An AI-based approach driven by genotypes and phenotypes to uplift the diagnostic yield of genetic diseases.

Identifying disease-causing variants in Rare Disease patients' genome is a challenging problem. To accomplish this task, we describe a machine learning framework, that we called "Suggested Diagnosis", whose aim is to prioritize genetic variants in an exome/genome based on the probability of being disease-causing. To do so, our method leverages standard guidelines for germline variant interpretation as defined by the American College of Human Genomics (ACMG) and the Association for Molecular Pathology (AMP), inheritance information, phenotypic similarity, and variant quality. Starting from (1) the VCF file containing proband's variants, (2) the list of proband's phenotypes encoded in Human Phenotype Ontology terms, and optionally (3) the information about family members (if available), the "Suggested Diagnosis" ranks all the variants according to their machine learning prediction. This method significantly reduces the number of variants that need to be evaluated by geneticists by pinpointing causative variants in the very first positions of the prioritized list. Most importantly, our approach proved to be among the top performers within the CAGI6 Rare Genome Project Challenge, where it was able to rank the true causative variant among the first positions and, uniquely among all the challenge participants, increased the diagnostic yield of 12.5% by solving 2 undiagnosed cases.

Perivascular Fat Density and Contrast Plaque Enhancement: Does a Correlation Exist?

BACKGROUND AND PURPOSE: Inflammatory changes in the fat tissue surrounding the coronary arteries have been associated with coronary artery disease and high-risk vulnerable plaques. Our aim was to investigate possible correlations between the presence and degree of perivascular fat density and a marker of vulnerable carotid plaque, namely contrast plaque enhancement on CTA. MATERIALS AND METHODS: One-hundred patients (76 men, 24 women; mean age, 69 years) who underwent CT angiography for investigation of carotid artery stenosis were retrospectively analyzed. Contrast plaque enhancement and perivascular fat density were measured in 100 carotid arteries, and values were stratified according to symptomatic (ipsilateral-to-cerebrovascular symptoms)/asymptomatic status (carotid artery with the most severe degree of stenosis). Correlation coefficients (Pearson ρ product moment) were calculated between the contrast plaque enhancement and perivascular fat density. The differences among the correlation ρ values were calculated using the Fisher r-to-z transformation. Mann-Whitney analysis was also calculated to test differences between the groups. RESULTS: There was a statistically significant positive correlation between contrast plaque enhancement and perivascular fat density (ρ value = 0.6582, P value = .001). The correlation was stronger for symptomatic rather than asymptomatic patients (ρ value = 0.7052, P value = .001 versus ρ value = 0.4092, P value = .001). CONCLUSIONS: There was a positive association between perivascular fat density and contrast plaque enhancement on CTA. This correlation was stronger for symptomatic rather than asymptomatic patients. Our results suggest that perivascular fat density could be used as an indirect marker of plaque instability.

Step-and-Shoot IMRT by Siemens Beams: An EPID Dosimetry Verification During Treatment.

PURPOSE: This work reports the extension of a semiempirical method based on the correlation ratios to convert electronic portal imaging devices transit signals into in vivo doses for the step-and-shoot intensity-modulated radiotherapy Siemens beams. The dose reconstructed at the isocenter point Diso, compared to the planned dose, Diso,TPS, and a γ-analysis between 2-dimensional electronic portal imaging device images obtained day to day, seems to supply a practical method to verify the beam delivery reproducibility. METHOD: The electronic portal imaging device images were obtained by the superposition of many segment fields, and the algorithm for the Diso reconstruction for intensity-modulated radiotherapy step and shoot was formulated using a set of simulated intensity-modulated radiotherapy beams. Moreover, the in vivo dose-dedicated software was integrated with the record and verify system of the centers. RESULTS: Three radiotherapy centers applied the in vivo dose procedure at 30 clinical intensity-modulated radiotherapy treatments, each one obtained with 5 or 7 beams, and planned for patients undergoing radiotherapy for prostatic tumors. Each treatment beam was checked 5 times, obtaining 900 tests of the ratios R = Diso/Diso,TPS. The average R value was equal to 1.002 ± 0.056 (2 standard deviation), while the mean R value for each patient was well within 5%, once the causes of errors were removed. The γ-analysis of the electronic portal imaging device images, with 3% 3 mm acceptance criteria, showed 90% of the tests with Pγ < 1 ≥ 95% and γmean ≤ 0.5. The off-tolerance tests were found due to incorrect setup or presence of morphological changes. This preliminary experience shows the great utility of obtaining the in vivo dose results in quasi real time and close to the linac, where the radiotherapy staff may immediately spot possible causes of errors. The in vivo dose procedure presented here is one of the objectives of a project, for the development of practical in vivo dose procedures, financially supported by the Istituto Nazionale di Fisica Nucleare.

A 512-channels, whole array readout, CMOS implantable probe for acute recordings from the brain.

The integration of implantable CMOS neural probes with thousands of simultaneously recording microelectrodes is a promising approach for neuroscience and might allow to literally image electrophysiological neuronal activity in multiple brain circuits as we have previously shown in vitro. Here, we present a complete system based on a fully multiplexed CMOS neural probe that was designed for in-vivo acute recordings with a scalable circuit architecture. In particular, a first prototype of a single-shaft probe with 512 electrodes was realized in a standard CMOS 0.18µm technology and post-processed to structure the shaft with a wedge-like geometry of 30µm in thickness at the tip and 80µm at the base. The design of the system and of the probe as well as the post-processing techniques are discussed. Finally, preliminary results on electrical, mechanical and implantation tests are presented to demonstrate the feasibility of our approach.

Quasi-VMAT in high-grade glioma radiation therapy.

PURPOSE: To compare a quasi-volumetric modulated arc therapy (qVMAT) with three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) for the treatment of high-grade gliomas. The qVMAT technique is a fast method of radiation therapy in which multiple equispaced beams analogous to those in rotation therapy are radiated in succession. PATIENTS AND METHODS: This study included 12 patients with a planning target volume (PTV) that overlapped at least one organ at risk (OAR). 3D-CRT was planned using 2-3 non-coplanar beams, whereby the field-in-field technique (FIF) was used to divide each field into 1-3 subfields to shield the OAR. The qVMAT strategy was planned with 15 equispaced beams and IMRT was planned using 9 beams with a total of 80 segments. Inverse planning for qVMAT and IMRT was performed by direct machine parameter optimization (DMPO) to deliver a homogenous dose distribution of 60 Gy within the PTV and simultaneously limit the dose received by the OARs to the recommended values. Finally, the effect of introducing a maximum dose objective (max. dose < 54 Gy) for a virtual OAR in the form of a 0.5 cm ring around the PTV was investigated. RESULTS: The qVMAT method gave rise to significantly improved PTV95% and conformity index (CI) values in comparison to 3D-CRT (PTV95% = 90.7 % vs. 82.0 %; CI = 0.79 vs. 0.74, respectively). A further improvement was achieved by IMRT (PTV95% = 94.4 %, CI = 0.78). In qVMAT and IMRT, the addition of a 0.5 cm ring around the PTV produced a significant increase in CI (0.87 and 0.88, respectively), but dosage homogeneity within the PTV was considerably reduced (PTV95% = 88.5 % and 92.3 %, respectively). The time required for qVMAT dose delivery was similar to that required using 3D-CRT. CONCLUSION: These findings suggest that qVMAT should be preferred to 3D-CRT for the treatment of high-grade gliomas. The qVMAT method could be applied in hospitals, for example, which have limited departmental resources and are not equipped with systems capable of VMAT delivery.

Decline of maternal hepatitis A virus antibody levels in infants.

UNLABELLED: Hepatitis A is a common viral infection causing substantial morbidity and mortality. The anti-hepatitis A virus (HAV) vaccination in infants would guarantee control of the infection. However, the immunogenicity of the HAV vaccine in infants could be impaired by the presence of passively acquired maternal HAV antibodies. This study evaluated the prevalence of HAV antibodies in 103 women at delivery and in their babies in the first year of life. Eighteen mothers (17.5%) had anti-HAV serum level >10 mIU ml(-1). In their infants the anti-HAV level was still positive in 11 out of 18 (61.1%) at 12 mo. Two out of 85 infants born to anti-HAV-negative mothers and anti-HAV negative at birth were found to be positive at 5 mo of age. CONCLUSION: It is proposed that all women be screened at delivery for anti-HAV antibodies. Children born to anti-HAV-negative mothers could be vaccinated early during the first year of life, whereas vaccination could be postponed in children born to anti-HAV-positive mothers, if necessary.

Prospective multicenter study on the clinical utility of ca-72.4 in postmenopausal patients with pelvic mass.

The study objective was to evaluate the sensitivity and specificity as well as the positive predictive value and negative predictive value of CA 72.4 and CA 125 determination, separately and in combination, for diagnosing ovarian tumors in post-menopausal women with pelvic mass. The 299 patients recruited in this study underwent gynecological examination, plasma determination of CA 72.4 and CA 125, and laparotomy with histological definition of pelvic mass. CA 72.4 assay values were under 3.9 U/ml in 194 cases (70.8%); values ranged from 3.9 to 4.5 U/ml in 7 cases (2.5%) and were greater than 4.5 U/ml in 73 cases (26.6%). CA 72.4 assay was positive (>4.5 U/ml) in 56 cases (57.1%) of malignant ovarian pathology, in 4 cases (25%) of malignant extra-ovarian pathology as well as in 9 cases (7.1%) of benign ovarian pathology and in 4 cases (11.8%) of benign extra-ovarian pathology. With a cut-off at 3.9 U/ml, CA 72.4 showed a specificity of 91.3% and a sensitivity of 62.2%, whereas with a cut-off at 4.5 U/ml specificity was 92.9% and sensitivity 57.1%. Results of CA 125 assay for diagnosing a pelvic neoplasia (ovarian or extra-ovarian), showed a specificity of 85.3% and sensitivity of 68.8%. The agreement of the two markers (CA 125 and CA 72.4) as negative or positive shows a specificity of 77% and a sensitivity of 84.7% for ovarian cancer and a specificity of 73.5% and sensitivity of 75% for the diagnosis of pelvic neoplasias.

Prospective multicenter study on CA 125 in postmenopausal pelvic masses.

The purpose of this study was to determine the diagnostic value of CA 125 in comparison with transabdominal ultrasound (US) in the evaluation of postmenopausal women with pelvic mass to detect malignant epithelial ovarian tumors. Postmenopausal patients with pelvic mass were studied with gynecologic examination, US and CA 125 determination. Three hundred eighty-eight patients were entered in the study. According to stratification based on US (probably benign, equivocal, possibly malignant) and CA 125 (< 35 U/ml, negative; between 35 and 65 U/ml, borderline; > 65 U/ml, positive), 290 patients were considered eligible for surgery. Specificity, sensitivity, positive and negative predictive value, and accuracy of US and CA 125 were calculated with respect to histological examination. Out of 290 operated patients, 134 had a benign ovarian pathology, 34 had extraovarian benign pathology, 106 had an ovarian malignancy, and 16 presented with an extraovarian malignant pathology. The results according to ovarian malignant pathology were as follows. CA 125 (> 65 U/ml): Specificity, 92.5%; sensitivity, 71.7%; accuracy, 83.3%. CA 125 (> 35 U/ml): Specificity, 82.0%; sensitivity, 78.3%; accuracy, 80.4%. US: Specificity, 77.6%; sensitivity, 84.9%; accuracy, 80.3%. Combination of US and CA 125 (> 65 U/ml): Specificity, 96.1%; sensitivity, 91.7%; accuracy, 94.3%. Determination of CA 125 is a highly specific method in predicting ovarian cancer in postmenopausal women with a pelvic mass. The association with US significantly improves the overall accuracy and may support therapeutical decision making by distinguishing between a significant percentage of women most likely to benefit from prompt intervention and women who may be managed following minor surgical diagnostic approach, such as fine-needle aspiration.

Absent end-diastolic velocity in umbilical artery: risk of neonatal morbidity and brain damage.

OBJECTIVE: We conducted a cohort study in growth-retarded fetuses to establish if absent or reverse end-diastolic flow in the umbilical artery was associated with increased perinatal mortality and morbidity and neurologic damage at long-term follow-up. STUDY DESIGN: Thirty-one fetuses with intrauterine growth retardation and absent or reverse end-diastolic flow in the umbilical artery (study group) and 40 growth-retarded fetuses with detectable diastolic flow in the umbilical artery, divided into two control groups, were followed up with serial nonstress tests, Doppler flow studies, and biophysical profiles. Twenty newborns from the study group survived the perinatal period and were observed for a mean of 18 months (range 12 to 24 months). Their neurologic outcomes were compared with those of 26 neonates from the two control groups. RESULTS: Study group fetuses had a higher incidence of abnormal karyotype (9.7% vs 0%) and corrected perinatal mortality (26% vs 6% and 4%) and a greater risk of permanent neurologic sequelae (35% vs 0% and 12%) compared with the fetuses from the two control groups. CONCLUSIONS: Growth-retarded fetuses with absent or reverse end-diastolic flow in the umbilical artery not only have an increased fetal and neonatal mortality but also a higher incidence of long-term permanent neurologic damage when compared with growth-retarded fetuses with diastolic flow in the umbilical circulation.

The role of sonographically guided aspiration in the clinical management of ovarian cysts.

This study was undertaken to verify the role of fine-needle aspiration (FNA) followed by cytologic examination as a possible alternative to surgery in case of cystic pelvic masses. From January 1988 to March 1989, 204 patients with a proven cystic pelvic mass underwent FNA under sonographic guidance. In 20 cases the aspiration was performed transvaginally. Thirty-six patients were postmenopausal. In all cases the aspirated fluid was collected for cytologic evaluation. Other than one case of persistent hematuria, no complications occurred. The overall recurrence rate, verified 3 months from FNA, was 65%. Fifty-two per cent of patients developed a new cyst after a complete aspiration. Fifty-three patients underwent a laparotomy, allowing a comparison between cytologic and histologic patterns. The sensitivity of cytologic examination of aspirated fluids was 40% (3 of 5 malignancies were missed) and the specificity was 100% (no false positives were observed). We conclude that FNA might be proposed in young women with a unilocular ovarian cyst to avoid a surgical procedure. In postmenopausal women with a unilocular cystic mass 5 cm or less, FNA may be considered as an important step in the diagnosis. In all instances the ultrasonographic appearance of the cyst (echo texture and regularity of wall) and the characteristics of aspirated fluid are the most important findings. When the aspirated fluid contains mucus or blood, or when a complex mass is present, exploratory laparotomy or a laparoscopy is recommended.

Fitting growth curves to head and abdomen measurements of the fetus: a multicentric study.

Three different mathematical models were fitted to ultrasonic measurements of the biparietal diameter, head circumference, and abdomen circumference obtained from 1,426 healthy fetuses. The linear cubic function gives coefficients comparable with most previous studies, but it does not thoroughly explain fetal growth throughout pregnancy. Both the exponential-power function and the logistic-logarithmic function fit the raw data well and theoretically reflect the biological phenomena of human fetal growth. The characteristics of each model are discussed.