1 Department of Epidemiology, School of Public Health and Community Medicine and
2 Department of Pediatrics, School of Medicine, University of Washington, Seattle, WA 98105, USA
Received 10 August 2000; in revised form 16 October 2000; accepted 30 October 2000
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ABSTRACT |
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INTRODUCTION |
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The present report illustrates how to measure the magnitude of expression of the FAS facial phenotype using the 4-Digit Diagnostic Code and D-score, and demonstrates how the 4-Digit Diagnostic Code and D-score measures of the FAS facial phenotype correlate with brain function and structure; correlations that fail to be identified by the standard gestalt method of diagnosis and facial measurement (Rosett, 1980; Sokol and Clarren, 1989
).
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SUBJECTS AND METHODS |
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FAS facial phenotype
Three features (PFL, philtrum smoothness, and upper lip thinness) are measured to document the magnitude of expression of the FAS facial phenotype (Astley and Clarren, 1996). All other major and minor craniofacial anomalies are measured and recorded for clinical and research purposes, but are not used to rank the magnitude of expression of the FAS facial phenotype. PFL is the distance from the endocanthion to the exocanthion (Fig. 1
). The philtrum furrow is the vertical groove extending from the midline of the upper lip to the nose (Fig. 2
). The upper lip thinness refers to the area demarcated by the vermilion border (Fig. 2
). These three features are measured directly by a physician or measured from a digital photograph using image analysis software. PFL is measured in mm and transformed to a standardized z-score using appropriate published normal anthropometric charts (Iosub et al., 1985
; Thomas et al., 1987
; Hall et al., 1989
). The z-score reflects how many SD above or below the population norm the patient's PFL is, based on the patient's age. The z-score is defined as the patient's PFL minus the mean PFL for the normal population divided by the SD of the mean PFL for the normal population. Philtrum smoothness and upper lip thinness are measured on five-point Likert scales using the pictorial lipphiltrum guide (Fig. 3
) (Astley and Clarren, 2000
). This method for measuring the facial phenotype directly or photographically is demonstrated on a CD ROM with the aid of animations and video (Astley et al., 1999a
).
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Philtrum smoothness and upper lip thinness are measured on five-point Likert pictorial scales by holding the lipphiltrum guide next to the patient's face and assigning each feature the Likert rank of the photograph that best matches each feature (Figs 3 and 4). Philtrum smoothness and upper lip thinness are ranked independently of one another. For example, a child could present with a rank 5 philtrum and rank 1 upper lip. The physician's eyes must be aligned in the patient's Frankfort horizontal plane (demarcated by a line drawn through the patient's auditory meatus and the lowest border of the bony orbital rim) (Figs 4 and 6
). If the physician's eyes are above or below this plane, the upper lip can appear thinner or thicker respectively than it is. The patient must have a relaxed facial expression with no smile and lips gently closed. A smile can cause the philtrum and upper lip to appear smoother and thinner than they are (Fig. 5
).
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Photographic measurement of facial features
An internal measure of scale is placed on the patient's forehead between the eyebrows (Figs 1 and 6). A small, adhesive paper sticker
in. to
in. in size serves well and can be purchased from an office supply store. A frontal and
view photograph of the patient's face is obtained using a digital or 35-mm camera. Polaroid cameras do not provide sufficient image resolution. A close-up photograph is taken, such that the patient's head fills the entire frame (Fig. 6
). When using a digital camera, a minimum of 3 megapixel resolution is recommended. The lens of the camera is placed in line with the patient's Frankfort horizontal plane, as described above and illustrated in Fig. 4
. To judge the Frankfort horizontal plane when viewing the face through the camera, an imaginary line drawn between the upper border of the left and right tragus should fall across the left and right lower bony orbital rim (Fig. 6
). There should also be no left-to-right rotation of the image; both ears should be equally visible in the frontal photograph. The facial expression should be relaxed with no smile, lips gently closed, eyes wide open, and no eyeglasses. The
view is taken to facilitate ranking philtrum smoothness by purposely driving a flash of light across the philtrum to see if a shadow is cast. The
view is particularly important to obtain if the camera has a centrally mounted flash that can diminish the appearance of a grooved philtrum in a frontal photograph. Properly aligned facial photographs are obtained in the FAS DPN clinics with a hand-held camera and freestanding patient. Stereotaxic equipment and tripods are not necessary.
The digital image is measured using image analysis software (e.g. Sigma Scan Pro 5, 1999 or FAS DPN software to be distributed in 2001). This software allows one to enlarge the image, enhance the exposure if necessary, make all the necessary measurements, and store the data in an electronic database. If the image is obtained with a 35-mm camera, the slide, print or negative is scanned to generate a digital copy of the image. It is important to note that the resolution (or clarity) of a scanned image as small as a slide or negative may not be sufficiently high. The right and left PFLs are measured by clicking the mouse on the endocanthion and exocanthion landmarks and having Sigma Scan Pro compute the distance between the landmarks in pixels (dots of light on the computer monitor). The length of the internal measure of scale (paper sticker) is also measured in pixels. The real size of the PFL (mm) is computed from the PFL (pixels), the length of the paper sticker (pixels) and the real length of the paper sticker (mm) using the following equation:
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If the image is rotated right or left, insert the mean PFL in pixels into the equation to compute a mean PFL in mm. The margin of error between this mean PFL (mm) and the true mean PFL measured directly with calipers is less than 1%.
The 1.07 adjustment factor is included in the formula to increase the computed PFL by 7% to adjust for the foreshortening effect of measuring a facial feature that is slightly off the midline of the photograph (Farkas, 1994). This adjustment was confirmed to be accurate by comparing computed PFLs from photographs with measures obtained directly from the subjects with calipers. The computed PFL (mm) is transformed into a z-score, as described above, to standardize it to the popuation norm. The PFL can also be computed by placing a clear plastic ruler directly under the eye prior to taking the facial photograph (Fig. 1
). The actual PFL (mm) would be computed using the equation above without the adjustment factor.
The real size of the ICD (mm) is computed from the ICD (in pixels), the length of the paper sticker (pixels) and the real length of the paper sticker (mm) using the following equation:
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No adjustment factor is added to the equation, because the sticker and ICD are on the midline, thus there is no foreshortening error.
Philtrum smoothness and upper lip thinness are measured using the lipphiltrum guide described above. Philtrum smoothness is ranked by holding the lipphiltrum guide next to the image on the computer monitor and selecting the picture that best matches the patient's philtrum. Upper lip thinness is measured by tracing the outline of the vermilion border with the mouse and having Sigma Scan Pro compute a measure called circularity (perimeter2/area) (see Fig. 2). Some image analysis software programs call circularity compactness'. Circularity ranges from 12.8 for a circle to infinity as the circle is squashed into a line (or becomes thinner). The thinner the upper lip, the larger the circularity (Fig. 3
). The circularity scores of the five lips pictured on the lipphiltrum guide allow the physician to select the picture that best matches the patient's upper lip thinness. The process of taking a facial photograph and measuring the features takes about 10 min.
Computing the facial D-score
The facial D-score is computed when a true measure of PFL cannot be obtained (e.g. home photographs or retrospective photograph sets that did not contain an internal measure of scale). The facial D-score is computed using the equation:
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A facial phenotype with a D-score 0.8 is classified as screen-positive for the facial phenotype of FAS (Fig. 7
). This discriminant function and cut off value differentiated 42 patients with FAS from 84 controls with 100% sensitivity and specificity in an earlier study (Astley and Clarren, 1996
).
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Computing the facial 4-Digit Diagnostic Code rank
The facial 4-Digit Diagnostic Code rank is the most accurate diagnostic measure of the magnitude of expression of the FAS facial phenotype, because it uses the actual PFL, rather than the proxy measure (PFL/ICD) used by the D-score. It can be computed from direct measures or from photographs that contain internal measures of scale. The first step in deriving the facial 4-Digit Diagnostic Code rank is to derive the facial ABC-score. The magnitude of palpebral fissure length deficiency, philtrum smoothness, and upper lip thinness are ranked by circling A, B, or C in each column in the ABC-score table (Table 1A). The facial ABC-score is converted to the facial 4-Digit Diagnostic Code rank using Table 1B
.
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The gestalt FAS facial phenotype
Prior to the development of the 4-Digit Diagnostic Code, all patients (n = 462) seen in the FAS DPN were diagnosed using the typical gestalt (Sokol and Clarren, 1989) method of diagnosis. The gestalt method uses a less specific qualitative definition for the FAS facial phenotype and records the outcome on a dichotomous scale (present/absent). As reported by Sokol and Clarren (1989), A characteristic face is currently qualitatively described as including short palpebral fissures, an elongated midface, a long and flattened philtrum, thin upper lip and flattened maxilla. The specific clinical features will vary with patient age'. It is rare to find documentation in a patient's medical record or even in the medical literature as to what facial features were present when a diagnosis of FAS was given, thus, if an individual received a gestalt diagnosis of FAS, one can only infer that the FAS facial phenotype described by Sokol and Clarren (1989) was present.
Measures of brain function and structure
Structural (occipital frontal circumference (OFC) magnetic resonance imaging/computed tomography/positron emission tomography), neurological (seizures, cerebral palsy, etc) and functional (standardized psychometric tests of intellect, achievement, adaptation, language, neuropsychological performance, development, and behaviour) measures of the brain are assessed during the FAS DPN diagnostic evaluation. Many of these measures are obtained from the patient's school and medical records; others are collected at the time of the patient's diagnostic evaluation. A few examples of the types of standardized psychometric tests most frequently obtained within each domain include: Intelligence: Wechsler Intelligence Scale for Children 3rd Edition (Wechsler, 1996), Wechsler Adult Intelligence Scale Revised (Wechsler, 1981
), Test of Nonverbal Intelligence (Martin et al., 1990
); Achievement: Woodcock-Johnson Psycho-educational Battery (Woodcock and Johnson, 1990
), Wide Range Achievement Test (Wilkinson, 1994
); Adaptation: Vineland Scales of Adaptive Behaviour Survey (Sparrow et al., 1984
); Language: Test of Word Knowledge (Wiig and Secord, 1992
), Test of Auditory Comprehension of Language Revised (Carrow-Woolfolk, 1985
), Peabody Picture Vocabulary Test Revised (Dunn and Dunn, 1981
), Clinical Evaluation of Language Function (Semel et al., 2000
), Test of Language Development P:3 (Newcomer and Hammill, 2000
); Neuropsychological: Rey Complex Figure Test (Spreen and Strauss, 1998
), Tests of VisualMotor Integration (Berry, 1989
), Wide Range Memory and Learning Test (Adams and Sheslow, 2000
), California Verbal Learning TestC (Delis et al., 1994
); Infant Development: Bayley Scales of Infant Development (Bayley, 1969
), Battelle Developmental Inventory (Newborg et al., 1984
); Behaviour: Child Behavior Check List (Achenbach, 1991
), Conners Parent Rating Scale (unpublished, Children's Hospital National Medical Center, Washington DC). Due to the age range of the patients and the multiple sources of data, no two patients have an identical, comprehensive set of data. To assess the correlation between the facial phenotype and brain structure and function, three types of brain outcome measures were generated from the FAS DPN clinic database. (1) When a sufficient number of patients had the same standardized assessment performed [e.g. OFC centile, full-scale intelligence quotient (FSIQ), Quick Neurologic Screening Test (QNST; a test of soft neurologic signs), visual motor integration], the standardized scores from these assessments served as outcome measures. (2) More typically, the clinical data set included a broad array of standardized assessments within and across one or more of the following domains: intelligence, achievement, adaptation, language, sensory processing integration, motor skills, behavioural regulation, memory, and infant development. The patient's performance across all tests in each domain was ranked on a four-point Likert scale. The ranks were defined as follows: 0 (no tests conducted, most likely because child was too young) 1 (all test outcomes were in the normal range; no test score was lower than 0.9 SD below the norm), 2 (one or more test outcomes were in the borderline range, between 1.0 SD and 1.9 SD below the norm, but no test was 2 or more SD below the norm) and 3 (one or more tests were below normal, defined as 2 or more SD below the norm). (3) Finally, the four-point Likert scale used by the 4-Digit Diagnostic Code to rank evidence of organic brain damage was used as a global composite measure of brain structure and function. The case definitions and clinical names applied to each rank are: rank 4 (microcephaly or abnormalities on brain images or evidence of persistent neurologic findings or an IQ
60); rank 3 (performance on standardized psychometric tests > 2 SD below the norm across three or more of the following areas: sensory processing/integration, motor skills, behavioural regulation, adaptive behaviour, memory language, achievement, intelligence); rank 2 (observational data strongly suggest the possibility of brain damage, but data do not permit a rank 3 or 4 classification); rank 1 (no evidence of problems likely to reflect brain damage). The FAS DPN assigns the clinical term static encephalopathy to brain rank 3 and 4 and neurobehavioural disorder to brain rank 2. More detailed definitions of these terms are presented in Astley and Clarren (1999, 2000).
Prenatal alcohol exposure
All patients in this study had a confirmed history of prenatal alcohol exposure (4-Digit Diagnostic Code alcohol rank = 3 or 4) (Astley and Clarren, 1999, 2000
). A history was considered confirmed if the birth mother reported consumption of alcohol during pregnancy, another individual directly observed the birth mother drinking during pregnancy and/or there was information available in the medical records that confirmed that the birth mother had been drinking during pregnancy (e.g. blood-alcohol concentrations, reported intoxicated at the time of delivery, etc). During the diagnostic evaluation, the following maternal alcohol use information is recorded on a standardized diagnostic evaluation form: average and maximum number of drinks/drinking occasion just before and during pregnancy, average number of days she drank/week just before and during pregnancy, type of alcohol consumed, trimester(s) in which alcohol was consumed, was she ever diagnosed with alcoholism, did she ever receive treatment for alcoholism and finally, what was the source and reliability of the above reported information.
Statistical analyses
Descriptive statistics were used to summarize the profile of the study population. Pearson correlation coefficients were computed to assess correlations between outcomes recorded on continuous scales. Regression analysis was used to determine if significant Pearson correlations were influenced by covariates, such as age and gender. 2-Tests were used to assess trends between outcomes recorded on nominal and ordinal scales. One-way ANOVA with post-hoc tests for linear trends was used to compare mean outcomes across three or more groups. Stepwise discriminant analysis (maximizing Wilk's
) was used to identify the facial feature(s) that best differentiated patients with and without FAS diagnosed using the gestalt and 4-Digit Diagnostic Code methods. Prior probability of FAS was set equal to the prevalence in the study samples. The probability of F to enter was 0.05, and F to remove was 0.10. The unstandardized canonical discriminant function coefficients were computed to derive the discriminant equation for calculation of each subject's discriminant score. The discriminant score was used to predict each subject's diagnostic classification (FAS, not FAS). The predicted diagnoses were compared to the actual diagnoses to compute sensitivity and specificity.
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RESULTS |
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Variability of the FAS facial phenotype
When patients were diagnosed using the gestalt method, the facial phenotype of those receiving a gestalt diagnosis of FAS was highly variable (Table 5). In contrast, when the same patients were diagnosed using the 4-Digit Diagnostic Code, the facial phenotype among those receiving a 4-Digit diagnosis of FAS showed little variability. Of the 462 patients who received diagnostic evaluations using both the gestalt and 4-Digit Diagnostic Code methods, 445 had sufficiently complete data sets for inclusion in the following descriptive comparison of the gestalt and 4-Digit Diagnostic Code methods of diagnosis. When the gestalt method was used, 52 of the 445 patients (11.7%) received a diagnosis of FAS. When the 4-Digit Diagnostic Code method was used, 10 of the 445 patients (2.2%) received a diagnosis of FAS. Of the 52 patients who received a gestalt diagnosis of FAS, only 34% had growth deficiency (height and weight below the 10th percentile), only 27% had the full FAS facial phenotype (as defined by rank 4 in the 4-Digit Diagnostic Code) and only 52% had psychometric, structural and/or neurological evidence of brain damage. In contrast, 100% of the 10 patients with a 4-Digit Diagnostic Code of FAS had growth deficiency, the full FAS facial phenotype and evidence of brain damage as defined in the sentence above. The magnitude and frequency of expression of nine minor facial anomalies frequently reported to be associated with the gestalt FAS facial phenotype were compared between the patients who did and those who did not receive a diagnosis of FAS using the two diagnostic methods (Table 5
). The prevalence of all other minor anomalies was relatively low. Hypertelorism (an ICD greater than 2 SD above the norm), often referred to in the literature as a diagnostic feature of FAS, was not observed in any of the 52 patients with either a gestalt or 4-Digit Diagnostic Code of FAS. The most prevalent minor anomaly in the gestalt group was small palpebral fissure lengths. When the same patients were diagnosed using the 4-Digit Diagnostic Code, the facial phenotype of the patients who received a diagnosis of FAS did not vary from patient to patient. All patients diagnosed with FAS had small palpebral fissures, a smooth philtrum (rank 4 or 5) and a thin upper lip (rank 4 or 5).
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DISCUSSION |
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The facial anomalies used to generate the 4-Digit Diagnostic Code and D-score measures of the FAS facial phenotype were identified by multivariate discriminant analyses, and found to be highly sensitive and specific to FAS and prenatal alcohol exposure (Astley and Clarren, 1996). In contrast, the gestalt approach relies on anomaly checklists that purportedly characterize the FAS facial phenotype, leaving it up to the physician or researcher to select arbitrarily which anomalies define the phenotype, how many must be present, and how severe they must be expressed (Rosett, 1980
; Sokol and Clarren, 1989
; Wiedemann et al., 1989
; Gorlin et al., 1990
; Jones, 1997
). This approach has led to highly variable outcomes with no documented sensitivity or specificity to prenatal alcohol exposure (Centers for Disease Control, 1993
; Floyd et al., 1994
). Consider the following series of studies that utilized anomaly checklists to address an important diagnostic question Does the FAS facial phenotype diminish with age?. In a follow-up study of 54 patients, Spohr and Steinhausen (1987) reported a statistically significant reduction in facial features defined as characterizing the craniofacial dysmorphology of FAS (epicanthal folds, blepharophimosis, ptosis, short upturned nose, high arched palate/cleft palate, and retrognathia). The one feature that did not change with age was a thin upper vermilion. PFL and philtrum smoothness were not measured. In a retrospective study of 200 alcohol-exposed children, Majewski (1993) reported that, in older cases, the nose was no longer short and upturned, the lips were no longer thin, and the chin often became rather prominent. The one feature that did not change with age was short PFLs. Finally, in a 10-year follow-up study of eight of the first 11 children to be diagnosed with FAS, Streissguth et al. (1985) reported that, while some craniofacial features changed with age (nasal bridges became more prominent and mandibles became relatively prognathic), others did not change with age (palpebral fissures remained short, philtrums remained hypoplastic, the vermilion border of the upper lip remained thin, and the midface remained flat). From these and similar studies, the 1996 report by the Institute of Medicine concluded that some FAS craniofacial anomalies may be less evident at birth, become more conspicuous during early infancy and childhood, and often diminish or even disappear during adolescence and adulthood (Stratton et al., 1996
). But most of the features that were reported to diminish with age: (1) have never been confirmed to be sensitive or specific to prenatal alcohol exposure; and (2) are remarkably consistent with descriptions of normal facial growth. Enlow and Hans (1996) reported that, when one compares the face of a normal child to that of a normal adult, the child's nose is short and upturned, the nasal bridge is low and the mandible is small and retrusively placed. Interestingly, the features that were least likely to change with age (short PFL, smooth philtrum, and a thin upper lip) are the only features confirmed to be sensitive and specific to prenatal alcohol exposure in our previous (Astley and Clarren, 1996
) and current studies and match the features originally identified as defining the face of FAS by David Smith back in 1979. As stated by Smith (1979), as far as the diagnosis is concerned, perhaps the most important point to emerge in the last few years is that the facial abnormalities seen in affected infants are the key cluster of features that tend to make FAS a clinically discernible entity. Many disorders result in mental and growth deficiency, but in FAS the deficiencies are typically present in a patient whose face has short palpebral fissures, a hypoplastic upper lip with a thinned, vermilion border and a smoothed or absent philtrum. Up to now, the descriptions of the facial features of FAS that have appeared in the literature have not always emphasized the same abnormalities. This has led to some confusion, but inspection of the photographs accompanying these reports leaves no doubt about the facial similarities of FAS patients. While clinical judgement plays an important role in the initial identification and definition of a new syndrome, more analytical approaches to pattern recognition, such as discriminant analysis, supported by objective, quantitative measures of outcome, can and should be used to hone the definition. The match between the facial features identified by our discriminant analysis and reported by Smith (1979) further demonstrates that the analytical approach used by the FAS DPN has succeeded in objectively case-defining, not redefining, the original FAS facial phenotype.
Correlations between face and brain
The correlations observed between the magnitude of expression of the FAS facial phenotype and brain structure and function: (1) further validate that short PFLs, a smooth philtrum and a thin upper lip are key diagnostic facial features; (2) are consistent with the clinical literature that midline defects can predict underlying brain dysfunction (DeMeyer, 1975; Astley et al., 1999b
); (3) provide evidence that an intermediate expression of the FAS facial phenotype may serve as an important clinical risk factor for brain damage caused by prenatal alcohol exposure. The FAS facial features (short PFLs, a smooth philtrum, and a thin upper lip) selected by the discriminant analyses in this study and the previous study (Astley and Clarren, 1996
) are midline anomalies derived from the anterior frontal neural crest primordia of the early forebrain (Johnston, 1975
). Deficiencies in the numbers of crest cells most frequently affect development of the frontonasal derivatives and are usually associated with defective forebrain and eye development (Johnston, 1975
). It has long been speculated that some extreme forms of midline facial anomalies (i.e. cyclopia, holoprosencephaly, arhinencephaly) are pathognomonic of brain malformation (DeMeyer, 1975
). This speculation was further supported by the presence of a proportional increase in midventral forebrain deficiencies and the severity of facial dysmorphia in mice and a non-human primate with holoposencephaly, all of which were exposed to ethanol early in gestation (Sulik and Johnston, 1982
, 1983
; Sulik, 1984
; Seibert et al., 1991
). Now, two additional studies have demonstrated that much more subtle midline facial anomalies (craniofacial bony alterations in non-human primates and soft-tissue facial anomalies in this current human clinical population) appear to be pathognomonic of brain malformation/dysfunction (Astley and Clarren, 1999
). Smith (1979) reported similar findings: the severity of dysmorphic features appears to be related to the degree of mental deficiency. The dysmorphic features he was referring to were small palpebral fissures, a smooth philtrum, and a thin upper lip. No other studies, to our knowledge, have reported significant linear correlations between the magnitude of expression of the FAS facial phenotype and cognitive impairment among individuals with prenatal alcohol exposure. Other clinical research teams have reported correlations between the number of physical anomalies observed over the entire body and brain dysfunction in individuals with prenatal alcohol exposure, although not all were reported to be statistically significant (Majewski, 1993
; Spohr et al., 1993
). No correlations were observed between the gestalt FAS facial phenotype and brain dysfunction in this study. Failure to detect statistically significant correlations between face and brain, when a gestalt approach to diagnosis was used, has also been reported by others (Graham et al., 1988
; Spohr et al., 1993
).
In summary, thousands of individuals with FAS have been identified and thousands of laboratory, clinical and population-based studies have been conducted. While these studies have greatly advanced our understanding of alcohol's teratogenic potential, advancements in the clinical and public health arenas are less impressive. To date, we still cannot derive an accurate estimate of the prevalence of FAS (Floyd et al., 1994) nor can we document success in preventing FAS. Advancements in these two arenas are contingent upon physicians making accurate diagnoses. Accurate diagnoses require specific and objective case definitions that document the full range of outcomes associated with prenatal alcohol exposure. These definitions should be continually honed to incorporate the latest technological advances (e.g. magnetic resonance spectroscopy and functional magnetic resonance imaging, digital image analysis etc.) and should be guided by more sophisticated, multivariate, analytical approaches to pattern recognition.
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FOOTNOTES |
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