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Application of DNA analysis in a population-screening program for neonatal diagnosis of cystic fibrosis (CF): comparison of screening protocols.

We compare two protocols for newborn screening for cystic fibrosis (CF). The first uses the immunoreactive trypsinogen (IRT) assay with a cutoff of > or = 180 ng/ml and a sweat test to identify CF patients. The second uses the IRT assay with a 100 ng/ml cutoff in conjunction with direct analysis for the delta F508 CF transmembrane conductance regulator (CFTR) mutation in a two-tiered (i.e., IRT/DNA) protocol, followed by a sweat test. We screened 220,865 newborns from Wisconsin for CF, using the IRT protocol identifying 369 infants with an elevated IRT, of whom 46 were found to have CF. Another 7 CF patients were identified who had a false-negative IRT level. The CF incidence in the white population was 1 in 3,431 (carrier incidence of 1 in 30). The IRT protocol had a sensitivity of 87% and a positive predictive value of 12.5%. We subsequently used the IRT/DNA protocol to screen 21,258 infants. Of 518 infants with an IRT level > or = 100 ng/ml, 24 carried at least one copy of the delta F508 CFTR mutation, and 4 of these infants were found to have CF, yielding a positive predictive value for this protocol of 16.7%. Direct comparison of the positive predictive value of the two protocols is not valid, because of the different populations screened. However, had the IRT protocol been used on the IRT/DNA cohort, 50 infants, including the 4 with CF, would have received sweat tests, yielding a positive predictive value of 8%. Because of the small sample size, this positive predictive value is not significantly different from that obtained for the IRT/DNA test. However, from a practical point of view the IRT/DNA approach does decrease considerably the number of sweat tests that must be undertaken. The number of false positives for the IRT protocol (46 in 21,258) is increased significantly compared with that for the IRT/DNA approach (20 in 21,258; P < .001). The incidence of delta F508 carriers detected in cohorts with an elevated IRT level was increased compared with the incidence in the general population. The direct costs for the IRT/DNA approach (100 ng/ml) were $11,374 per CF patient detected, compared with $10,187 per CF patient detected for the IRT protocol. Therefore, we conclude that the IRT/DNA approach to CF newborn screening decreases the number of false-positive subjects contacted, without a significant increase in cost.

Analysis of Variance↗

Clinical effectiveness and cost-effectiveness of the use of the thyroxine/thyroxine-binding globulin ratio to detect congenital hypothyroidism of thyroidal and central origin in a neonatal screening program.

CONTEXT: Since the introduction of screening for congenital hypothyroidism (CH) in 1974, the optimal laboratory strategy has been the subject of debate. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of various types of thyroxine (T(4))-based strategies to screen for CH. DESIGN, SETTING, AND PARTICIPANTS: In the Netherlands, since January 1, 1995, a primary T(4) determination with supplemental thyroid-stimulating hormone (TSH) and T(4)-binding globulin (TBG) measurements has been used. Results were calculated from cumulative findings for 1181079 children screened between January 1, 1995, and December 31, 2000. MAIN OUTCOME MEASURES: Rates of detection of patients with CH of thyroidal origin (CH-T) or CH of central origin (CH-C), false-positive rates, laboratory costs, and costs of initial diagnostic evaluations. RESULTS: All known infants (n = 393) with CH-T and 92% (n = 66) of infants with CH-C were detected on the basis of low T(4) levels, TSH elevation, and/or low T(4)/TBG ratios. If the decision to refer had been based solely on TSH elevation, then 94% of patients with CH-T and none of the patients with CH-C would have been detected. If low T(4) levels (<or=-3.0 SD) and TSH elevation had been used as the criteria for referral, then the rates of detection would have been 96% for CH-T and 31% for CH-C. The false-positive rates for the 3 approaches were 0.5, 3.3, and 4.7 cases per case detected, respectively. The introduction of the T(4)/TBG ratio into a program using a primary T(4) with supplemental TSH approach generates an extra cost of 11206 dollars per additional case detected. The average costs to detect 1 patient are comparable for the 3 approaches. In addition, our data revealed a substantially greater prevalence of CH-C than reported previously (1 case per 16404 children, compared with earlier estimates of 1 case per 26000 infants to 1 case per 29000 infants). CONCLUSIONS: The T(4) plus TSH plus TBG approach is a recommendable strategy for neonatal CH screening. It offers outstanding detection of patients with CH-C, in addition to those with CH-T, with acceptable costs.

Congenital Hypothyroidism↗

Structure and implementation of comprehensive state preadmission screening programs for nursing home applicants: 1978-1994.

This paper examines the structure and implementation of comprehensive state preadmission screening (PAS) programs for nursing home applicants from 1978 to 1994 in all 50 states and the District of Columbia. A state was considered to have comprehensive PAS if a majority of nursing home applicants were screened in-person by state or contract agency staff. Twenty-six states had implemented these programs by 1994, with the most growth taking place during the 1980s. The primary changes in program structure were an increased reliance on private providers to screen a subset of applicants and a higher percentage of states screening private pay applicants. All programs but one referred or authorized the use of community-based services, while most programs diverted well over 10 percent of nursing home applicants.

Case Management↗

Experiences of a state-sponsored notification and screening program for asbestos workers.

Worker notification can involve a broad range of activities including medical screening, personal and mass communications, cohort identification and tracing, and even litigation. The inclusion or exclusion of various supporting activities in a worker notification program may pose significant medical, public health, financial, logistical, and even legal implications for targeted individuals as well as for the agencies involved. This report describes some experiences in a state-sponsored notification and screening program of approximately 4,500 asbestos workers in Minnesota. In this program, a variety of factors led to the decision to provide medical screening to 1,101 workers and 451 spouses. It is anticipated that another 3,400 workers will be notified but not screened. A follow-up survey of notified workers showed overwhelming support for this program. It is estimated that this program will cost more than $650,000 by its completion. The decision to institute medical screening and other support activities should be made with careful consideration of the diverse implications of these activities to the individuals, communities, and agencies involved.

Asbestos↗

Estimates of lead time and length bias in a breast cancer screening program.

Assume that the benefit of screening for breast cancer with a combination of mammography and a clinical examination is measured by comparing the five-year survival rate of women detected by screening to the five-year survival rate of women surface clinically with breast cancer, e.g., to the survival rate of women reported in End Results In Cancer. In this paper a mathematical model is used to estimate the percentage of the observed difference in five-year survival rates between women in these two groups that is due to lead time and length bias. For women detected at an initial screen, the best estimate is that about 50% of the observed difference is due to bias and 50% to earlier detection. However, the percent due to bias may be as low as 20% and as high as 72%. These estimates are relatively insensitive to the age of the women screened. For women detected at a second screen given one year later, the estimated percentage of the observed difference in survival rates between women detected at the screen and a control group that is due to bias is between 33 and 42%.

Adult↗

Analysis of a mass colorectal cancer screening program for cost-effectiveness.

Mass screening of the general population with the stool blood test is a costly means of increasing the incidence of colorectal cancer identification; however, the test is worthwhile as a screening tool in patients at risk. We found the incidence of positive results to increase with age, as does the risk of colorectal cancer. Further efforts to increase the incidence of colorectal cancer detection should be directed toward increasing the awareness of primary care physicians and improving their screening practices. We stress that high-risk populations should be given special attention and the use of flexible proctosigmoidoscopes should be encouraged.

Colonic Neoplasms↗

Chonemorphine, stigmasterol, and ecdysterone: steroids isolated through bioassay-directed plant screening programs.

In a bioassay-directed screening programme of plants for the identification of active constituents the following steroids were isolated. Chonemorphine was identified as the antiamoebic and antitrichomonad principle of Chonemorpha fragrans. Stigmasterol from Coleus forskohlii and ecdysterone from Diploclisia glaucescens were inactive constituents isolated during the process of purifying the active principles of the plants. D. glaucescens roots are a high-yielding source (0.5% of the dry root weight) of ecdysterone.

Antiprotozoal Agents↗

[Diagnostic role of mammography and clinical examination in the framework of a screening program for breast carcinoma in Brescia].

Screening by mammography is at present the only way to obtain good results in terms of diagnosis of breast cancer at an early stage. In this paper we present the results of first and second rounds of a mammographic and clinical screening programme carried out in the health district of Brescia. At the first round out of 129 cancers detected, mammography was diagnostic in 124 cases; in 82 cases, the examination also allowed the identification of a suspicious nodule, while in 42 cases non palpable neoplasm was diagnosed with mammography alone. In the remaining 5 cases mammography was negative and only clinical examination led to the discovery of breast neoplasms. In the second round, in the 125 cancers detected, mammography was diagnostic in 124 cases; clinical examination allowed the identification of 59 of these tumours, while in 65 cases non palpable tumours were found with mammography alone. Only in one case mammography was negative and clinical examination led to the identification of the tumour.

Breast Neoplasms↗

Determinants of non-attendance to mammographic screening. Analysis of a population sample of the screening program in the District of Florence.

The characteristics associated with non-attendance to mammographic breast cancer screening were studied by interviewing a random sample (213 attenders, 121 non-attenders in the 1989 screening) of residents in one of the municipalities of the Florence District Program, where screening has been ongoing since 1970. The overall attendance rate was 60%, and it was dependent on age (40-49 years, 66.5%; 50-59 years, 62.5%; 60-70 years, 55.5%), whereas a significant association with socio-economic status, educational level and health-behavior reported in other programs was not confirmed in the study. This finding suggests that determinants of non-attendance may vary and should be evaluated in each local setting. The belief that screening is useless, fear of cancer being detected, postponement and laziness were the most common motivations of refusal stated by non-attenders, and such a negative attitude towards screening was rather strong since most non-attenders stated they would not like to be informed or stimulated to attend future screenings. Rapid improvement of attendance rates in such a context might be achieved only by putting special pressure on women aimed to change their negative attitude towards screening and their opinion about the benefits of early breast cancer detection. This might be regarded as unacceptable and however would involve high costs and a major organization effort.

Age Factors↗

Consequences of a National Mammography Screening Program on diagnostic procedures and tumor sizes in breast cancer. A retrospective study of 1540 cases diagnosed and histologically confirmed between 1995 and 1997.

In 1992, a national screening mammography program, including female patients between 50 and 64 years of age, was launched in Luxembourg. The effects of this campaign on the different diagnostic procedures, especially fine needle aspirations (FNA), large core needle biopsies (LCNB), and surgical specimens, were analyzed. From 1983 to 1997, the National Cancer Registry recorded 3167 new cases of invasive female breast cancer, all histologically diagnosed in one central pathology department. In 1996, the population consisted of 418,300 inhabitants (212,900 females). The number of breast cancer, tumor size, the nature of the diagnostic procedures, their diagnostic value as well as the number of physicians, "aspirators", and "biopsists" were evaluated. Between 1992 and 1994, the incidence of invasive breast cancers increased, concomitant with the launching of a National Screening Mammography Program. The diagnosis of in situ cancers tripled, and the mean size of invasive breast cancer decreased from 2.1-2.4 cm to 1.1-1.4 cm. Since 1994, the number of FNA had remained stable, LCNB had increased by 417.5%, and surgical biopsies had decreased by 18.95%. Between 1995 and 1997, 28.37% of 1075 FNA, and only 9.6% of 465 LCNB yielded inadequate samples. FNA were done by 77 different doctors (53.25% being gynecologists) and LCNB by 34 (52.94% being radiologists). The first diagnoses of all invasive cancers (n = 790) were made by using frozen sections from surgical specimens in 58.35% (n = 461), LCNB in 18.23% (n = 144), mastectomy in 10.13% (n = 80), formalin-fixed biopsies in 9.49% (n = 75), and FNA in 3.17% (n = 25). There are beneficial effects (increase in the number of diagnoses of in situ cancer; decrease in tumor sizes) not only for the "target" age group (50-64 years), but also for all female age groups (> 15 years). For quality assurance purposes, it is absolutely recommended to carry out pathological, radiological, and diagnostic work in specialized centers.

Aged↗

Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program.

CONTEXT: A nationwide systematic preparticipation athletic screening was introduced in Italy in 1982. The impact of such a program on prevention of sudden cardiovascular death in the athlete remains to be determined. OBJECTIVE: To analyze trends in incidence rates and cardiovascular causes of sudden death in young competitive athletes in relation to preparticipation screening. DESIGN, SETTING, AND PARTICIPANTS: A population-based study of trends in sudden cardiovascular death in athletic and nonathletic populations aged 12 to 35 years in the Veneto region of Italy between 1979 and 2004. A parallel study examined trends in cardiovascular causes of disqualification from competitive sports in 42,386 athletes undergoing preparticipation screening at the Center for Sports Medicine in Padua (22,312 in the early screening period [1982-1992] and 20,074 in the late screening period [1993-2004]). MAIN OUTCOME MEASURES: Incidence trends of total cardiovascular and cause-specific sudden death in screened athletes and unscreened nonathletes of the same age range over a 26-year period. RESULTS: During the study period, 55 sudden cardiovascular deaths occurred in screened athletes (1.9 deaths/100,000 person-years) and 265 sudden deaths in unscreened nonathletes (0.79 deaths/100,000 person-years). The annual incidence of sudden cardiovascular death in athletes decreased by 89% (from 3.6/100,000 person-years in 1979-1980 to 0.4/100,000 person-years in 2003-2004; P for trend < .001), whereas the incidence of sudden death among the unscreened nonathletic population did not change significantly. The mortality decline started after mandatory screening was implemented and persisted to the late screening period. Compared with the prescreening period (1979-1981), the relative risk of sudden cardiovascular death in athletes was 0.56 in the early screening period (95% CI, 0.29-1.15; P = .04) and 0.21 in the late screening period (95% CI, 0.09-0.48; P = .001). Most of the reduced mortality was due to fewer cases of sudden death from cardiomyopathies (from 1.50/100,000 person-years in the prescreening period to 0.15/100,000 person-years in the late screening period; P for trend = .002). During the study period, 879 athletes (2.0%) were disqualified from competition due to cardiovascular causes at the Center for Sports Medicine: 455 (2.0%) in the early screening period and 424 (2.1%) in the late screening period. The proportion of athletes who were disqualified for cardiomyopathies increased from 20 (4.4%) of 455 in the early screening period to 40 (9.4%) of 424 in the late screening period (P = .005). CONCLUSIONS: The incidence of sudden cardiovascular death in young competitive athletes has substantially declined in the Veneto region of Italy since the introduction of a nationwide systematic screening. Mortality reduction was predominantly due to a lower incidence of sudden death from cardiomyopathies that paralleled the increasing identification of athletes with cardiomyopathies at preparticipation screening.

Adolescent↗

Characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: implications for screening programs.

OBJECTIVE: Retinopathy of prematurity (ROP) is a potentially avoidable cause of blindness in children. The proportion of blindness as a result of ROP varies greatly among countries depending on their level of development, being influenced by the availability of neonatal care, neonatal outcomes, and whether effective screening and treatment programs are in place. The objective of this study was to compare characteristics of premature infants who developed severe ROP between 1996 and 2002 in highly developed countries with less developed countries. METHODS: This was an observational study. A questionnaire was completed by ophthalmologists in countries with low, moderate, and high development rankings (3 highly developed countries and from 10 less well-developed countries) who screen for ROP in which they supplied birth weights and gestational ages (GAs) of infants who were treated for threshold ROP or identified with more advanced stages of the disease. Birth weights and GAs of infants with severe ROP were measured. RESULTS: The mean birth weights of infants from highly developed countries ranged from 737 to 763 g compared with values ranging from 903 to 1527 g in less developed countries. Mean GAs of infants from highly developed countries ranged from 25.3 to 25.6 weeks compared with 26.3 to 33.5 weeks in less developed countries. A total of 13.0% of 1091 infants from poorly developed countries exceeded United Kingdom screening criteria; 3.6% exceeded a criteria of <34 weeks' GA and/or <1750 g birth weight. CONCLUSIONS: These findings suggest that larger, more mature infants are developing severe ROP in countries with low/moderate levels of development compared with highly developed countries. ROP screening programs need to use criteria that are appropriate for their local population.

Birth Weight↗

Is the promise of cancer-screening programs being compromised? Quality of follow-up care after abnormal screening results.

Cancer screening has increased dramatically in the United States, yet in some populations, particularly racial minorities or the poor, advanced disease at diagnosis remains high. One potential explanation is that follow-up of abnormal tests is suboptimal, and the benefits of screening are not being realized. The authors used a conceptual model of access to care and integrated constructs from models of provider and patient health behaviors to review published literature on follow-up care. Most studies reported that fewer than 75 percent of patients received some follow-up care, indicating that the promise of screening may be compromised. They identified pervasive barriers to follow-up at the provider, patient, and health care system levels. Interventions that address these barriers appear to be effective. Improvement of data infrastructure and reporting will be important objectives for policy makers, and further use of conceptual models by researchers may improve intervention development and, ultimately, cancer control.

Breast Neoplasms↗

Effectiveness of newborn screening programs for congenital hypothyroidism: prevalence of missed cases.

The author reviews the background information and technical developments leading to newborn screening for congenital hypothyroidism as well as the effectiveness and problems of the programs during the past decade. The success of the programs in terms of prevention of mental retardation now is clear. It is also clear, however, that a significant number of affected infants, perhaps 8 to 10 per cent of the total, can be missed in the best of screening programs. Physicians must be aware of the possibility and alert to early clinical evidence of congenital hypothyroidism.

Congenital Hypothyroidism↗