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Virtual screening to enrich hit lists from high-throughput screening: a case study on small-molecule inhibitors of angiogenin.

"Hit lists" generated by high-throughput screening (HTS) typically contain a large percentage of false positives, making follow-up assays necessary to distinguish active from inactive substances. Here we present a method for improving the accuracy of HTS hit lists by computationally based virtual screening (VS) of the corresponding chemical libraries and selecting hits by HTS/VS consensus. This approach was applied in a case study on the target-enzyme angiogenin, a potent inducer of angiogenesis. In conjunction with HTS of the National Cancer Institute Diversity Set and ChemBridge DIVERSet E (approximately 18,000 compounds total), VS was performed with two flexible library docking/scoring methods, DockVision/Ludi and GOLD. Analysis of the results reveals that dramatic enrichment of the HTS hit rate can be achieved by selecting compounds in consensus with one or both of the VS functions. For example, HTS hits ranked in the top 2% by GOLD included 42% of the true hits, but only 8% of the false positives; this represents a sixfold enrichment over the HTS hit rate. Notably, the HTS/VS method was effective in selecting out inhibitors with midmicromolar dissociation constants typical of leads commonly obtained in primary screens.

Binding Sites↗

Prevalence and associated factors of cancer screening: why are so many older Mexican American women never screened?

OBJECTIVES: The aim of this study was to identify patterns of mammogram and Papanicolaou (Pap) screenings among Mexican American women ages 67 and over. METHODS: Data on 1,403 Mexican American women from the Hispanic Established Population for the Epidemiological Study of the Elderly, a cohort study of community-dwelling Mexican Americans ages 65 years or over from the southwestern United States, were analyzed. RESULTS: Mexican American women age 75 or older were less likely to ever have had breast or cervical screening than women ages 67 to 74, even controlling for sociodemographic, cultural, and selected health factors. Overall, fewer medical conditions and never having had a hysterectomy were found to be associated with a decreased chance of ever having had a mammogram or a Pap test. Women who lacked insurance coverage and had fewer doctor visits were less likely to ever have had a mammogram, whereas women with low education, low acculturation, and lower cognitive status scores were less likely to ever have had a Pap test. CONCLUSIONS: If these results withstand more detailed studies (e.g., with the addition of important variables such as awareness), better communication with health professional doctors and improvement of access to heath care services should increase rates of both mammogram and Pap screenings.

Acculturation↗

Predictors of gender differences in sunscreen use and screening outcome among skin cancer screening participants.

This study identified predictors of sunscreen use in males and females and examined the extent to which gender differences in sunscreen use were associated with skin cancer screening outcomes. Subjects were 351 adult Southern California residents who participated in one of five free skin cancer screenings. Logistic regression models showed that sunscreen use was significantly associated with sex, personal and family history of skin cancer, and a sun sensitivity index. The latter three factors were found to be confounders of the sex-sunscreen use relationship. Whereas female use of sunscreen was best predicted by her sun sensitivity, male use of sunscreen was best predicted by a family history of skin cancer. Screening outcomes also varied by sex, suggesting that the interrelationships among gender, family history of skin cancer, and sun sensitivity have important implications for sunscreen use, which may in turn impact clinical outcomes.

Adult↗

Prenatal screening for group B Streptococcus. II. Impact of antepartum screening and prophylaxis on neonatal care.

OBJECTIVES: Our purpose was to evaluate the current practice of antimicrobial prophylaxis of preterm and low-birth-weight infants and to determine the impact of intrapartum fever, group B Streptococcus carriage, intrapartum antimicrobial therapy, and duration of membrane rupture on neonatal therapy. STUDY DESIGN: A total of 1356 members of the American Academy of Pediatrics were asked their practice regarding neonatal screening and antimicrobial prophylaxis. Respondents were asked to define how maternal fever, group B Streptococcus carriage, intrapartum antimicrobial therapy, and prolonged membrane rupture would affect their decisions regarding neonatal therapy. RESULTS: A total of 982 responses were obtained (72.4%). Routine antimicrobial prophylaxis is given to asymptomatic preterm neonates by 33.7% of pediatricians. Prophylaxis is inconsistently given at 32 to 36 weeks but is nearly universal after intrapartum fever, regardless of intrapartum therapy. If empiric intrapartum prophylaxis was given before a preterm birth, both the incidence (47.1% vs 29.1%) and frequency of prolonged neonatal therapy (30.1% vs 17.4% > or = 7 days) would be increased. Knowledge of maternal group B Streptococcus carriage would lead to a 2.6-fold increase in treatment (75.1% vs 29.1%) and 1.8-fold increase in the incidence of prolonged therapy of preterm infants (30.9% vs 17.4%), with 45.3% giving antibiotics for > or = 1 week if intrapartum treatment had been instituted. Surprisingly, 18% of pediatricians would treat term neonates without any risk factors other than maternal group B streptococcal carriage, and 32.7% would continue treatment for > or = 7 days. The majority of pediatricians (82.6%) felt that intrapartum prophylaxis would reduce early-onset group B streptococcal sepsis, but only 46.0% felt overall neonatal sepsis would be decreased by such therapy. CONCLUSIONS: Antepartum screening and intrapartum prophylaxis against group B Streptococcus by obstetricians may lead to an increased incidence and duration of treatment of preterm and term neonates by the pediatrician. The efficacy, cost, and risk of such treatment in broadly applied screening and treatment programs should be considered before a standard of care is established.

Antibiotic Prophylaxis↗

Laboratory screening of connective tissue diseases by a new automated ENA screening assay (EliA Symphony) in clinically defined patients.

BACKGROUND: The measurement of antinuclear antibodies (ANA) is used in the autoimmune laboratory for the screening of connective tissue diseases (CTD). ANA measurements are mainly performed by indirect immunofluorescence (IIF) on HEp-2 cells or by enzyme immunoassay (EIA). The objective of this study was to clinically evaluate an automated EIA for extractable nuclear antigens (ENA) which lacks anti-dsDNA for the screening of CTD. METHODS: The study involved a total of 170 serum samples, 54 from patients with CTD, 26 from patients with other autoimmune diseases, and 90 from patients with non-autoimmune diseases. For all sera, ANA detection was performed by IIF and by EliA Symphony (Pharmacia Diagnostics, Freiburg, Germany), an ENA screening which detects the following autoantibodies: SSA/Ro, SSB/La, U1RNP (70 kDa, A, C), Scl-70, JO-1, centromere B and Sm. Also, anti-dsDNA (EliA dsDNA, Pharmacia Diagnostics, Freiburg, Germany) was measured on all samples. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), efficiency, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were calculated. RESULTS: Diagnostic efficiency was similar for IIF (82.6%) and EliA Symphony (82.3%), as well as PLR (6.5 for IIF, and 7.3 for Eli Symphony), and NLR (0.35 for IIF, and 0.41 for EliA Symphony). The combined measurement of EliA Symphony and dsDNA increased sensitivity but not PLR. Area under receiver operator characteristic (ROC) curve was similar for IIF (0.847) and EliA Symphony (0.823). CONCLUSIONS: The results of the study demonstrate that EliA Symphony solely or combined with anti-dsDNA detection has an efficiency similar to HEp-2 cells IIF with a cut-off of 1:160 for the diagnosis of CTD.

Antibodies, Antinuclear↗

Research perspectives for pre-screening alternatives to animal experimentation: on the relevance of cytotoxicity measurements, barrier passage determinations and high throughput screening in vitro to select potentially hazardous compounds in large sets of chemicals.

The MEIC study revealed a high predictivity of in vitro cytotoxicity data for human acute systemic toxicity. The idea, put forward by several authors, that compounds that show high cytotoxicity should not need further testing for confirmation but could be assumed toxic also in vivo provides a convenient concept for the selection of the most relevant compounds for further studies in large sets of chemicals, as in the REACH program. The automated techniques applied in high throughput screening (HTS) by the pharmaceutical and biotech industries to select hits in extensive compound collections represent an opportunity to significantly increase the capacity of cytotoxicity testing. Furthermore, it has been suggested that a combination of cytotoxicity data and some basic biokinetic information would greatly improve the accuracy in the extrapolation from in vitro to in vivo and thus make it possible to identify additional toxic compounds that might have escaped in the initial screen. Such information, which can be obtained in a medium throughput screening mode (MTS), includes biotransformation, absorption and some aspects of distribution. The measurement of the net flux of a compound over a cellular barrier, as the one formed in culture by human Caco-2 cells, gives useful, but limited, information on both gut absorption and blood-brain barrier penetration. The test procedures discussed here, as well as other supplementary in vitro tests, cannot always easily be described in terms of animal-based test replacements. In those instances, the necessary test validation cannot be carried out using animal reference data, and prediction models may have to be adapted to new ideas. Consequently, concepts of prospective validation to supplement the now well-established retrospective validation have to be developed.

Animal Testing Alternatives↗

Nutrition Screening Initiative Checklist may be a better awareness/educational tool than a screening one.

OBJECTIVE: To evaluate the Nutrition Screening Initiative (NSI) checklist as a screening and an awareness/educational tool in an elderly population. DESIGN: Epidemiologic follow-up study. Information similar to the questions of the NSI checklist was collected by the Nutrition Status Survey of Boston elders between 1981 and 1984. Vital status of volunteers was obtained during 8 to 12 years of follow-up. SUBJECTS/SETTING: Community-dwelling men (n = 200) and women (n = 381) aged 60 years and older who participated in the survey. STATISTICAL ANALYSES PERFORMED: Multivariate analysis was used to assess the association between mortality and each of the NSI-similar questions and the cumulative score, which is the sum of the values assigned to each question. Attributable risk percent, a measure of association, was calculated to measure the percentage of deaths that could potentially be prevented if the risk factors or their consequences were eliminated. RESULTS: Eating meals alone, problems biting or chewing, difficulties with shopping or cooking, and taking more than three medications per day were positively associated with mortality (P < .05). The cumulative score, although significant, was a weaker predictor of mortality. Attributable risk percent of mortality was 19.9% and 51.2% for men and women, respectively. APPLICATIONS/CONCLUSIONS: Some but not all of the individual questions of the NSI checklist equivalent were significantly associated with mortality and identify specific problems that may have a long-term negative effect yet may be missed if the cumulative score were the sole criterion for screening people. The attributable risk percent suggests that the checklist may be best used as an awareness/educational tool as intended originally and could have an important public health effect on early death of community-dwelling elderly people.

Aged↗

Combining maternal serum alpha-fetoprotein measurements and age to screen for Down syndrome in pregnant women under age 35. New England Regional Genetics Group Prenatal Collaborative Study of Down Syndrome Screening.

Eight prenatal diagnostic centers in New England enrolled 77,273 second-trimester pregnant women between January 1986 and March 1987 to study prospectively the sensitivity and detection efficiency of maternal serum alpha-fetoprotein measurement as a screening test for Down syndrome. The study was limited to women under the age of 35 because it is accepted practice to offer amniocentesis to all women above that age. Based on risk estimates derived from a combination of maternal age and maternal serum alpha-fetoprotein measurement, 4.7% of the study population was initially classified as being at high risk for having a Down syndrome fetus (second-trimester odds for Down syndrome greater than or equal to 1:270). Forty percent of the high-risk population were subsequently placed in the low-risk category, usually because ultrasound findings corrected the gestational dates and caused the maternal serum alpha-fetoprotein interpretation to be changed. Seventy-six percent of the 2.7% of women remaining at high risk had amniocentesis; 18 fetuses with Down syndrome and 4 fetuses with trisomy 18 were identified in that group. Overall, one fetus with Down syndrome was detected per 89 amniocenteses, and an estimated 25% of all fetuses with Down syndrome were identified. These data establish the feasibility of maternal serum alpha-fetoprotein measurements as a method to screen for Down syndrome and suggest the possibility that such screening might be applicable in women over age 35 as well.

Adult↗

Difficulties in screening for adjustment disorder, Part II: An attempt to develop a novel self-report screening instrument in cancer patients undergoing bone marrow transplantation.

OBJECTIVE: Screening for adjustment disorder (AD) in cancer patients presents a significant clinical challenge. As seen in Part I of this research, conventional, existing measures are rather poor at detecting this most common of psychiatric diagnoses. Bone marrow transplantation (BMT) has a high level of morbidity that can cause significant stress for patients faced with the procedure. METHODS: A sample of 95 BMT patients completed a semistructured interview and a novel self-report instrument, the Coping Flexibility Scale for Cancer (C-Flex), to determine if it could identify patients with adjustment disorder in need of further assessment and intervention. RESULTS: The screen yielded four factors but was not predictive of AD. However, the C-Flex was significantly related to the presence of any disorder (r = -0.44, p < 0.001) in this sample. In addition, Factor I of the screen was found to be correlated to the presence of any diagnosis (r = -0.44, p < 0.001) and to have adequate sensitivity (81.63%) and specificity (76.09%). SIGNIFICANCE OF RESULTS: Either because of problems with the scale or the amorphous nature of the AD category, or both, rapid identification of patients with this common problem has proven to be elusive.

Adjustment Disorders↗

Validation of accuracy of enzyme-linked immunosorbent assay in hybridoma screening and proposal of an improved screening method.

The 96-well plate format of enzyme-linked immunosorbent assay (ELISA) is the de facto standard in screening hybridomas for active antibody. Despite its widespread use, there have been few or no systematic attempts to validate its accuracy and answer the fundamental question, is it finding all the positives? We report here on a comparison between ELISA and a semiautomated flow-based kinetic exclusion assay (KinExA), both used in screening the same hybridoma cell line. Our finding is that ELISA is both overreporting (false positives) and underreporting (false negatives) compared to the KinExA system. The large number of hybridoma cells (e.g., cultured in six 96-well plates) that must be checked is daunting in considering any method other than ELISA for routine screening. To overcome this, we devised a sampling strategy in which wells are combined in a specified pattern, allowing a significant reduction in the total number of measurements required.

Animals↗

Screening for principal versus comorbid conditions in psychiatric outpatients with the Psychiatric Diagnostic Screening Questionnaire.

In examining the performance of screening scales, a distinction should be made between principal and additional diagnoses. The Psychiatric Diagnostic Screening Questionnaire (PDSQ) is a brief, psychometrically strong self-report scale designed to screen for the most common Diagnostic and Statistical Manual of Mental Disorders (4th ed; DSM-IV) Axis I disorders encountered in outpatient mental health settings. In the present report, the authors compared the performance of the PDSQ in identifying principal and comorbid disorders. Seven hundred ninety-nine psychiatric outpatients completed the PDSQ and were interviewed with the Structured Clinical Interview for DSM-IV. The sensitivity and negative predictive values of the PDSQ subscales were similar for principal and additional diagnoses.

Adolescent↗

Screen detected breast cancer in an Asian population: pathological findings of the Singapore breast screening project.

We document the pathological characteristics of 135 cancers detected in 132 predominantly Chinese women in the Singapore breast screening project. Thirty-four (25%) screen detected tumours were in situ ductal cancers; 98 (73%) invasive, while three (2%) women with malignant fine needle aspirate smears refused further treatment. The median size of in situ cancers was 10 mm; the majority (56%) demonstrated a comedo pattern. Of the invasive tumours which had a median size of 15 mm, three (3%) were microinvasive, 75 (77%) infiltrative ductal, three (3%) invasive lobular, and the remaining 17 (17%) special types or others. Histologic grading revealed 23 (24%) grade I, 52 (53%) grade II, 19 (19%) grade III and four (4%) ungraded cases. Sixty-three (65%) of the invasive cancers were node negative, while 64% of all screen detected malignancies were Stages 0 (in situ) or I. From the pathological perspective, problems of borderline lesions, microinvasion, grade assessment and histological subtyping have to be addressed.

Journal Article↗

[Allergic rhinopathy: Magic Lite SQ Allergy Screen Inhalant and CAP-FEIA SX1--comparison of two allergen-specific screening tests in serum].

Although total IgE determination in the diagnosis of allergic rhinitis has been proposed for screening, specific tests seem to be more efficient. In this study, Magic Lite SQ Allergy Screen Inhalant (ML) and CAP-FEIA Phadiatop (CF) were compared in serum in a group of 101 patients with allergic rhinitis (41 women, 60 men, mean age 31.4 years, range 7-69) and 37 controls (17 women, 20 men, mean age 38.3 years, range 6-68). All patients were suffering from nasal disease. The diagnosis based on case history, skin prick test, total and specific IgE determination and nasal challenge tests. ML was found to have a sensitivity of 96% and a specificity of 83.8% while CF achieved a sensitivity of 94.1% and a specificity of 94.6%. Efficiency was 92.8% for ML and 94.2% for CF. A positive predictive value of 94.2% for ML and of 97.9% for CF was calculated while the negative predictive value was 88.6% for ML and 85.4% for CF. It is concluded, that both ML and CF are suitable allergy screening tests able to give a 100% diagnostic security in combination with further examinations, especially regarding the case history.

Adolescent↗

Screening for Down's syndrome: experience of two district general hospitals having different screening strategies.

The aim of this retrospective study is to determine the rate of reduction in the number of Down's syndrome babies delivered in two hospitals having different screening strategies. The total number of Down's syndrome babies during the study period was 0.6/1000 births at Birch Hill Hospital and 1.9/1000 births at Oldham Hospital. Antenatal diagnosis of Down's syndrome was made in 1/4 of women (25%) at Birch Hill and 7/19 of women (37%) in Oldham. The reduction rate of Down's syndrome was similar in both hospitals (25 and 26%). This retrospective analysis and comparison between two neighbouring units, highlights the fact that there is little standardisation of screening policies and screening programmes have not resulted in a substantial reduction in Down's syndrome babies.

Journal Article↗

Cardiac anatomy screening: what is the best time for screening in pregnancy?

PURPOSE OF REVIEW: To consider the ideal gestational age for cardiac evaluation during pregnancy. RECENT FINDINGS: Screening the heart during routine obstetric ultrasound has become well established and is increasingly successful in the initial detection of major congenital heart disease. When the option of termination of pregnancy is available, the earlier the diagnosis of any major fetal malformation is made, the better for the patient. An important group who have recently been found to be at increased risk of fetal heart malformation are those with increased nuchal translucency measurements, who are identified between 11 and 14 weeks. Thus, screening for fetal anomalies is being attempted much earlier in pregnancy, aided by advances in technology. However, some forms of cardiac malformations do not become evident until the third trimester of pregnancy; as a result, some of the late-developing lesions may go undetected during very early evaluation. SUMMARY: The ideal timing for screening is a compromise between obtaining adequate images for diagnosis in the majority of routine patients, scanning sufficiently late not to miss late-developing lesions and yet offering diagnosis as early as possible for parents to consider their options, if there are any applicable to their particular diagnosis. For low-risk patients, the best compromise appears to be at around 20 weeks of gestation. For patients at increased risk of congenital heart disease, such as those found to have substantially increased nuchal translucency or those with a family history of the disease, an initial scan to exclude major malformations should be performed by the fetal cardiology expert at 12-14 weeks, with follow-up at around 20 weeks to exclude more minor defects and those lesions which may become evident later.

Echocardiography↗

Can we screen for problematic back pain? A screening questionnaire for predicting outcome in acute and subacute back pain.

OBJECTIVES: Because musculoskeletal pain is the second most frequent reason for seeking health care, the aims of this study were to determine the value of psychosocial variables in evaluating risk for developing chronic back pain problems and to develop a screening methodology to identify patients likely to have a poor prognosis. STUDY DESIGN: A prospective study was conducted on consecutive patients with acute or subacute back pain, in which patients completed a screening questionnaire and were then followed up for 6 months to determine outcome. The primary outcome variable was accumulated sick leave. METHODS: One hundred forty-two consecutive patients were asked to complete a questionnaire designed for this study. This questionnaire contained 24 items concerning psychosocial aspects of the problem. Six months later, patients were contacted to complete outcome questions about accumulated sick leave. RESULTS: A total of 97% of the patients completed both questionnaires. Although patients, on average, improved greatly, 18% had 1-30 days and 20% had fewer than 30 days of sick leave during the follow-up period. Five variables were found to be the strongest predictors of sick leave outcome (fear-avoidance work beliefs, perceived improvement, problems with work function, stress, and previous sick leave), correctly classifying 73% of the patients as opposed to a chance rate of 33%. A total score was evaluated as a means of judging risk and found to be strongly related to outcome. CONCLUSION: Potent psychosocial risk factors associated with future sick absenteeism were identified. Because the total score was related to outcome, the instrument may have use in screening patients with acute or subacute spinal pain in clinical situations.

Acute Disease↗

Screening for asymptomatic bacteriuria in pregnant patients: three office screening systems versus quantitative culture.

We screened 691 asymptomatic prenatal patients by quantitative culture of clean voided urine specimens and one of three office screening devices to detect bacteriuria. The ability of each screening system to detect a single pathogenic organism in concentration equal to or greater than 100,000/ml was analyzed. Microstix-3 reagent strips had 87.5% accuracy, with the smallest number of false-positive results (6.7%). The Bacturcult system was correct in 75% of cases, but yielded 30% false-positive results. The Testuria system was least accurate (62.5%) and had the highest incidence of false-positive tests (71%).

Bacteriological Techniques↗

Screening for alcohol problems in the U.S. general population: comparison of the CAGE, RAPS4, and RAPS4-QF by gender, ethnicity, and service utilization. Rapid Alcohol Problems Screen.

BACKGROUND: The purpose of this study was to compare the performance (sensitivity and specificity) of two brief screening instruments, CAGE and the Rapid Alcohol Problems Screen 4 (RAPS4), against ICD-10 and DSM-IV criteria for alcohol dependence and abuse in a representative sample of the U.S. adult household population by gender, ethnicity, and service utilization (emergency room and primary care) in the last year. METHODS: Data are from the Alcohol Research Group's 2000 National Alcohol Survey (n = 7612), which is a computer-assisted telephone interview survey of the U.S. general population 18 and over in all 50 U.S. states and the District of Columbia. RESULTS: Sensitivity of the RAPS4 (0.86) was better than the CAGE (0.67) given similar specificity (0.95 vs. 0.98) and outperformed the CAGE for alcohol dependence across all gender, ethnic, and service utilization groups, except among blacks and Hispanics. The RAPS4 also performed equally well for females and males (0.88 vs. 0.85), whereas sensitivity of the CAGE was lower for females. Although sensitivity of the RAPS4 was better than the CAGE for alcohol abuse, sensitivity was low for both (0.56 and 0.36, respectively). When quantity-frequency (QF) questions (drinking five or more drinks on at least one occasion during the last year and drinking as often as once a month during the last year) were added to the RAPS4, the RAPS4-QF performed significantly better for alcohol abuse and outperformed the CAGE at a cut point of one across all gender, ethnic, and service utilization groups. The RAPS4-QF appeared to be most sensitive for alcohol abuse among both males and females reporting emergency room use (0.90). CONCLUSIONS: The data suggest that the RAPS4 outperforms the CAGE in this general population sample. The addition of a QF question to the RAPS4 improves performance in relation to sensitivity for alcohol abuse, and the RAPS4 and RAPS4-QF may be the instruments of choice in brief screening for alcohol use disorders. Additional research is needed to further explore these issues.

Adolescent↗