Suggested statistical standards for NTT manuscripts: notes from two of your reviewers.

The purpose of a scientific paper in this journal is to persuade the reader of some important or potentially important facts. For a reader to be persuaded, first the manuscript reviewers must be persuaded, and if the manuscript involves statistical reasoning, at least one of those reviewers is likely to be a statistician. This invited article, by two long-time reviewers for Neurotoxicology and Teratology (NTT) who are also contributors of statistical papers, surveys some of the principles that render a manuscript more persuasive or less persuasive in our eyes. These principles are overwhelmingly not statistical but logical. For one typical NTT manuscript theme, the relation between some toxic exposure and one or more negative outcomes in humans, the aspects of manuscripts we scrutinize most closely include biological plausibility, dose-response relationships, breadth of evidence, adjustments for measurement bias, attention to assumptions and scatterplots in the search for confounds, and, in general, a sincere attempt to enunciate and then refute plausible hypotheses rival to the one the investigators prefer. The literature of excellent studies in other fields provides ample instances of good practice in these matters; we review it in those fields for applications in ours. Formal statistical significance testing plays almost no role in the most persuasive papers. In particular, findings that appear only after "adjustment for covariates" are never considered credible by these reviewers; we explain our reasons at length, and suggest alternatives.

Geometric morphometrics of corpus callosum and subcortical structures in the fetal-alcohol-affected brain.

BACKGROUND: Although experienced clinicians have been diagnosing fetal alcohol syndrome (FAS) for nearly 30 years, the rest of the spectrum of fetal alcohol damage is not being classified effectively. This article describes a quantification of neuroanatomical structure that may supply a useful discriminator of prenatal brain damage from alcohol. It is demonstrated in a data set of adults of both sexes. METHODS: Ninety adults (45 males) were examined by magnetic resonance imaging (MRI). These subjects were group-matched for age and ethnicity across three diagnoses: FAS, fetal alcohol effects (FAE), and normals. All FAS and FAE were heavily alcohol-exposed in utero; normals were not. From T(1)-weighted MR brain images, we extracted 3D morphometric representations of shape for 33-landmark point configurations and 40-point outlines of the corpus callosum along its midline (a slightly nonplanar structure). RESULTS: There are striking differences between exposed and unexposed in the statistical distributions of these two shapes. The differences are better characterized by excess variance in the exposed group than by any change in average landmark or outline shape. For each sex, combining the callosal outline data with the landmark data leads to a powerful quadratic discriminator of exposed from unexposed. The discriminating features include the relationship of brain stem to diencephalon, and localized variabilities of callosal outline shape, but not diagnosis (FAS vs. FAE). CONCLUSIONS: Statistical analysis of brain shape is a powerful new source of information relevant to fetal alcohol spectrum nosology and etiology. Patients with FAS and FAE do not differ in these brain shape features, but both differ from the unexposed. The aspects of brain shape that are especially variable may be entailed in the underlying neuroteratogenetic mechanisms.

On categorizations in analyses of alcohol teratogenesis.

In biomedical scientific investigations, expositions of findings are conceptually simplest when they comprise comparisons of discrete groups of individuals or involve discrete features or characteristics of individuals. But the descriptive benefits of categorization become outweighed by their limitations in studies involving dose-response relationships, as in many teratogenic and environmental exposure studies. This article addresses a pair of categorization issues concerning the effects of prenatal alcohol exposure that have important public health consequences: the labeling of individuals as fetal alcohol syndrome (FAS) versus fetal alcohol effects (FAE) or alcohol-related neurodevelopmental disorder (ARND), and the categorization of prenatal exposure dose by thresholds. We present data showing that patients with FAS and others with FAE do not have meaningfully different behavioral performance, standardized scores of IQ, arithmetic and adaptive behavior, or secondary disabilities. Similarly overlapping distributions on measures of executive functioning offer a basis for identifying alcohol-affected individuals in a manner that does not simply reflect IQ deficits. At the other end of the teratological continuum, we turn to the reporting of threshold effects in dose-response relationships. Here we illustrate the importance of multivariate analyses using data from the Seattle, Washington, longitudinal prospective study on alcohol and pregnancy. Relationships between many neurobehavioral outcomes and measures of prenatal alcohol exposure are monotone without threshold down to the lowest nonzero levels of exposure, a finding consistent with reports from animal studies. In sum, alcohol effects on the developing human brain appear to be a continuum without threshold when dose and behavioral effects are quantified appropriately.

Direct and indirect effects of prenatal alcohol damage on executive function.

Patients with Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Effects (FAE) often have difficulty functioning appropriately in everyday life and seem to employ poor problem-solving strategies. Tests of executive function are relevant for quantifying the functional deficits and underlying real-life problems associated with prenatal alcohol exposure. This study considers two pathways for the effects of prenatal alcohol on executive function: a direct effect and an indirect effect through prenatal alcohol's effect on IQ. We compared 30 men who had been diagnosed with FAS or FAE with young adults participating in a longitudinal prospective study (n = 419) and 15 control participants that comprised a comparison group. This study is unique in its analysis of the same battery of assessments of executive function in both a large low dose longitudinal study sample and a clinically diagnosed group. Participants were evaluated on 9 tests (including 58 scores) of executive function. For some but not all of the tests in this executive function battery, the decrement in the alcohol exposure group is greater than would be predicted from their IQ scores. We found that 3 of 6 Stroop scores, 2 of 4 Trails scores, 9 of 16 Wisconsin Card Sorting scores, 1 of 2 Ruff's Figural Fluency scores, and 2 of 4 Consonant Trigrams scores appear to be particularly sensitive to the direct effects of prenatal alcohol damage for patients with FAS and FAE. The findings suggest that these executive function tests would be particularly useful in clinical evaluations of persons suspected of fetal alcohol damage because they would not simply reflect deficits in IQ or facial stigmata.

Prenatal cocaine and neuromotor outcome at four months: effect of duration of exposure.

The effect of prenatal cocaine exposure on the motor development of full-term infants was examined in a prospective study, controlling for maternal characteristics and exposure to other substances. Intrauterine cocaine exposure was determined at birth by maternal self-report and was verified by hair analysis. At 4 months, 120 cocaine-exposed (COC) and 186 non-cocaine-exposed (NON-COC) infants were assessed by blinded examiners using a standard evaluation of neuromotor function, the Movement Assessment of Infants (MAI). Relative to NON-COC infants, COC infants had significantly higher full-scale MAI total risk scores after adjusting for covariates (p = .05). Infants exposed through the third trimester of pregnancy (n = 48) had higher MAI scores for both total risk (p = .02) and Volitional Movement (p = .01), and when compared with infants exposed only within the first two trimesters (n = 72), they had significantly more deficits in Volitional Movement (p = .03). Although MAI scores for the majority of exposed infants were within the normal range, infants exposed through the third trimester were at significantly increased risk for motor dysfunction (relative risk = 1.6; 95% confidence interval = 1.1, 2.8). Intrauterine cocaine exposure had an adverse effect on infant motor development after the neonatal period; this association was related to the timing and duration of gestational exposure. Further study is needed to evaluate the long-term clinical implications of neuromotor abnormalities in prenatally exposed infants.

Individual differences in auditory and visual attention among fetal alcohol-affected adults.

BACKGROUND: Deficits in attention are commonly identified among patients who have been prenatally exposed to alcohol, and they often affect the ability of the patients to function appropriately in society. METHODS: Eleven adult patients with fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE) were compared with nine adult subjects with no history of prenatal alcohol exposure, using four tests of visually and auditorially mediated attention. RESULTS: In relation to the comparison group, patients with FAS/FAE exhibited substantial deficits in both auditory and visual attention; the auditory deficits were greater. We observed two predominant patterns of deficits among patients with FAS/FAE, one involving both auditory and visual attention problems and the other involving less severe auditory problems and even fewer visual problems. Most subjects with FAS or FAE had some manifestations of attention problems in at least one of the tests of attention used in this study. We present a new graphical representation of individual auditory Continuous Performance Test data across a 6-min period, which, compared with conventional scores, more clearly reveals the markedly disrupted and variable attention patterns displayed by some individuals with FAS or FAE. CONCLUSIONS: These findings suggest that detailed analysis of the pattern of individual performance for each subject is an important aspect of Continuous Performance Test assessment. Our findings further suggest that intellectual performance (intelligence quotient score) alone is not sufficient to account for the patterns of disrupted attention for individuals with FAS/FAE. Assessment of individuals with FAS or FAE should include measurement of attentional functioning in both the visual and auditory modalities.

A preliminary statistical examination of the effects of uncertainty and variability on environmental regulatory criteria for ozone.

Basing the quantitative expression of environmental regulatory standards and associated compliance criteria on statistical principles has recently received attention in Europe, most visibly in a study by the UK Royal Commission on Environmental Pollution. These issues are timely for consideration in the USA, where a recent periodic review of National Ambient Air Quality Standards (NAAQS) has led to revision of the regulatory standards for ambient ozone and particulate matter. Salient statistical issues include accounting for errors of the first and second kind due to sampling and measurement error. These issues appear routine statistically and also may seem absent from regulations, but neither is necessarily the case. This paper is directed towards developing a methodology for examining the problem of dealing with uncertainty and variation in environmental regulations and compliance criteria. Our approach is illustrated through statistical analysis of the (old) 1 hour and the (new) 8 hour standards for ambient ozone, based on intensive monitoring in California's San Joaquin Valley during summer 1990 performed under the SARMAP Project. This paper presents preliminary findings based on quantifying measurement error or precision in terms of small-scale spatial and temporal variability, laying the groundwork for future work.

Prenatal alcohol exposure and family history of alcoholism in the etiology of adolescent alcohol problems.

OBJECTIVE: To examine the relative importance of prenatal alcohol exposure and family history of alcoholism for the prediction of adolescent alcohol problems. METHOD: In 1974-75, a population-based, longitudinal prospective study of alcohol and pregnancy began with self-report of alcohol use by pregnant women. In a 14-year follow-up, 439 parents provided information on the family history of alcohol problems for these adolescent offspring. The 14-year-old adolescents provided information on the frequency and quantity of their own alcohol consumption within the past month, on the consequences of their drinking over the past 3 years, and on their age at first intoxication. Additional covariates were assessed prenatally and at follow-up. RESULTS: Prenatal alcohol exposure was more predictive of adolescent alcohol use and its negative consequences than was family history of alcohol problems. Prenatal exposure retained a significant predictive effect even after adjustment for family history and other prenatal and environmental covariates. By contrast, the nominally significant correlation of family history with adolescent drinking is weaker after adjustment for prenatal alcohol exposure and disappears entirely after adjustment for other relevant covariates. We observed no evidence for an interactive effect of fetal exposure and family history in predicting adolescent alcohol use. CONCLUSIONS: Fetal alcohol exposure is a risk factor for adolescent alcohol involvement and alcohol-related problems and may account for variance in prediction of problems otherwise attributed to family history of alcoholism. Studies of alcoholism etiology and family history need to include consideration of even modest levels of fetal alcohol exposure.

A fetal alcohol behavior scale.

This research aimed to develop a Fetal Alcohol Behavior Scale (FABS) that describes the behavioral essence of fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE), regardless of age, race, sex, and IQ. Using a reference sample of 472 diagnosed patients with FAS or FAE, ages 2 to 51, five studies are described. The FABS demonstrates high item-to-scale reliability (Cronbach's alpha = 0.91) and good test-retest reliability (r = 0.69) over an average interval of 5 years. It identifies many of the subjects with known or presumed prenatal alcohol exposure in detection studies using both prison and general samples. FABS scores also predict dependent living among adult patients with FAS/FAE. The FABS is uncorrelated with IQ, sex, age, race, and diagnosis (FAS versus FAE). We outline areas of further work to define the specificity and utility of this FABS.

Neuropsychological deficits in adolescents with fetal alcohol syndrome: clinical findings.

Understanding the nature of cognitive deficits among adolescent patients with fetal alcohol syndrome (FAS) can direct future research on assessment and intervention. In an exploratory study, nine nonretarded teenagers with FAS were administered tests of IQ and adaptive behavior, and neuropsychological tests presumed sensitive to alcohol effects. Their performance was compared with psychometric norms and to data from a sample of 174 adolescents with minimal or no prenatal alcohol exposure. These nonretarded FAS patients commonly showed behavior problems, decreased social competence, and poor school performance. Neuropsychological testing revealed significant deficits, although no one neuropsychological profile characterized all patients and not all tests revealed problems. Relatively intact performance was observed in procedural memory, some measures of reaction time, and some reading measures. Deficits were seen on attentional and memory tasks tapping visual-spatial skills, short-term auditory attention and memory, declarative learning, and cognitive flexibility and planning. Difficulties in processing speed and accuracy were also seen. Comparison with a subgroup of 52 nonalcohol-exposed or minimally alcohol-exposed adolescents with a similar range of IQ scores demonstrated that deficits among these FAS patients were not fully explained by a general lowering of IQ.

Association of prenatal alcohol exposure with behavioral and learning problems in early adolescence.

OBJECTIVE: To examine the association of moderate levels of prenatal alcohol exposure with learning and behavior in early adolescence. METHOD: A population-based cohort of 464 children were followed longitudinally from birth to age 14 years. Alcohol exposure was assessed via in-depth maternal self-report in the fifth month of pregnancy. At age 14, learning and behavior were assessed with multiple measures, tapping parent, teenager, and psychologist viewpoints, drawn from adolescent laboratory examination and parent phone interview. The underlying pattern of association between prenatal alcohol and adolescent outcome was detected using partial least-squares statistical techniques; confounding factors were dealt with by regression methods. RESULTS: Analyses revealed a statistically significant, subtle relationship between greater prenatal alcohol use and increased behavior/learning difficulties during adolescence, even after accounting for other developmental influences. "Binge" maternal drinking and exposure early in pregnancy were associated with a profile of adolescent antisocial behavior, school problems, and self-perceived learning difficulties. CONCLUSIONS: Fetal alcohol exposure (even at "social drinking" levels) is associated with developmental difficulties in adolescence that are consistent with problems seen earlier in life. Clinicians should understand the potential role prenatal alcohol exposure plays in behavioral and cognitive problems.

Modelling non-stationary spatial covariance structure from space-time monitoring data.

Accurate interpolation of soil and climate variables at fine spatial scales is necessary for precise field management. Interpolation is needed to produce the input variables necessary for crop modelling. It is also important when deciding on regulations to limit environmental impacts from processes such as nitrate leaching. Non-stationarity may arise due to many factors, including differences in soil type, or heterogeneity in chemical concentrations. Many geostatistical methods make stationarity assumptions. Substantial improvements in interpolation or in the estimation of standard errors may be obtained by using non-stationary models of spatial covariances. This paper presents recent methodological developments for an approach to modelling non-stationary spatial covariance structure through deformations of the geographic coordinate system. This approach was first introduced by Sampson & Guttorp, although the estimation approach is updated in more recent papers. They compute a deformation of the geographic plane so that the spatial covariance structure can be considered stationary in terms of a new spatial coordinate system. This provides a non-stationary model for the spatial covariances between sampled locations and prediction locations. In this paper, we present a cross-validation procedure to avoid over-fitting of the sample dispersions. Results concerning the variability of the spatial covariance estimates are also presented. An example of the modelling of the spatial correlation field of rainfall at small regional scale is presented. Other directions in methodological development, including modelling temporally varying spatial correlation, and approaches to model temporal and spatial correlation are mentioned. Future directions for methodological development are indicated, including the modelling of multivariate processes and the use of external spatially dense covariables. Such covariates are frequently available in precision agriculture.

Incidence of fetal alcohol syndrome and prevalence of alcohol-related neurodevelopmental disorder.

We critique published incidences for fetal alcohol syndrome (FAS) and present new estimates of the incidence of FAS and the prevalence of alcohol-related neurodevelopmental disorder (ARND). We first review criteria necessary for valid estimation of FAS incidence. Estimates for three population-based studies that best meet these criteria are reported with adjustment for underascertainment of highly exposed cases. As a result, in 1975 in Seattle, the incidence of FAS can be estimated as at least 2.8/1000 live births, and for 1979-81 in Cleveland, approximately 4.6/1,000. In Roubaix, France (for data covering periods from 1977-1990), the rate is between 1.3 and 4.8/1,000, depending on the severity of effects used as diagnostic criteria. Utilizing the longitudinal neurobehavioral database of the Seattle study, we propose an operationalization of the Institute of Medicine's recent definition of ARND and estimate its prevalence in Seattle for the period 1975-1981. The combined rate of FAS and ARND is thus estimated to be at least 9.1/1,000. This conservative rate--nearly one in every 100 live births--confirms the perception of many health professionals that fetal alcohol exposure is a serious problem.

Prenatal alcohol and offspring development: the first fourteen years.

This report summarizes findings from a prospective longitudinal study of the effects of prenatal alcohol exposure on a birth cohort of 500 offspring selected from 1,529 consecutive pregnant women in prenatal care by mid-pregnancy at two representative community hospitals. Effects of prenatal alcohol observable on size measures at birth were insignificant after 8 months. Morphometric analysis of facial features identified effects only at the very highest alcohol exposure levels. By contrast, dose-dependent effects on neurobehavioral function from birth to 14 years have been established using partial least squares (PLS) methods jointly analysing multiple measures of both alcohol dose and outcome. Particularly salient effects included problems with attention, speed of information processing, and learning problems, especially arithmetic.

Prenatal alcohol exposure, birthweight, and measures of child size from birth to age 14 years.

OBJECTIVES: The purpose of the study was to examine the effect of prenatal alcohol exposure on offspring's weight, height, and head circumference from birth through 14 years of age. METHODS: This longitudinal prospective study examined a cohort of approximately 500 offspring (oversampled for heavier drinkers and stratified for smoking from a population of 1529 women in prenatal care at the 5th gestational month) at birth; 8 and 18 months; and 4, 7, and 14 years of age. Covariates were examined by means of multiple regression. Birth size measures were also examined as predictors of 7-year neurodevelopmental outcomes. RESULTS: Effects of alcohol were observed on weight, length, and head circumference at birth; these effects were not altered by adjustment for covariates including smoking. However, the birthweight effect is clearly transient: although alcohol effects remained observable at 8 months, they were not measurable thereafter through age 14 years. CONCLUSIONS: In this population-based sample, neither birthweight nor any later size measure was as useful an indicator of the enduring effects of prenatal alcohol exposure as were certain neurodevelopmental outcomes.

Drinking during pregnancy decreases word attack and arithmetic scores on standardized tests: adolescent data from a population-based prospective study.

Women (1529) were interviewed in midpregnancy, and a cohort of their children has been examined at various ages. The two standardized tests presented herein are part of a large battery of tests administered when the children were 14 years old. "Word Attack" (n = 462) measures phonological processing on a task involving the reading of pseudowords in nontimed performance. "Arithmetic" (n = 191) measures auditorily processed mental computations in timed performance. Scores on both tests were associated with prenatal alcohol exposure in a dose-dependent fashion. These effects were robust when considered in relation to a wide variety of potentially confounding variables, such as prenatal exposure to tobacco and other drugs, sociodemographic characteristics, and traumatic postnatal events. A variety of alcohol scores were related to these two performance measures, but those involving a massing of drinks on a given occasion had the strongest association. The higher the average number of drinks/occasion, the poorer the offspring performance on tasks thought to underlie numerical problem solving and reading proficiency. Earlier reports of prenatal, alcohol-related neurobehavioral deficits in childhood have now been extended into adolescence.

Maternal drinking during pregnancy: attention and short-term memory in 14-year-old offspring--a longitudinal prospective study.

A large and compelling experimental literature has documented the adverse impact of prenatal alcohol exposure on the developing brain of the offspring. This is the first report of adolescent attention/memory performance and its relationship with prenatal alcohol exposure in a population-based, longitudinal, prospective study (n = 462) involving substantial covariate control and "blind" examiners. Prenatal alcohol exposure was significantly related to attention/memory deficits in a dose-dependent fashion. A latent variable reflecting 13 measures of maternal drinking was correlated 0.26 with a latent variable representing 52 scores from 6 tests measuring various components of attention and short-term memory performance. The number of drinks/occasion was the strongest alcohol predictor. Fluctuating attentional states, problems with response inhibition, and spatial learning showed the strongest association with prenatal alcohol exposure. A latent variable reflecting the pattern of attention/memory deficits observed at 14 years correlated 0.67 with a composite pattern of deficits previously detected on neurobehavioral tests administered during the first 7 years of life. The 14-year attention/memory deficits observed in the present study appear to be the adolescent sequelae of deficits observed earlier in development. As is usual in such studies, not all exposed offspring showed deficits.

Analysis of facial shape in children gestationally exposed to marijuana, alcohol, and/or cocaine.

The association between fetal marijuana and/or alcohol exposure and facial features resembling fetal alcohol syndrome was investigated in a sample of 80 children. Standardized lateral and frontal facial photographs were taken of 40 children, 5 to 7 years of age, whose mothers reported frequent use of marijuana during the first trimester of pregnancy and 40 children whose mothers reported no use of marijuana during pregnancy. The marijuana-exposed and unexposed children were group-matched on alcohol exposure prior to and during pregnancy, sex, race, and age at the time of assessment. The photographs were assessed clinically by a study staff dysmorphologist and morphometrically by computerized landmark analysis. Fetal alcohol syndrome-like facial features were not associated with prenatal marijuana exposure in this study sample. No consistent patterns of facial features were identified among the marijuana-exposed group. Maternal consumption of two or more ounces of alcohol per day, on average, in early gestation was found to be associated with fetal alcohol syndrome-like facial features identified both clinically and morphometrically. Cocaine use reported by 13 of the 80 women was independently associated with mild facial dysmorphic features of hypertelorism and midfacial flattening. The results demonstrate the usefulness of this diagnostic technique for quantifying anomalies apparently unique to fetal alcohol syndrome and for targeting clusters of anomalies in new conditions for future evaluation.

Moderate prenatal alcohol exposure: effects on child IQ and learning problems at age 7 1/2 years.

This longitudinal, prospective, population-based study examined the long-term effects of moderate prenatal alcohol exposure on 482 school aged children. Maternal reports of alcohol use obtained during pregnancy were significantly related to child IQ, achievement test scores, and classroom behaviors in second grade children, even after statistical adjustment for appropriate covariates. Consumption of two drinks per day or more on the average was related to a 7-point decrement in IQ in 7-year-old children even after statistically adjusting for appropriate covariates. Low paternal education and more children in the household were identified as environmental factors exacerbating the effect of prenatal alcohol exposure on child IQ. Learning problems were associated with the alcohol "BINGE" pattern of five or more drinks on at least one occasion. This study shows that alcohol use patterns within the social drinking range can have long lasting effects on IQ and learning problems in young school aged children. These patterns should not be interpreted as biologic thresholds. It should also be noted that these are group effects of prenatal alcohol exposure, not necessarily predictable in the individual child, and that for the most part these children were functioning within the normal range of intelligence.