The interdependence between screening methods and screening libraries

The most common methods for discovery of chemical compounds capable of manipulating biological function involves some form of screening. The success of such screens is highly dependent on the chemical materials - commonly referred to as libraries - that are assayed. Classic methods for the design of screening libraries have depended on knowledge of target structure and relevant pharmacophores for target focus, and on simple count-based measures to assess other properties. The recent proliferation of two novel screening paradigms, structure-based screening and high-content screening, prompts a profound rethink about the ideal composition of small-molecule screening libraries. We suggest that currently utilized libraries are not optimal for addressing new targets by high-throughput screening, or complex phenotypes by high-content screening.     

筛选蛋白质结晶条件的试剂盒研发进展

蛋白质结晶条件筛选是蛋白质分子三维结构解析的主要限速环节之一,因此发展筛选效率较高的结晶条件筛选试剂盒有着十分重要的意义.目前广泛应用的结晶条件筛选试剂盒的设计方法主要有不完全因子法、稀疏矩阵法和系统筛选法.结晶学家基于这三种方法研发了一系列用于蛋白质结晶条件筛选的试剂盒.评述了20世纪以来筛选试剂盒的设计方法及应用进展,并展望了其未来的发展方向.     

Effects of Population Based Screening for Chlamydia Infections in The Netherlands Limited by Declining Participation Rates

Background

A large trial to investigate the effectiveness of population based screening for chlamydia infections was conducted in the Netherlands in 2008–2012. The trial was register based and consisted of four rounds of screening of women and men in the age groups 16–29 years in three regions in the Netherlands. Data were collected on participation rates and positivity rates per round. A modeling study was conducted to project screening effects for various screening strategies into the future.

Methods and Findings

We used a stochastic network simulation model incorporating partnership formation and dissolution, aging and a sexual life course perspective. Trends in baseline rates of chlamydia testing and treatment were used to describe the epidemiological situation before the start of the screening program. Data on participation rates was used to describe screening uptake in rural and urban areas. Simulations were used to project the effectiveness of screening on chlamydia prevalence for a time period of 10 years. In addition, we tested alternative screening strategies, such as including only women, targeting different age groups, and biennial screening. Screening reduced prevalence by about 1% in the first two screening rounds and leveled off after that. Extrapolating observed participation rates into the future indicated very low participation in the long run. Alternative strategies only marginally changed the effectiveness of screening. Higher participation rates as originally foreseen in the program would have succeeded in reducing chlamydia prevalence to very low levels in the long run.

Conclusions

Decreasing participation rates over time profoundly impact the effectiveness of population based screening for chlamydia infections. Using data from several consecutive rounds of screening in a simulation model enabled us to assess the future effectiveness of screening on prevalence. If participation rates cannot be kept at a sufficient level, the effectiveness of screening on prevalence will remain limited.     

Effectiveness of the public health policy for breast cancer screening in Finland: population based cohort study.

OBJECTIVE: To evaluate the effectiveness of screening for breast cancer as a public health policy. DESIGN: Follow up in 1987-92 of Finnish women invited to join the screening programme in 1987-9 and of the control women (balanced by age and matched by municipality of residence), who were not invited to the service screening. SETTING: Finland. SUBJECTS: Of the Finnish women born in 1927-39, 89893 women invited for screening and 68862 controls were followed; 1584 breast cancers were diagnosed. MAIN OUTCOME MEASURES: Rate ratio of deaths from breast cancer among the women invited for screening to deaths among those not invited. RESULTS: There were 385 deaths from breast cancer, of which 127 were among the 1584 incident cases in 1987-92. The rate ratio of death was 0.76 (95% confidence interval 0.53 to 1.09). The effect was larger and significant (0.56; 0.33 to 0.95) among women aged under 56 years at entry. 20 cancers were prevented (one death prevented per 10000 screens). CONCLUSIONS: A breast screening programme can achieve a similar effect on mortality as achieved by the trials for breast cancer screening. However, it may be difficult to justify a screening programme as a public health policy on the basis of the mortality reduction only. Whether to run a screening programme as a public health policy also depends on its effects on the quality of life of the target population and what the resources would be used for if screening was not done. Given all the different dimensions in the effect, mammography based breast screening is probably justifiable as a public health policy.     

An economic view of high compliance as a screening objective.

Accepted wisdom holds that high compliance is essential for a screening programme to be successful. Indeed, a reason that the national breast screening programme is not routinely offered to women aged 65 or more is on the grounds of predicted poor compliance by older women. Increasing compliance is often associated with increased costs. These costs represent a lost opportunity for screening alternative target populations. We question the need for screening programmes to achieve high compliance, and we argue that a screening programme can be efficient with very low levels of compliance. Adopting compliance as a screening objective and as a measure of the success of screening may be detrimental to the efficiency of a screening programme.     

Cost effectiveness of antenatal screening for cystic fibrosis.

OBJECTIVE--To estimate the cost effectiveness of different antenatal screening programmes for cystic fibrosis. SETTING--Antenatal clinics and general practices in the United Kingdom. DESIGN--Four components of the screening process were identified: information giving, DNA testing, genetic counselling, and prenatal diagnosis. The component costs were derived from the literature and from a pilot screening study in Yorkshire. The cost of a given screening programme was then obtained by summing the components according to the specific screening strategy adopted (sequential and couple), the proportion of carriers detected by the DNA test, and the uptake of screening. Baseline assumptions were made about the proportion with missing information on carrier status from previous pregnancies (20%), the proportion changing partners between pregnancies (20%), and the uptake of prenatal diagnosis (100%). Sensitivity analysis was performed by varying these assumptions. MAIN OUTCOME MEASURE--Cost per affected pregnancy detected. RESULTS--Under the baseline assumptions sequential screening costs between pounds 40,000 and pounds 90,000 per affected pregnancy detected, depending on the carrier detection rate and uptake. Couple screening was more expensive, ranging from pounds 46,000 to pounds 104,000. From the sensitivity analysis a 10% change in the assumed proportion with missing information from a previous pregnancy alters the cost by pounds 4000; a 10% change in the proportion with new partners has a similar effect but only for couple screening; and cost will change directly in proportion to the uptake of prenatal diagnosis. CONCLUSIONS--While economic analysis cannot determine screening policy, the paper provides the NHS with the information on cost effectiveness needed to inform decisions on the introduction of a screening service for cystic fibrosis.     

微藻抗菌物质及筛选模型

由于海洋环境和微藻本身的特殊性,从微藻中筛选抗菌物质已成为当今研究的热点之一,并且具有广阔的应用前景。对近年来从微藻中筛选抗菌物质的研究现状和进展进行了综述,重点总结了抗菌活性物质筛选过程中的模型选用,并介绍了新筛选模型的发展,指出了难点问题及可行的解决方法。     

Cost analysis of PAPNET-assisted vs. conventional Pap smear evaluation in primary screening of cervical smears

OBJECTIVE: To assess the difference in costs between PAPNET-assisted and conventional microscopy of cervical smears when used as a primary screening tool. STUDY DESIGN: We performed time measurements of the initial screening of smears by four cytotechnologists in one laboratory. Time was measured in 816 conventionally screened smears and in 614 smears with PAPNET-assisted screening. Data were collected on the components of initial screening, clerical activities and other activities in the total work time of cytotechnologists in the routine situation and on resource requirements for both techniques. RESULTS: PAPNET saved an average of 22% on initial screening time per smear. Due to costs of processing and additional equipment, the costs of PAPNET-assisted screening were estimated to be $2.85 (and at least $1.79) higher per smear than conventional microscopy. The difference in costs is sensitive to the rate of time saving, the possibility of saving on quality control procedures and the component of the initial screening time in the total work time of cytotechnologists. CONCLUSION: Although PAPNET is time saving as compared with conventional microscopy, the associated reduction in personnel costs is outweighed by the costs of scanning the slides and additional equipment. This conclusion holds under a variety of assumptions. Using PAPNET instead of conventional microscopy as a primary screening tool will make cervical cancer screening less cost-effective unless the costs of PAPNET are considerably reduced and its sensitivity and/or specificity are considerably improved.     

Cost-Effectiveness Analysis of Risk-Factor Guided and Birth-Cohort Screening for Chronic Hepatitis C Infection in the United States

Background

No consensus exists on screening to detect the estimated 2 million Americans unaware of their chronic hepatitis C infections. Advisory groups differ, recommending birth-cohort screening for baby boomers, screening only high-risk individuals, or no screening. We assessed one-time risk assessment and screening to identify previously undiagnosed 40–74 year-olds given newly available hepatitis C treatments.

Methods and Findings

A Markov model evaluated alternative risk-factor guided and birth-cohort screening and treatment strategies. Risk factors included drug use history, blood transfusion before 1992, and multiple sexual partners. Analyses of the National Health and Nutrition Examination Survey provided sex-, race-, age-, and risk-factor-specific hepatitis C prevalence and mortality rates. Nine strategies combined screening (no screening, risk-factor guided screening, or birth-cohort screening) and treatment (standard therapy–peginterferon alfa and ribavirin, Interleukin-28B-guided (IL28B) triple-therapy–standard therapy plus a protease inhibitor, or universal triple therapy). Response-guided treatment depended on HCV genotype. Outcomes include discounted lifetime costs (2010 dollars) and quality adjusted life-years (QALYs).Compared to no screening, risk-factor guided and birth-cohort screening for 50 year-olds gained 0.7 to 3.5 quality adjusted life-days and cost $168 to $568 per person. Birth-cohort screening provided more benefit per dollar than risk-factor guided screening and cost $65,749 per QALY if followed by universal triple therapy compared to screening followed by IL28B-guided triple therapy. If only 10% of screen-detected, eligible patients initiate treatment at each opportunity, birth-cohort screening with universal triple therapy costs $241,100 per QALY. Assuming treatment with triple therapy, screening all individuals aged 40–64 years costs less than $100,000 per QALY.

Conclusions

The cost-effectiveness of one-time birth-cohort hepatitis C screening for 40–64 year olds is comparable to other screening programs, provided that the healthcare system has sufficient capacity to deliver prompt treatment and appropriate follow-on care to many newly screen-detected individuals.     

Implementation and evaluation of a new automated interactive image analysis system

OBJECTIVE: To compare automated interactive screening using the ThinPrep Imaging System with independent manual primary screening of 12,000 routine ThinPrep slides. STUDY DESIGN: With the first 6,000 cases, the Review Scopes (RS) screening results from the 22 fields of view (FOV) only were compared to independent manual primary screening. In the next 6,000 cases, any abnormality detected in the 22 FOV resulted in full manual screening on the cytotechnologist's own microscope. Sensitivity and specificity together with their 95% CIs were calculatedfor each method. RESULTS: In the first set of 6, 000 cases, diagnostic sensitivity and specificity of the imager were 85.19% and 96.67%, respectively. The diagnostic sensitivity and specificity of manual primary screening were 89.38% and 98.42%. This highersensitivity and specificity of manual primary screening were found to be statistically significant. The second set of 6,000 cases demonstrated no significant statistical difference in sensitivity or specificity between the sets of data. CONCLUSION: The results from our study show that the sensitivity and specificity of the imager technology are equivalent to those of manual primary screening. The system is ideally suited to the rapid screening of negative cases, allowing increased laboratory productivity and greater throughput of cases on a daily basis.     

农用抗生素筛选模型的发展概述

农用抗生素是指微生物产生的,可用于防治农业有害生物的次级代谢产物。随着筛选模型的贫乏,发现新型农用抗生素的难度越来越大,同时农用抗生素的研究应用与筛选模型密切相关,并随筛选模型的不断改进而向前推进。近年来,随着新技术特别是现代生物技术在微生物研究中的应用,从微生物中筛选新的农用抗生素的几率逐渐加大。主要对传统筛选模型、特定筛选模型以及高通量筛选模型进行了阐述,并对我国未来农用抗生素筛选模型的发展方向提出了预测。     

CHALLENGING THE RHETORIC OF CHOICE IN PRENATAL SCREENING

Prenatal screening, consisting of maternal serum screening and nuchal translucency screening, is on the verge of expansion, both by being offered to more pregnant women and by screening for more conditions. The Society of Obstetricians and Gynaecologists of Canada and the American College of Obstetricians and Gynecologists have each recently recommended that screening be extended to all pregnant women regardless of age, disease history, or risk status. This screening is commonly justified by appeal to the value of autonomy, or women's choice. In this paper, I critically examine the value of autonomy in the context of prenatal screening to determine whether it justifies the routine offer of screening and the expansion of screening services. I argue that in the vast majority of cases the option of prenatal screening does not promote or protect women's autonomy. Both a narrow conception of choice as informed consent and a broad conception of choice as relational reveal difficulties in achieving adequate standards of free informed choice. While there are reasons to worry that women's autonomy is not being protected or promoted within the limited scope of current practice, we should hesitate before normalizing it as part of standard prenatal care for all.     

Quantification of overdiagnosis in randomised trials of cancer screening: an overview and re-analysis of systematic reviews

The degree of overdiagnosis in common cancer screening trials is uncertain due to inadequate design of trials, varying definition and methods used to estimate overdiagnosis. Therefore, we aimed to quantify the risk of overdiagnosis for the most widely implemented cancer screening programmes and assess the implications of design limitations and biases in cancer screening trials on the estimates of overdiagnosis by conducting an overview and re-analysis of systematic reviews of cancer screening. We searched PubMed and the Cochrane Library from their inception dates to November 29, 2021. Eligible studies included systematic reviews of randomised trials comparing cancer screening interventions to no screening, which reported cancer incidence for both trial arms. We extracted data on study characteristics, cancer incidence and assessed the risk of bias using the Cochrane Collaboration’s risk of bias tool. We included 19 trials described in 30 articles for review, reporting results for the following types of screening: mammography for breast cancer, chest X-ray or low-dose CT for lung cancer, alpha-foetoprotein and ultrasound for liver cancer, digital rectal examination, prostate-specific antigen, and transrectal ultrasound for prostate cancer, and CA-125 test and/or ultrasound for ovarian cancer. No trials on screening for melanoma were eligible. Only one trial (5%) had low risk in all bias domains, leading to a post-hoc meta-analysis, excluding trials with high risk of bias in critical domains, finding the extent of overdiagnosis ranged from 17% to 38% across cancer screening programmes. We conclude that there is a significant risk of overdiagnosis in the included randomised trials on cancer screening. We found that trials were generally not designed to estimate overdiagnosis and many trials had high risk of biases that may draw the estimates of overdiagnosis towards the null. In effect, the true extent of overdiagnosis due to cancer screening is likely underestimated.     

Appraisal of a new scheme for prenatal screening for Down's syndrome.

OBJECTIVE--To appraise a new method of prenatal screening for Down''s syndrome based on maternal serum concentrations of alpha fetoprotein, unconjugated oestriol, and human chorionic gonadotrophin combined with maternal age--the "triple test." DESIGN--Examination of the cost effectiveness of the triple test relative to screening only by maternal age over a range of population detection rates. SETTING--Leicestershire Health Authority. MAIN OUTCOME MEASURES--Costs per affected fetus detected. RESULTS--The triple test is more cost effective than screening only by maternal age for risk cut off points for amniocentesis, resulting in a detection rate over 45%. The most efficient detection rate is around 60-65%, for which the cost per case detected is around 29,000 pounds, through screening with higher detection rates is still likely to be cost beneficial. CONCLUSIONS--Prenatal screening for Down''s syndrome based on the triple test should replace screening based only on maternal age. Individual women''s preferences should be elicited by the use of structured decision analysis in order to maximise utility and so increase the benefits of the screening programme.     

Etiology of breast cancer III. Opportunities for prevention

Breast cancer, or its effects, may be preventable. Childbearing at an early age will confer some protection. Until there are other methods of primary prevention the physician must concentrate on secondary prevention, including screening. In presenting risk factors as criteria for screening we have attempted to make rational the use of screening technology. We should not easily accept screening for breast cancer as of proved value. Rather we must encourage clinical trials of various screening methods. In the meantime, while we engage in a moderate amount of screening we do so under the Scottish verdict of “not proven”.     

On the optimal policies of cancer screening.

Some problems of optimal screening are considered. A screening strategy is allowed to be nonperiodic. Two approaches to screening optimization are used: the minimum delay time approach and the minimum cost approach. Both approaches are applied to the analysis of an optimization problem when the natural history of the disease is known and when it is unknown (a minimax problem). The structure of optimal screening policies is investigated as well as the benefit they can provide compared to the periodic screening policy. The detection probability is assumed to depend only on the stage of the disease, though it may not be constant throughout each stage. It is shown that periodic screening appears to be optimal when one has no information on the natural history of the disease, the minimum delay time criterion being used for optimization. Some applications to lung cancer screening are presented.     

Group screening for rare events based on incomplete block designs

Fields such as, diagnostic testing, biotherapeutics, drug development, and toxicology among others, center on the premise of searching through many specimens for a rare event. Scientists in the business of “searching for a needle in a haystack” may greatly benefit from the use of group screening design strategies. Group screening, where specimens are composited into pools with each pool being tested for the presence of the event, can be much more cost-efficient than testing each individual specimen. A number of group screening designs have been proposed in the literature. Incomplete block screening designs are described here and compared with other group screening designs. It is shown under certain conditions, that incomplete block screening designs can provide nearly a 90% cost saving compared to other group screening designs such as when prevalence is 0.001 and screening 3876 specimens with an ICB-sequential design vs. a Dorfman design. In other cases, previous group screening designs are shown to be most efficient. Overall, when prevalence is small (≤0.05) group screening designs are shown to be quite cost effective at screening a large number of specimens and in general there is no one design that is best in all situations. © 2018 American Institute of Chemical Engineers Biotechnol Progress, 35: e2770, 2019.     

基于受体的药物高通量筛选研究进展

受体是药物筛选的重要靶标,基于受体的药物高通量筛选是药物筛选的主要类型之一。本文根据受体作用原理,按照检测对象的不同,从直接与间接检测的角度,将基于受体的药物高通量筛选进行了分类,总结了基于受体的几种不同的药物筛选模型,并简要介绍了高通量筛选技术在中药研究中的应用,对药物筛选的发展进行了展望。     

An assessment of partial rescreening as an internal quality control method for cervical smears

Partial screening was performed on 10 800 cervical smears, comprising 8640 filed negative and unsatisfactory smears and 2160 newly received smears prior to conventional screening. Each slide was screened for 30 s and those considered abnormal were reviewed by standard screening. Partial screening led to the detection of 27 additional infections and 44 additional cytological abnormalities. These detection rates are better than those obtained with the traditional method of rescreening only a proportion of smears. Amongst the smears partially screened before conventional screening, partial screening detected 37-66% of infections and 22-71% of cytological abnormalities. We recommend the use of partial rescreening of all negatively reported smears as a method of internal quality control in cervical cytology laboratories.