PR = 0.71, CI = 0.33-1.57), and slightly higher among foreign-born Filipinos relative to their U.S.-born counterparts (PR = 1.37, CI = 0.57-3.53), although confidence intervals around these risk estimates were wide owing to sparse data. For CP, lower prevalences were observed among African Americans (PR = 0.72, CI = 0.58-0.91) and Hispanics (PR = 0.77, CI = 0.67-0.87) than among Whites. The risk of CP was higher among foreign-born Filipinos compared to U.S.-born Filipinos (PR = 1.52, CI = 0.58-4.33), although the confidence interval around this estimate included unity. These prevalence variations may reflect differences in both environmental and genetic factors affecting clefting risk.

Maternal residential proximity to hazardous waste sites and risk for selected congenital malformations.

Using data from two population-based case-control studies, we investigated whether maternal residential proximity to hazardous waste sites increased the risk for neural tube defects, conotruncal heart defects, and oral cleft defects in California. We obtained a residential history by interview for mothers of 507 neural tube defect cases (82.7% of eligible) and their 517 controls (84.6%); and 201 heart cases (84.4%), 439 cleft cases (82.2%), and their 455 controls (72.1%). We identified the locations of 764 inactive hazardous waste sites and systematically collected information on site-related contamination for the subset of 105 National Priority List sites. After controlling for several potential confounders, we found little or no increased risk for maternal residence in a census tract containing a site [odds ratio (OR) = 0.9, 95% confidence interval (CI) = 0.7-1.3 for neural tube defects; OR = 1.3, 95% CI = 0.8-2.1 for heart cases; OR = 1.2, 95% CI = 0.8-1.8 for clefts], but elevated risks for neural tube defects (OR = 2.1, 95% CI = 0.6-7.6) and heart defects (OR = 4.2, 95% CI = 0.7-26.5) for maternal residence within 1/4 mile of a National Priority List site. Furthermore, we observed elevated ORs (> or = 2.0) for neural tube defects and heart defects in association with maternal residence within 1 mile of National Priority List sites containing selected chemical contaminants. Among controls, only 0.6% and 4.4% lived within 1/4 mile and 1 mile of a National Priority List site, respectively, resulting in imprecision in risk estimation.

A longitudinal study of substance use and abuse in a single class of medical students.

PURPOSE: A longitudinal study to ascertain the attitudes toward, and habits of, substance use among a single class of medical students. METHOD: A single class from a northeastern medical school was surveyed in both its first year (February 1991, 176 students) and its third year (May 1993, 170 students). The students were asked to report how frequently during the prior year they had used drugs or alcohol, and whether their use of each substance had increased, decreased, or remained the same since entering medical school; to identify any family members with histories of alcohol or drug problems; and to report any incidence during the prior year of ten behaviors associated with substance dependence. The students were also asked to indicate their agreement or disagreement with 11 attitudinal statements. Additional attitudinal items asked the students to identify three major deterrents to the abuse of drugs and alcohol, and what they had done if they had become aware of a classmate with a drug or alcohol problem. Chi-square analysis and two-tailed t-tests were used to compare data from the two surveys. RESULTS: The response rates in the first and second surveys were 96.9% and 81.8%, respectively. Use of licit and illicit substances was comparable to that of chronological peers and prior national studies of medical trainees. Most of the students admitted to using alcohol at least once in the prior year (91.8% and 95%, respectively). In both years marijuana was the illicit drug used most often. Although there was a slight increase over time in the use of benzodiazepines (2.4% to 5.8%) and a decrease in the use of marijuana (29.4% to 21.7%), these changes were not significant. Few of the students in their third year reported using any substance other than alcohol more than once a month. In general, a greater percentage of the students reported a decrease rather than an increase in the use of a substance since entering medical school; the primary exception was for wine. As they progressed in their training, the students became less concerned about the effect of substance use on their performance and more likely to be embarrassed about admitting to an addiction. Although in each year a few of the students appeared to be at risk for substance dependence (8.9% and 3.5%, respectively), no student came to the attention of the administration because of problems related to substance use. While most of the students were unaware of any classmate who had a problem, half of those who were aware had done nothing, and the balance had rarely sought assistance from the faculty or administration. CONCLUSION: Although there was no evidence that substance use was a major problem, a few of the students appeared to be at risk for drug or alcohol dependence. Appropriate intervention, support, and referral systems should be identified for the few who may be at risk, and increased educational efforts are needed to help all students address this issue with their peers and, ultimately, with their patients.

Holoprosencephaly: epidemiologic and clinical characteristics of a California population.

Holoprosencephaly is a brain defect resulting from incomplete cleavage of the embryonic forebrain. It involves forebrain and facial malformations that can range from mild to severe. The epidemiology of holoprosencephaly is largely unknown. Published prevalence estimates have been derived from clinic-based case series, and suggested risk factors for holoprosencephaly have been identified in case reports, without confirmation from systematically conducted population-based studies. Using data from a population-based birth defects registry in California, we describe the epidemiologic and clinical characteristics of cytogenetically and phenotypically distinct types of holoprosencephaly. A total of 121 cases was identified among a cohort of 1,035,386 live births and fetal deaths. The prevalence of holoprosencephaly was 1.2 per 10,000 births (95% confidence interval 1.0-1.4 per 10,000). Of all cases, 41% (50/121) had a chromosomal abnormality, most commonly Trisomy 13. Among the 71 cytogenetically apparently normal cases, 18 had recognizable syndromes and the remaining 53 were of unknown cause. Among the cytogenetically abnormal cases, females had a greater risk than males (odds ratio = 2.3,95% confidence interval [1.2, 4.4]). Among the cytogenetically normal cases, increased risks were observed among Hispanic whites (OR = 1.8 [0.9, 3.6]) and cases whose mother was born in Mexico (OR = 2.2 [1.0, 4.5]). Approximately 46% of all cases had alobar holoprosencephaly, the most severe form of the forebrain malformation. The facial phenotype did not strongly predict the severity of the brain defect; however, severity was inversely correlated with length of survival. This study is the first to present findings based on such a large population-based series of infants/fetuses affected by holoprosencephaly, and demonstrates the importance of investigating the component subgroups of this rare phenotype.

Young maternal age and congenital malformations: a population-based study.

This study examined the prevalence of congenital malformations across the maternal age spectrum and identified specific malformation types that contributed to the overall prevalence among mothers under the age of 20 years. Data were derived from the California Birth Defects Monitoring Program for 1983 through 1988 live births. The distribution of prevalences of all nonchromosomal malformations was U-shaped across maternal age. Furthermore, several specific malformation types, representing nearly every organ system, were elevated among the infants of women under 20 years of age in comparison with those of women 25 to 29 years old.

Pilot-testing a holistic approach to scoring performance on standardized-patient examinations.

BACKGROUND: Scoring protocols for most standardized-patient (SP) examinations have not received extensive scrutiny and their validity has not been well established. METHOD: A holistic method (i.e., one based on raters' overall impressions) of scoring performance on an SP examination was pilot-tested in the spring of 1992 by administering an examination to two cohorts of fourth-year students at the Albert Einstein College of Medicine at Yeshiva University. The examination consisted of eight SP stations, representing a range of medical problems. Two to three experienced clinical teachers independently reviewed all the written material for each encounter. In Phase I of the study, holistic ratings of outstanding, competent, marginal, or inadequate were given for overall clinical competence for a cohort of 16 students; in Phase II, holistic ratings were given separately for data-gathering and communication skills for a cohort of 26 students. Intercase and interrater reliability analyses were performed. RESULTS: Adequate reliability coefficients were obtained on a two-hour test; total scores (i.e., students' scores across all eight cases) discriminated between groups of examinees; and, on average, less than two minutes were required to score an encounter. CONCLUSION: Although based on a small sample, the study's results suggest that this holistic method of scoring performance may be useful in some situations. Since experienced clinical teachers know and agree about clinical competence when they see it, developers of scoring protocols for SP examinations need to establish that the results obtained are congruent with the judgments of expert teachers.