ACMG statement on noninvasive prenatal screening for fetal aneuploidy.

Noninvasive assessment of the fetal genome is now possible using next-generation sequencing technologies. The isolation of fetal DNA fragments from maternal circulation in sufficient quantity and sizes, together with proprietary bioinformatics tools, now allows patients the option of noninvasive fetal aneuploidy screening. However, obstetric care providers must become familiar with the advantages and disadvantages of the utilization of this approach as analysis of cell-free fetal DNA moves into clinical practice. Once informed, clinicians can provide efficient pretest and posttest counseling with the goal of avoiding patient harm. It is in the public's best interest that test results contain key elements and that laboratories adhere to established quality control and proficiency testing standards. The analysis of cell-free fetal DNA in maternal circulation for fetal aneuploidy screening is likely the first of major steps toward the eventual application of whole fetal genome/whole fetal exome sequencing.

Multiple diagnostic task performance in CT examination of the chest.

OBJECTIVES: In three experiments, we studied the detection of multiple abnormality types using the satisfaction of search (SOS) paradigm, the provision of a computer-aided detection (CAD) of pulmonary nodules and a focused nodule detection task. METHODS: 51 chest CT examinations (24 that demonstrated subtle pulmonary nodules and 27 that demonstrated no pulmonary nodules) were read by 15 radiology residents and fellows under two experimental conditions: (1) when there were no other abnormalities present except test abnormalities in the exams (non-SOS condition), and (2) when other abnormalities were present in the exams (SOS condition). Trials from the two conditions were intermixed. Readers were invited to return for two sessions: one in which the SOS condition was repeated with a simulated CAD; another in which only the non-SOS condition was presented. Detection accuracy was measured using receiver operating characteristic (ROC) analysis. RESULTS: An SOS effect (reduced detection accuracy for the test nodules in the presence of the diverse added abnormalities) was not found. Average accuracy was much higher when the CAD prompt was provided, without cost in the detection of the added abnormalities. Accuracy for detecting nodules appearing without intermixed SOS trials was also substantially improved. CONCLUSIONS: CT interpretation was highly task dependent. Nodule detection was poor in the general search task. Therefore, CAD may offer a greater performance improvement than demonstrated in experiments assessing CAD using focused search. The absence of SOS may be due to limited nodule detection even without other abnormalities. Advances in knowledge CAD prompts of nodules increase the detection accuracy of nodules and decrease the time to detection-without impairing the detection accuracy-of non-nodule abnormalities.

Multiple diagnostic task performance in CT examination of the chest.

Objectives In three experiments, we studied the detection of multiple abnormality types using the satisfaction of search (SOS) paradigm, the provision of a computer-aided detection (CAD) of pulmonary nodules and a focused nodule detection task. Methods 51 chest CT examinations (24 that demonstrated subtle pulmonary nodules and 27 that demonstrated no pulmonary nodules) were read by 15 radiology residents and fellows under two experimental conditions: (1) when there were no other abnormalities present except test abnormalities in the exams (non-SOS condition), and (2) when other abnormalities were present in the exams (SOS condition). Trials from the two conditions were intermixed. Readers were invited to return for two sessions: one in which the SOS condition was repeated with a simulated CAD; another in which only the non-SOS condition was presented. Detection accuracy was measured using receiver operating characteristic (ROC) analysis. Results An SOS effect (reduced detection accuracy for the test nodules in the presence of the diverse added abnormalities) was not found. Average accuracy was much higher when the CAD prompt was provided, without cost in the detection of the added abnormalities. Accuracy for detecting nodules appearing without intermixed SOS trials was also substantially improved. Conclusions CT interpretation was highly task dependent. Nodule detection was poor in the general search task. Therefore, CAD may offer a greater performance improvement than demonstrated in experiments assessing CAD using focused search. The absence of SOS may be due to limited nodule detection even without other abnormalities. Advances in knowledge CAD prompts of nodules increase the detection accuracy of nodules and decrease the time to detection-without impairing the detection accuracy-of non-nodule abnormalities.

Usefulness of the Framingham risk score and body mass index to predict early coronary artery calcium in young adults (Muscatine Study).

The value of a coronary artery disease prediction algorithm, the Framingham risk score (score), for detecting coronary artery calcium (CAC) was examined in 385 men and 472 women, aged 29 to 43 years. Scores were compared in subjects with and without CAC and were also used to predict presence of CAC. Receiver-operating characteristic curves were computed to compare different prediction models. The score model was compared with age only, natural logarithm of body mass index (lnBMI) only, and score plus lnBMI models. CAC was detected in 30% of men and 16% of women. The mean score was significantly higher in men and women with CAC. For every 2-point increase in the score, the odds of CAC increased by 30% in women and 20% in men. Significant associations between CAC status and risk factors were observed for age in women, and high- density lipoprotein cholesterol and blood pressure in men and women. The area under the receiver-operating characteristic curve for the score was 0.67 and 0.57 for women and men, respectively. When lnBMI was added to the score model, the area increased to 0.76 in women (lnBMI p <0.0001, score p <0.005). For men, the area increased from 0.57 to 0.67, and the score was no longer significant (p >0.60) in the model with lnBMI (p <0.0001). Score predicts CAC in asymptomatic young adults. Inclusion of lnBMI in the score model adds significantly to the prediction of CAC in women and men. The lnBMI model has a greater predictive value than the score in this young population.

High-performance liquid chromatography multiplex detection of two single nucleotide mutations associated with hereditary hemochromatosis.

High-performance liquid chromatography (HPLC) has been applied to the multiplex detection of the two single nucleotide mutations commonly found in hereditary hemochromatosis (HH). HH is associated with a major G to A transition at position 845 (mutation Cys282Tyr) and a minor C to G transition at position 187 (mutation His63Asp) in the cDNA of the HFE gene. Two detection assays were developed based on HPLC analysis of restriction fragment length polymorphism (RFLP) or single nucleotide extension (SNE) products following multiplex PCR amplification. RFLP genotypes the two sites as dsDNA fragments of different lengths generated by restriction enzymes Rsa I/Bcl I. SNE extends primers 5'-adjacent to the sites of interest with a dideoxynucleotide triphosphate (ddNTP) to generate extended ssDNA. The identity of the added ddNTP reveals the identity of the original possible mutation site(s). Application of these methods with HPLC analysis provides simple and reliable genotyping for HH and can be applied to other single nucleotide polymorphism studies.

Imaging of coronary calcium: a case for electron beam computed tomography.

Coronary arterial calcification has unequivocally been shown to be a marker of atherosclerosis. To date, much research interest has been generated regarding the quantification of coronary calcification by electron beam computed tomography, and how best to use such measurements to identify and predict those at greatest risk for an adverse cardiac event. This article represents an attempt to provide an objective review of the literature regarding the potential role electron beam computed tomography (EBCT) has as an accurate and cost effective screening modality for coronary arterial disease, as well as a predictor for coronary heart disease.

MR imaging of pulmonary and mediastinal malignancies.

The primary goal of performing cross-sectional imaging of the chest in the radiologic evaluation of lung cancer is to obtain information about the character and magnitude of the neoplasm. Patient prognosis and therapy decisions depend directly on identifying the size and full extent of the tumor. The ideal imaging modality therefore should provide reliable information that can be used to assist in accurately staging the malignancy. Traditionally, CT scanning has been used exclusively as part of the preoperative evaluation of primary lung carcinomas. Recent advances in CT scanning technology have greatly improved image acquisition times and image quality and consequently have enhanced the role of CT imaging in the evaluation of bronchogenic carcinomas. Single-breath CT acquisitions of the chest can now be accomplished in a matter of seconds. These rapid acquisitions improve image quality by decreasing respiratory motion, while enhancing patient compliance and throughput. Clearly, CT scanning has matured into an efficient and accurate diagnostic tool to stage primary lung malignancies noninvasively. In its present state of development, MR imaging has one distinct disadvantage that makes it significantly less attractive as a routine lung cancer examination, namely the inability to produce images of the lung that are high in spatial resolution. Also, the sensitivity and specificity of MR imaging, which are similar to those of CT scanning in identifying mediastinal and hilar metastases, offer no clinical advantages. Longer image acquisition times and time constraints force most MR imaging examinations to be abbreviated and limited in coverage. As a result, the necessary exclusion of important anatomic areas routinely visualized by CT scanning may limit the diagnostic power of MR imaging. Finally, MR imaging requires greater physician supervision than CT scanning to direct imaging and to maintain examination quality and thoroughness. Although MR imaging can contribute significantly to the radiologic evaluation of patients with lung cancer, its role is somewhat limited, and it is most useful as a complement to CT scanning. The additional versatility offered by pulse sequences that take advantage of the intrinsic relaxation of tissues greatly facilitates identification of tumor, particularly when local invasion is present. By virtue of the short T1 value of fat, MR imaging may improve the detection of mediastinal disease, particularly in cases in which the sensitivity of CT scanning cannot be optimized because of allergies to contrast or renal insufficiency. MR imaging is superior to CT scanning in demonstrating musculoskeletal anatomy and the neurovascular structures of the neck and mediastinum. Although MR imaging has a potential usefulness in the radiographic evaluation of lung carcinoma, technical shortcomings relegate this modality to a role that is primarily complementary to CT scanning. With time, technological improvements will undoubtedly redefine the role of MR imaging in the radiographic evaluation and staging of bronchogenic carcinomas.

Detection of hemochromatosis through the analysis of single- nucleotide extension products by capillary electrophoresis.

Hereditary hemochromatosis is one of the most common hereditary disorders in Caucasians.The disease is linked to two single-nucleotide polymorphisms (SNPs) in the HFE gene.The two point mutations result in a change of Cys to Tyr at position 282 and His to Asp at position 63 in the resultant protein.We have developed a single-nucleotide extension (SNE) assay for hereditary hemochromatosis genetic testing, which employs capillary electrophoresis to simultaneously detect the SNE products generated from the two SNP sites. An upstream or a downstream primer adjacent to the possible mutation site is designed and extended one nucleotide further at the 3' end, complementary to the nucleotide at the possible mutation site.The extended nucleotide is one of four fluorescently labeled dideoxynucleotide triphosphates that also act as terminators. Analysis of the extended products by laser-induced fluorescence capillary electrophoresis (LIF-CE) directly reflects the identity of the possible mutation site. Using one primer upstream or downstream from the possible mutation site, three genotypes at one mutation site can be distinguished. Using both upstream and downstream primers provides a second level of specificity and increases the accuracy of the genetic test. The protocol can also be applied to the study of other SNP analyses and to simultaneous detection of multiple mutation sites.

PET, CT, and MRI with Combidex for mediastinal staging in non-small cell lung carcinoma.

BACKGROUND: To determine the relative utility of positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging with Combidex (MRI-C) in the non-invasive staging of non-small cell lung cancer (NSCLC) mediastinal lymph nodes (MLN), we compared the three tests' individual performance with surgical mediastinal sampling. In contrast to prior studies, cytology was not used. METHODS: The MLN were evaluated using PET and CT in 64 NSCLC patients. MRI-C was performed in 9 of these patients. MLN with a PET standard uptake value greater than or equal to 2.5, or greater than 1 cm in the short axis by CT or lack of MRI-C signal change were considered positive for metastatic disease. All MLN were sampled and subjected to standard pathologic analysis. PET, CT, and MRI-C scans were interpreted blinded to the histopathological results. Sensitivity, specificity, and accuracy for each scan type to appropriately stage MLN was determined using pathologic results as the standard. RESULTS: Thirty patients had stage I disease, 8 stage II, 9 stage IIIA, 7 stage IIIB, and 10 stage IV. Two-hundred-and-thirty MLN were sampled. Sixteen patients had metastatic mediastinal disease. Compared to the pathological results, PET, CT, and MRI-C had a sensitivity, specificity, and accuracy of 70%, 86%, 84%; 65%, 79%, 76%; 86%, 82%, and 83%, respectively. PET and MRI-C were statistically more accurate than CT (p<0.001). In cases where PET and CT did not identify MLN involvement with NSCLC, 8% (2/25) were pathologically positive. CONCLUSIONS: PET and MRI-C are statistically more accurate than CT. However, the differences are small and may not be clinically relevant. No technique was sensitive or specific enough to change the current recommendation to perform mediastinoscopy for MLN staging in NSCLC.

Multicenter clinical trial of ultrasmall superparamagnetic iron oxide in the evaluation of mediastinal lymph nodes in patients with primary lung carcinoma.

The purpose of this study was to evaluate the clinical efficacy of ultrasmall superparamagnetic iron oxide particles as a magnetic resonance (MR) contrast agent in differentiating metastatic from benign lymph nodes. Eighteen patients with primary lung malignancy and suspected regional lymph node metastases underwent MR imaging before and after Combidex(R) infusion in a multi-institutional study. All MR sequences were interpreted by one or more board-certified radiologists experienced in imaging thoracic malignancy. Each patient was evaluated for the number and location of lymph nodes, homogeneity of nodal signal, and possible change of MR signal post contrast. All patients underwent resection or sampling of the MR-identified lymph node(s) 1-35 day(s) post contrast MR imaging. In all, 27 lymph nodes or nodal groups were available for histopathologic correlation. Combidex had a sensitivity of 92% and a specificity of 80% in identifying pathologically confirmed metastatic mediastinal lymph nodes. Based on our preliminary data, Combidex MR imaging may provide additional functional information useful in the staging of mediastinal lymph nodes.

Imaging of coronary artery calcification. Its importance in assessing atherosclerotic disease.

Coronary artery calcification is a marker for atherosclerotic disease. The calcifications frequently occur early in the disease process and often before the development of luminal narrowing or cardiac events. Electron beam CT has a high accuracy in detecting calcifications, and thus has prognostic value in predicting luminal narrowing and future cardiac events.

Personnel exposure rates during simulated biopsies with a real-time CT scanner.

RATIONALE AND OBJECTIVES: Real-time computed tomography (CT) has the potential to expedite and improve CT-guided needle biopsies by allowing cross-sectional images to be viewed in real time as a needle is advanced toward the target lesion. A major concern about this procedure is the scattered and leaked radiation to which the operator is exposed. This study was undertaken to determine the exposure rates around a CT scanner during CT-guided needle biopsies and to identify the areas of greatest personnel exposure. MATERIALS AND METHODS: Pig and human cadavers were used to simulate patients undergoing a CT-guided needle biopsy. Various anatomic biopsy sites were used. The radiologist's exposure was assessed by timing the procedure and measuring the exposure rates around the CT scanner with an ionization-chamber survey meter. Ion-chamber measurements multiplied by the time the radiologist spent performing several mock biopsies were compared with film dosimeter results. Doses to the hands, wrists, and whole body were measured with ring, wrist, body, and collar film dosimeters. RESULTS: The average time required to perform a single biopsy was about 1 minute. The dose to the radiologist performing the simulated biopsies was calculated to be 123 mR, 68 mR, 14 mR, and less than 0.5 mR to the fingers, wrist, collar, and body, respectively, as calculated from ionization-chamber and time measurements. These exposure rates correlate well with the film dosimeter readings accumulated during the mock procedures. CONCLUSION: The dose received by the radiologist performing a CT-guided biopsy was comparable to that of other interventional procedures. In addition, operating from the head of the machine (ie, distal to the bed) appeared to markedly reduce personnel exposure, due to the shielding in the gantry of the CT scanner used in the study.

Coronary atherosclerosis and its effect on cardiac structure and function: evaluation by electron beam computed tomography.

Coronary artery disease affects millions of Americans annually. In evaluating coronary artery disease, it is important to develop diagnostic methodology that can screen patients before the onset of symptoms or cardiac events and, in addition, evaluate the functional aspects of coronary artery disease, including any residual effects on the heart after events have occurred. Electron beam computed tomography allows the identification of coronary calcium, which is a marker for coronary atherosclerotic disease, and also allows the quantification of cardiac function, which may be altered from coronary atherosclerosis or the occurrence of a cardiac event. Thus, electron beam computed tomographic imaging is having a major impact on the diagnosis and follow-up on coronary artery disease.

Identifying left lower lobe pneumonia at chest radiography: performance of family practice residents before and after a didactic session.

RATIONALE AND OBJECTIVES: The authors sought to determine whether the lateral chest radiograph is helpful in identifying left lower lobe pneumonia among inexperienced readers. MATERIALS AND METHODS: The authors selected all patients who presented to a family practice training program with radiologic and clinical evidence of left lower lobe pneumonia (n = 65). They then selected an equal number of patients in whom chest radiographs were taken to "rule out pneumonia" and were found to be normal. Eight 1st-year family practice residents were asked to read the radiographs before and after a didactic session that emphasized lateral chest radiograph interpretation. The radiographs were presented under two viewing conditions: posteroanterior (PA) only versus PA and lateral. Receiver operating characteristic (ROC) curve methods were used to compare the effect of both the didactic session and the viewing condition on diagnostic accuracy. RESULTS: There were no significant differences in performance before and after the didactic session and no differences between the two viewing conditions. After including only abnormal radiographs that demonstrated the "spine sign" (an apparent increased opacification of the lower vertebral bodies on the lateral view), the residents performed better when presented with both PA and lateral radiographs than when presented with the PA radiograph only (area under ROC curve, .8158 vs .7418, respectively; P = 0.24). CONCLUSION: In patients with left lower lobe pneumonia whose radiographs demonstrated the spine sign, diagnostic accuracy improved when the lateral chest radiograph was viewed.

Diagnosing left lower lobe pneumonia: usefulness of the 'spine sign' on lateral chest radiographs.

BACKGROUND: Left lower lobe pneumonia may be obscured by the heart on the postero-anterior (PA) chest radiograph. In such cases, the lateral projection may be helpful, especially if it exhibits the "spine sign", which is an interruption in the progressive increase in lucency of the vertebral bodies from superior to inferior. We investigated whether the spine sign would help family physicians diagnose left lower lobe pneumonia on chest radiographs. METHODS: We selected the chest radiographs of all patients with left lower lobe pneumonia who were seen between 1983 and 1995 at a family practice training program (N = 78) and an equal number of chest radiographs of patients without pneumonia. Six family physicians read these radiographs under two viewing conditions: PA only vs PA and lateral. We used receiver operating characteristic (ROC) curve methodology to compare the two viewing conditions. RESULTS: There was no significant difference in performance between the two viewing conditions. The lateral view was helpful in some patients but misleading in others. Among patients with pneumonia, the lateral view was helpful when the spine sign was present, but it was misleading when the spine sign was absent. CONCLUSIONS: In this study of family physicians, the lateral chest radiograph did not improve overall diagnostic accuracy in patients with left lower lobe pneumonia. Among pneumonia patients with the spine sign, however, the lateral view was often helpful.

The utility of the frontal chest radiograph in the evaluation of chest drain placement.

AIM: To define the utility of the frontal chest radiograph in the assessment of chest drain position. PATIENTS AND METHODS: Fifty-six frontal chest radiographs in 45 patients with 61 chest drains (18 anterior, 9 interlobar, and 34 posterior position) were reviewed retrospectively to determine radiographic characteristics. RESULTS: Eighty-nine percent of the anterior drains demonstrated a curved appearance at the insertion site, while 50% of posterior drains and all interlobar drains were straight at the insertion site. A curved intrapleural drain was a common finding when positioned anteriorly and posteriorly (67% and 59%, respectively). Interlobar drains were often straight throughout their course (89%). The tips of interlobar drains were usually positioned at the hilum (89%). CONCLUSION: Results suggest that interlobar positioning can be suspected on the frontal chest radiograph. A curving chest drain with straight appearance at the insertion site was indicative of a posterior location.

Coronary risk factors measured in childhood and young adult life are associated with coronary artery calcification in young adults: the Muscatine Study.

OBJECTIVES: This study was designed to estimate the prevalence of coronary artery calcification in young adult men and women and to examine the association between the presence of coronary artery calcification and coronary risk factors measured in childhood and young adult life. BACKGROUND: Electron beam computed tomography is a sensitive, noninvasive method for detecting coronary artery calcification, a marker of the atherosclerotic process. Coronary artery calcification is associated with coronary risk factors in older adults. METHODS: Subjects (197 men, 187 women) had coronary risk factors measured in childhood (mean age 15 years) and twice during young adult life (mean ages 27 and 33 years). Each underwent an electron beam computed tomographic study at their second young adult examination. RESULTS: The prevalence of coronary artery calcification was 31% in men and 10% in women. Increased body size, increased blood pressure and decreased high density lipoprotein (HDL) cholesterol levels were the coronary risk factors that showed the strongest association with coronary artery calcification. Significant odds ratios for coronary artery calcification, using standardized risk factor measurements at a mean age of 33 years in men and women, respectively, were 6.4 and 13.6 for the highest decile of body mass index, 6.4 and 6.4 for the highest decile of systolic blood pressure and 4.3 and 4.7 for the lowest decile of HDL cholesterol. CONCLUSIONS: Coronary artery calcification is more prevalent in men in this young adult population. Coronary risk factors measured in children and young adults are associated with the early development of coronary artery calcification. Increased body mass index measured during childhood and young adult life and increased blood pressure and decreased HDL cholesterol levels measured during young adult life are associated with the presence of coronary artery calcification in young adults.

Varied radiologic appearances of pulmonary aspergillosis.

Pulmonary aspergillosis represents a common, potentially lethal opportunistic infection that has four unique forms: allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, and invasive and semi-invasive aspergillosis. In individuals who are at risk, pulmonary aspergillosis is characterized by a spectrum of clinical and radiographic findings that are intrinsically related to the status of the immune system or the presence of structural lung disease. ABPA, occurring almost exclusively in asthma patients, is characterized radiographically by fleeting pulmonary alveolar opacities caused by deposition of immune complexes and inflammatory cells within the lung parenchyma. Mucus plugging and bronchial wall thickening can be expected in time. Aspergilloma, occurring in patients with structural lung disease, typically appears radiographically as a focal intracavitary mass and is characterized initially by an increase in the wall thickness of a preexisting cavity or cyst. Invasive aspergillosis, which occurs primarily in profoundly immunocompromised patients, may exhibit nonspecific patchy nodular opacities or lobar-type air-space disease in cases with vascular invasion. Computed tomography may reveal a halo or ground-glass attenuation and is more accurate in the detection of early disease. Cavitation often develops with time and typically results in the air crescent sign. Semi-invasive aspergillosis is radiographically similar to the invasive form but differs in clinical course, being associated with mild immunosuppression or chronic illness and typically progressing over the course of months rather than weeks.