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(Radiology. 2000;215:775-782.)
© RSNA, 2000

Obstetric Imaging

The "Genetic Sonogram": Comparison of the Index Scoring System with the Age-adjusted US Risk Assessment1

Thomas C. Winter, MD, Stefanie B. Uhrich, MS, CGC, Vivienne L. Souter, MRCOG and David A. Nyberg, MD

1 From the Department of Radiology, Division of Ultrasound (T.C.W.), and the Department of Obstetrics and Gynecology, Division of Perinatal Medicine (S.B.U.), University of Washington Medical Center, Seattle; and the Center for Perinatal Studies, Swedish Medical Center, Seattle, Wash (V.L.S., D.A.N.). Received May 5, 1999; revision requested July 15; revision received August 25; accepted August 30. Address correspondence to T.C.W., Department of Radiology, University of Wisconsin Hospital, E3/311 CSC Box 3252, 600 Highland Ave, Madison, WI 53792.


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To compare two ultrasonographic (US) methods for prenatal detection of fetal Down syndrome.

MATERIALS AND METHODS: Genetic amniocentesis was successfully performed in 3,303 consecutive women with high-risk pregnancies (mean gestational age, 17.1 weeks). All patients underwent a complete "genetic US" examination prospectively. Risk was assessed by using (a) various modifications of the index scoring system (ISS) and (b) the age-adjusted US risk assessment (AAURA).

RESULTS: The prevalence of Down syndrome in this population was 1.6% (53 of 3,303). By using a threshold of at least 2 points to detect trisomy 21, the best ISS had a sensitivity of 45.3%, false-positive rate of 4.9%, likelihood ratio of 9.3, and positive predictive value in the high-risk population in this study of 13.3%. Lowering the threshold to 1 point increased the sensitivity to 60.4% but increased the false-positive rate to 15.8%. Adding points for age increased the sensitivity to 67.9% but increased the false-positive rate to 24.3%. Results of using AAURA to detect trisomy 21 were nearly identical, with a sensitivity of 43.4% and false-positive rate of 4.9% at a 1 in 36 risk threshold and a sensitivity of 69.8% and false-positive rate of 26.1% at a 1 in 200 threshold. Trisomies 18 and 13 were detected with sensitivities of 80.0% and 100.0%, respectively, with either system.

CONCLUSION: The modified ISS and AAURA are equivalent in screening for Down syndrome, with detection of approximately half of all trisomy 21 fetuses at a 5% false-positive rate.

Index terms: Down syndrome, 856.87 • Fetus, abnormalities, 856.87 • Fetus, US, 856.1298, 856.86


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Trisomy 21 (Down syndrome) is the most common karyotypic abnormality in liveborn infants (one per 800 livebirths [1]) and is one of the leading causes of mental retardation. Various methods have been used to identify women at risk of carrying a fetus with trisomy 21, including consideration of maternal age (2) and biochemical markers (3).

Another approach is to recognize morphologic features of fetal Down syndrome with prenatal ultrasonography (US). During the 2nd trimester, a "genetic sonogram" (4) may depict both major structural defects and nonspecific markers of fetal Down syndrome, such as a thickened nuchal fold (5–7), rhizomelic limb shortening (8–14), mild fetal pyelectasis (15,16), echogenic bowel (17), and echogenic intracardiac focus (18–27). Other findings that have been described include a flared iliac crest (28–31), shortened frontothalamic distance (32,33), clinodactyly of the fifth digit (34,35), sandal toe deformity, ear lobe length, cerebellar hypoplasia (36,37), and, possibly, choroid plexus cyst (38). Because US markers are also common among karyotypically normal fetuses, it may not be clear when genetic amniocentesis should be offered. To help identify patients at risk, two US methods have been proposed.

Benacerraf and colleagues (39–41) have popularized a simple approach, referred to here as the index scoring system (ISS), in which a score of 2 is assigned for structural defects and nuchal thickening (>=6 mm) and a score of 1 is assigned for the US markers of echogenic intracardiac focus, echogenic bowel, pyelectasis, short femur, and short humerus. Using this method, the authors report a sensitivity of 73% (33 of 45 fetuses) for detecting trisomy 21, with a false-positive rate of only 4% (four of 106 fetuses) (40). More recent modifications that also account for maternal age (score of 1 for women aged 35–39 years and score of 2 for women aged 40 years or older) result in a higher sensitivity (87% [46 of 53]) at a cost of a higher false-positive rate (27% [48 of 177]) (41). The value of including choroid plexus cysts in this system is uncertain (38,41,42). We investigated the utility of this scoring system in our population with variations, which include the use of different published limb ratio formulas, the inclusion and/or exclusion of echogenic intracardiac foci and choroid plexus cysts, and the addition of points for maternal age.

In a different approach, termed the age-adjusted US risk assessment (AAURA), Nyberg et al (19,43) applied likelihood ratios from US markers to the a priori risk based on maternal age. This method provides patient-specific risk estimates based on maternal age, gestational age, and US findings, although it is more complicated than the ISS and requires computer calculations. By using a threshold of 1 in 200, this method has achieved a sensitivity of 74% (105 of 142) in a high-risk population (19).

The present study was designed to compare the accuracy of the ISS with the accuracy of the AAURA in the prenatal detection of fetal Down syndrome. To help determine optimal screening criteria, we also evaluated each method with the inclusion and/or exclusion of choroid plexus cysts.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
The study group consisted of 3,303 consecutive women at high risk of a genetically abnormal pregnancy who underwent a complete genetic US examination prior to genetic amniocentesis. All of our patients were referred for amniocentesis on the basis of one or more of the following indications: advanced maternal age, or age greater than 35 years at delivery; abnormal pregnancy risk profile, or abnormal "triple screening" results constituting abnormal {alpha}-fetoprotein, human chorionic gonadotropin, and unconjugated estriol levels; high or low maternal serum {alpha}-fetoprotein level; maternal anxiety; teratogen exposure; or family history of a previous fetal malformation.

US was performed prospectively at one of the two largest high-risk centers in Seattle, Washington (University of Washington Medical Center and Swedish Medical Center). Patients were examined at a mean gestational age of 17.1 weeks (range, 14.0–24.0 weeks; SD, 1.8 weeks); the mean maternal age was 35.1 years (range, 13.0–47.4 years; SD, 5.1 years). All patients were examined without knowledge of fetal karyotype. All US examinations were completed by registered diagnostic medical sonographers and board-certified radiologists (including T.C.W. and D.A.N.) who had additional subspecialty training in high-risk obstetric US. Direct scanning by the sonologist occurred in more than half of the patients; in the remaining patients, the sonologist was immediately available (eg, within 10 m of the scanning room). All consecutive fetuses at each institution that met the study criteria of gestational age of 14–24 weeks with complete prospectively performed genetic US and subsequent determination of karyotype were included. To ensure that this was a truly prospective study, no fetuses with any marker or structural anomaly were added to this population outside these guidelines.

The fetal structural survey followed the American Institute of Ultrasound in Medicine guidelines (44), with additional views obtained of the posterior fossa, outflow tracts, and the long bones in the extremities and hands and feet and coronal views obtained of the nose and lips, whenever possible. US markers that were specifically sought included the nuchal skin fold, femoral and humeral shortening, echogenic bowel, choroid plexus cysts, and echogenic intracardiac foci.

The ISS was used as previously described by Benacerraf et al (39–41). In brief, 2 points were assigned for structural anomalies and a thickened nuchal skin fold (>=6 mm), while 1 point was assigned for other US markers, which included echogenic intracardiac focus, pyelectasis (>=4 mm), echogenic bowel (grade II or III [17]), and femoral or humeral shortening ratios. Femoral or humeral shortening values were compared by using regression equations published both by Benacerraf et al (45,46) and by Nyberg et al (11). Maternal age was also incorporated by assigning 1 point for a maternal age of 35–40 years and 2 points for a maternal age of at least 40 years. A score of 2 or more was considered positive.

The following variations of the system by Benacerraf et al were investigated: (a) the original system, incorporating structural anomalies, nuchal skin fold, pyelectasis, choroid plexus cysts, femoral and humeral lengths, and echogenic bowel (39,40) (Fig 1, Tables 1–3); (b) the same as a, but with substitution of the limb ratios published by Nyberg et al for those by Benacerraf et al; (c) the modified scoring system by Benacerraf et al (41), with choroid plexus cysts replaced by echogenic intracardiac focus; (d) the same as c, but with substitution of the limb ratios published by Nyberg et al for those by Benacerraf et al; (e) and (f) inclusion of both choroid plexus cysts and echogenic intracardiac focus with the limb ratios by Benacerraf et al and by Nyberg et al, respectively; (g) the modified scoring system by Benacerraf et al (41) with incorporation of maternal age; (h) the same as g, but with substitution of the limb ratios published by Nyberg et al for those by Benacerraf et al; (i) finally, the same as d, but with a threshold of 1 point rather than 2 points.



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  		Figure 1. Data points for comparison of the different point scoring systems for detecting trisomy 21. The "perfect" system would be located in the top left corner of the graph, with 100% sensitivity and a 0% false-positive rate. Real-world scoring systems represent compromises between various sensitivities and specificities. Ben = Benacerraf and colleagues' limb length ratios (44,45), CPC = choroid plexus cysts, Nyb = Nyberg and colleagues' limb length ratios (11), + = with, - = without.

 

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  		TABLE 1. Raw Data for the Modified ISS with Benacerraf and Colleagues' Limb Length Ratios, without Choroid Plexus Cysts, and with Echogenic Intracardiac Focus
 

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  		TABLE 2. Sensitivities and Specificities for the ISS
 

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  		TABLE 3. US Markers for Down Syndrome
 
The AAURA was used as previously described (19), with a slight modification to attempt to more accurately account for the relative prevalence of trisomy 21 as a function of gestational age. The a priori livebirth risk for trisomy 21 based on maternal age was estimated by using information from Hecht and Hook (47) as 0.000631 + exp(-16.60785 + 0.2994 x maternal age in years). Instead of applying a uniform prevalence correction of 1.3 (relative increased prevalence of trisomy 21 at 20 weeks gestational age vs livebirth rate) to all 2nd-trimester pregnancies, as was done in the original article by Nyberg et al (19), we mathematically fit previously published data (48) for the relative prevalence of trisomy 21 as a function of gestational age. A fit to the inverse function provided the best regression analysis (r2 = 1.00) and yielded an estimated gestational age (EGA) risk adjustment of 0.6991 + 12.0227/EGA (in weeks). This does indeed yield 1.300 at 20 weeks EGA. The pre-US risk estimate, with incorporation of both maternal age and EGA, is therefore EGA risk adjustment x maternal age risk estimate.

The likelihood ratio for a US marker is defined as sensitivity/false-positive rate. Likelihood ratios for various US markers were assigned per Nyberg et al (19) and Snijders and Nicolaides (49), and the total post-US likelihood ratio was defined as the mathematical product of the individual likelihood ratios, which were 25 for a structural defect, 18.6 for nuchal thickening, 5.5 for echogenic bowel, 2.5 for a short humerus, 2.2 for a short femur, 2 for an echogenic intracardiac focus, and 1.6 for pyelectasis. When choroid plexus cysts were included, a likelihood ratio of 1.6 was assigned. If this mathematical product was 1 (eg, normal US findings), a total post-US likelihood ratio of 0.4 was used (19). The post-US (post priori) odds of Down syndrome are thus determined by using the three contributing factors (maternal age, gestational age, and US results). Unless the risk is unusually high, this can be approximated as the AAURA, which is the maternal age risk estimate x EGA risk adjustment x the total post-US likelihood ratio (19).

The positive predictive value depends heavily on the disease prevalence. The midtrimester, low-risk disease prevalence for positive predictive value calculations for this article was estimated at 1 in 600 (1,47,50-52). All AAURA calculations were performed by using FILEMAKER PRO, version 4.03 (Filemaker, Santa Clara, Calif). Receiver operating characteristic (ROC) calculations were performed with MATHCAD PLUS 6 (MathSoft, Cambridge, Mass). Statistical and curve-fitting analyses were performed by using SPSS for Macintosh, version 6.1.1 (SPSS, Chicago, Ill). The statistical analyses included mean, median, range, difference, maximum, minimum, and Student t test.


   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
There were 3,192 fetuses with euploid (1,555 fetuses with 46,XX, 1,615 fetuses with 46,XY) or phenotypically normal karyotypes (22 fetuses with balanced translocations or inversion 9), 53 with trisomy 21, 10 with trisomy 18, six with trisomy 13, eight with sex chromosomal abnormalities, seven with triploidy, six with Turner syndrome, and 21 with other potentially clinically important karyotypes. The prevalence of trisomy 21 in our high-risk population was 1.6% (53 of 3,303 fetuses). The mean gestational age of the 53 fetuses with Down syndrome was 17.2 weeks ± 1.8 (SD), while the mean gestational age of the 3,192 karyotypically normal fetuses was 17.1 weeks ± 1.7. The mean maternal age of the mothers of the 53 fetuses with Down syndrome was 35.0 years ± 6.1, while the mean maternal age of the 3,192 mothers of karyotypically normal fetuses was 35.2 years ± 5.0. The mean EGA difference of 0.15 weeks between the 3,192 karyotypically normal fetuses (17.09 weeks) and the 53 trisomy 21 fetuses (17.24 weeks) was not statistically significant (Student t test for independent samples, P = .54). The mean maternal age difference of 0.13 year between the 3,192 karyotypically normal fetuses (35.16 years) and the 53 trisomy 21 fetuses (35.03 years) was not statistically significant (Student t test for independent samples, P = .88).

A subset of the raw data is presented in Table 1, where the actual data for the scoring system used with Benacerraf and colleagues' limb length ratios, without choroid plexus cysts, and with echogenic intracardiac foci are listed. From these data and similar data from the remainder of the various proposed scoring systems, the percentages listed in Table 2 were calculated. The sensitivity and specificity for the individual markers in the euploid and Down syndrome populations are listed in Table 3. For example, 988 (31.0%) of 3,192 fetuses with normal karyotypes had a short femur according to Benacerraf and colleagues' published limb regression equations, which yielded a specificity for this marker of 69.0%. Data points for a ROC curve (eg, changes in sensitivity and specificity) calculated by substituting Nyberg and colleagues' limb length ratios for Benacerraf and colleagues' ratios are depicted graphically in Figure 1. The utilities of the other various proposed modifications of the ISS are also easily compared in Figure 1. As expected, higher detection rates were achieved for trisomy 18 (80%) and trisomy 13 (100%).

Thus, in Table 2 and Figure 1, two clusters are readily apparent. A sensitivity for the detection of Down syndrome of 40%–45% is obtained at a 4%–5% false-positive rate if Nyberg and colleagues' limb ratios and the three various combinations of choroid plexus cysts and echogenic intracardiac focus are used. The second cluster of four modifications of the ISS yields a sensitivity range of 53%–60% at a 16%–18% false-positive rate. This includes the three combinations of choroid plexus cysts and echogenic intracardiac focus with Benacerraf and colleagues' limb ratios and one of the 1-point thresholds (instead of the standard 2-point threshold for amniocentesis) with Nyberg and colleagues' limb ratios. The inclusion of choroid plexus cysts in both of these clusters did not substantially change the statistics. The addition of maternal age to the ISS further improved sensitivity but at the expense of higher false-positive rates: 68% sensitivity with a 24% false-positive rate and 74% sensitivity with a 42% false-positive rate for the two limb ratio scenarios. This reflects the change in risk with an increase in age in this population.

AAURA results are presented in Table 4 and Figure 2. For Figure 2, data for all patients were obtained from the 53 fetuses with Down syndrome and the 3,192 euploid fetuses, while data for the subset with a maternal age of less than 35 years were obtained from 26 fetuses with Down syndrome and 1,059 euploid fetuses. A threshold of 1 in 200 without consideration of choroid plexus cysts and for all ages (trisomy 21 birth risk for a 37.3-year-old woman) resulted in a 70% sensitivity with a high false-positive rate of 26.1%, which reflects the high-risk population. To decrease the false-positive rate to 4.9%, the sensitivity must decrease to 43% (threshold of 1 in 36). It is interesting that the AAURA curve in Figure 2 is essentially identical to the curve that would be obtained by using the different modifications of the ISS in Figure 1.


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  		TABLE 4. AAURA for Down Syndrome
 


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  		Figure 2. ROC curves for AAURA for different scenarios. Curves are plotted from data listed in Table 4. To preclude clutter, the curve obtained by including choroid plexus cysts (CPC) in the model was not plotted, since it almost identically tracked the curve obtained from excluding choroid plexus cysts from the model. yo = years old.

 
Adding choroid plexus cysts with a likelihood ratio of 1.6 resulted in no significant change in the configuration of the ROC curve, with areas under the curve of approximately 0.74 in both instances (a perfect test has an area under the ROC curve of 1, while a random test has an area under the ROC curve of 0.5; eg, an area of at least 0.5 represents a test performance better than chance, while an area less than 0.5 represents a performance worse than chance). Restricting the curve to those mothers younger than 35 years resulted in no major changes in sensitivity at the 5% and 15% false-positive rates, but performance did appear to be worse in the 20%–50% false-positive rate range, which perhaps reflects the lower risk in this population (although statistical variation could also account for this difference). As expected, even when using the 1 in 36 threshold (4.9% false-positive rate), the sensitivities of the AAURA for trisomies 13 and 18 were high, at 100% and 80%, respectively.


   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Both the ISS and AAURA are attempts to identify patients at risk of carrying a fetus with trisomy 21 on the basis of specific US findings combined with maternal age. The ISS is easily understood and is simple to use but does not provide a specific risk estimate. The AAURA model provides a risk estimate but is more complex to calculate. Theoretically, the US data could also be combined with maternal biochemical pregnancy risk profile analysis (triple screen) for a more useful and accurate risk estimate.

Use of the ISS and AAURA produced surprisingly similar results, with a sensitivity of nearly 50% at a 5% false-positive rate. As expected on the basis of the reports by Bromley et al (38) and Yoder et al (42), adding choroid plexus cysts to our data sets for either the ISS or the AAURA did not improve our statistics for the detection of trisomy 21 (choroid plexus cysts are associated with trisomy 18, however). Similar results were also achieved by excluding maternal age for ISS and considering only patients younger than 35 years for AAURA. Therefore, both the ISS and the more complex AAURA have potential individual benefits, but, practically speaking, they were equivalent in our hands in screening for trisomy 21.

The strength of this study of 3,303 midtrimester fetuses is that all data were prospectively acquired and measured, consecutive patients were entered into the study, and all karyotypes were specifically analyzed. As a limitation, all patients underwent amniocentesis and so were at particularly high risk.

The ISS is easily understood and is simple to use. The addition of maternal age into the ISS increased the sensitivity for detecting trisomy 21 but at the expense of a much higher false-positive rate. Decreasing the threshold for amniocentesis to 1 point also increased the sensitivity for detecting trisomy 21 but again at the expense of a higher false-positive rate. The association between sensitivity and the false-positive rate illustrated in Figure 1 should be borne in mind when evaluating any test and in this case while reading the wide body of literature on the topic of US detection of aneuploidy. A given sensitivity can never be evaluated in isolation but must be understood in the context of its associated false-positive rate.

The computed probabilistic AAURA model is theoretically appealing from an intellectual standpoint, but it is more complex to implement than the ISS. It permits the use of multiple US markers for Down syndrome and weights the individual findings relative to the strength of their relationships with Down syndrome (likelihood ratio). This allows the assignment of a patient-specific risk of fetal trisomy 21 when one or more US markers are present and is particularly useful in women who are considered to have low risk on the basis of maternal age alone.

The weakness of the AAURA system lies in the difficulties of obtaining accurate likelihood ratios. Published isolated likelihood ratios for various findings may differ substantially between institutions. In addition, one must prove that these US findings are all truly mathematically independent from one another to justify multiplying them together in this fashion. Finally, if the AAURA is to be combined with the pregnancy risk profile (triple screen) for a more useful and accurate probabilistic numeric risk, one must demonstrate that the US findings are mathematically independent of the biochemical analyses.

A weakness of both systems lies in the inherent subjectivity in determining the presence of some of the markers, such as echogenic intracardiac focus and echogenic bowel. Even measured parameters such as normative values for limb lengths show substantial variability between investigators (11,41), possibly because of the specific populations studied, measurement technique and variability, and/or the threshold chosen to represent a reasonable compromise between sensitivity and specificity. For these reasons, institutions may wish to establish their own normative data.

Choosing which subset of the pregnant population receives definitive karyotype determination is an important but very complex and controversial topic. Optimal risk assessment would ideally take into account the US findings and the a priori risk based on maternal age; biochemical analysis; and pregnancy, clinical, and family histories. A normal US scan has been used to help reduce the risk of Down syndrome in those women older than 35 years who wish to avoid amniocentesis (19,35,53,54). For example, Nyberg et al (19) concluded that a normal US scan reduces the risk of Down syndrome by approximately 60%, and Nadel et al (54) calculated that the probability of having a fetus with autosomal trisomy decreases from 18.8 in 1,000 pregnancies to 5.3 in 1,000 pregnancies for a 40-year-old woman with a normal US scan. Conversely, US is probably most useful in low-risk women younger than 35 years in whom US can help identify approximately half of fetuses affected with Down syndrome with an acceptable 5% false-positive rate (19). Future directions of investigation include combined 1st-trimester nuchal translucency screening and biochemical analysis, which may be substantially better than 2nd-trimester examination, and potentially even noninvasive fetal karyotype determination by means of analysis of fetal cells retrieved from maternal sources (55).

There is a great deal of interest in the US detection of aneuploidy, as evidenced by the large number of publications in the literature on this topic. However, despite the intellectual allure inherent in studying the pros and cons of various US detection systems for trisomy 21, parents and referring physicians should be repeatedly educated that the current state of the art is far from perfect and that a normal US scan does not equate to a normal baby. In this study, both the ISS and AAURA had similar results, with detection of just under half of Down syndrome fetuses at a 5% false-positive rate and two-thirds of Down syndrome fetuses at a 25% false-positive rate.

In conclusion, at a 5% false-positive rate, approximately half of all midtrimester fetuses with Down syndrome will be detected by using current US systems (ISS or AAURA). Both methods result in similar rates of detection, although AAURA provides a patient-specific risk estimate.


   Acknowledgments
 
We thank the ultrasonographers and laboratory personnel for their assistance with data collection and, in particular, Amy Anderson, BSc, and Aaron Ostrovsky, BA, for their help in compiling the database and Maureen Michaud, BA, for her help in manuscript preparation.


   Footnotes
 
Abbreviations: AAURA = age-adjusted US risk assessment, EGA = estimated gestational age, ISS = index scoring system, ROC = receiver operating characteristic

Author contributions: Guarantor of integrity of entire study, T.C.W.; study concepts and design, T.C.W., D.A.N.; definition of intellectual content, T.C.W.; literature research, T.C.W.; clinical studies, T.C.W., D.A.N.; data acquisition, T.C.W., D.A.N., S.B.U., V.L.S.; data analysis, T.C.W; statistical analysis, T.C.W.; manuscript preparation, T.C.W.; manuscript editing, T.C.W., D.A.N.; manuscript review, T.C.W.


   References
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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