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Editorial
Prevention of blindness: a lost opportunity.
J Burns-Cox. J Med Screen 1996 3: 169.

Comment
Screening for haemochromatosis.
CQ Edwards. J Med Screen 1996 3: 170.

Journal Articles
Population screening for haemochromatosis: expectations based on a study of relatives of symptomatic probands.
LA Bradley, JE Haddow, and GE Palomaki. J Med Screen 1996 3: 171-177.
OBJECTIVES: The frequency of symptomatic haemochromatosis in the general population and the potential efficacy of population screening is uncertain. Data from family members of clinically diagnosed index cases were used to estimate the frequency of the haemochromatosis genotype, the proportion of homozygous individuals with clinical manifestations, and the efficacy of transferrin saturation and serum ferritin measurements as screening tests.
SETTING: English language studies from Europe, North America, and Australia.
METHODS: Haemochromatosis zygosity was classified only by HLA haplotyping, the most reliable available method. All subsequent analyses were based on family members classified in this way.
RESULTS: An estimated 53 individuals per 10,000 are homozygous for haemochromatosis. Overall, 67% of male and 41% of female family members display at least one clinical manifestation; for men, the frequency increases with age. Transferrin saturation levels are 70% or above in an estimated 72% of homozygous men, along with three per 1000 heterozygous or unaffected men. Transferrin saturation levels are 60% or above in an estimated 67% of homozygous women, along with six per 1000 heterozygous or unaffected women. Serum ferritin levels, but not transferrin saturation levels, are associated with clinical manifestations.
CONCLUSIONS: This information can be used to compare expected versus actual screening performance for intervention trials aimed at detecting haemochromatosis in the general population.

Population screening for haemochromatosis: a unifying analysis of published intervention trials,
LA Bradley, JE Haddow, and GE Palomaki. J Med Screen 1996 3: 178-184.
OBJECTIVES: To examine the efficacy of population screening for haemochromatosis by analysing the screening performance of seven intervention trials, and to compare this with the expected performance derived from family studies.
SETTING: Seven population intervention trials carried out between 1983 and 1995 in Australia, Scandinavia, Iceland, and the United State.
METHODS: Seven of 23 English language trials identified were suitable for the meta-analysis. Transferrin saturation and serum ferritin measurements derived from family studies were used to predict detection and false positive rates for each trial.
RESULTS: The seven trials used various screening and diagnostic criteria. A total of 18,396 men and 12,254 women were screened. Because some cases were not detected by screening, and some screen positive individuals did not complete diagnostic testing, the prevalence of homozygous individuals was underestimated in all the trials. The reported and predicted percentages of screen positive individuals nearly always agreed. The homozygote prevalence was estimated to be 34 men and 40 women per 10,000 (prevalence predicted from family studies is 53 per 10,000). Clinical manifestations were present in 50% of male and 44% of female homozygotes.
CONCLUSIONS: False positive rates, homozygote prevalences, and frequency of clinical manifestations were in general agreement with predictions from family studies. However, incomplete understanding about a number of issues requires that further pilot trials be carried out before screening can be considered part of routine medical practice.

Empirical validation of risk screening for Down's syndrome.
NJ Wald, AK Hackshaw, W Huttly, and A Kennard. J Med Screen 1996 3: 185-187
OBJECTIVE: To validate individual risk estimates in antenatal serum screening for Down's syndrome.
METHODS: Women screened for Down's syndrome using maternal serum alpha fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotrophin (hCG) with maternal age (the triple test) or AFP, uE3, free beta subunit and free alpha subunit of hCG with maternal age (the quadruple test) were grouped according to their predicted risk of having an affected pregnancy. The mean predicted risk in each category was then compared with the observed prevalence based on the number of affected and unaffected pregnancies in each category.
SUBJECTS: About 100,000 pregnant women screened for Down's syndrome from 1989 to 1995.
RESULTS: There was close agreement between the predicted term risk and the prevalence at birth for both the triple test and the quadruple test. For example, with the quadruple test the predicted risk in the highest risk group was 1 in 3.3 and the prevalence was 1 in 2.6; in the lowest risk group these were 1 in 3000 and 1 in 2300 respectively.
CONCLUSION: Risk estimates based on multiple marker screening for Down's syndrome are accurate. The technique used to demonstrate this is simple and offers a useful empirical check on screening performance.

Screening for toxoplasmosis in pregnancy: what is the evidence of reducing a health problem?
A Eskild, A Oxman, P Magnus, A Bjorndal, and LS Bakketeig. J Med Screen 1996 3: 188-194.
OBJECTIVES: Toxoplasma gondii is a parasite which may give rise to congenital infection. Screening pregnant women for antibodies against toxoplasmosis is being debated in many countries. The preventive impact of toxoplasmosis screening of pregnant women depends on the magnitude of disease caused by congenital toxoplasmosis (incidence x transmission rate to fetus x diseased proportion of infected children), on the one hand, and the preventable proportion of disease (sensitivity of the screening test x efficacy of the treatment x compliance), on the other. In this study the preventive impact of screening pregnant women for toxoplasmosis antibodies is assessed by letting the value for these variables change within reasonable limits.
METHODS: To obtain information on these variables, relevant publications were reviewed in the Medline database from 1983 to February 1996 and the Cochrane Pregnancy and Childbirth Database. References in review articles on congenital toxoplasmosis were also studied.
RESULTS: The literature review showed that no population based prospective studies of the natural history of toxoplasmosis infection during pregnancy, nor any randomised controlled trials of the efficacy of antiparasitic treatment, had been carried out. In the empirical studies which have been performed the values of most variables show considerable differences. According to these values, the estimates in this study of the impact of toxoplasmosis screening in pregnancy may range from 0 to 40 children in whom disease is preventable per 100,000 pregnant women susceptible to toxoplasmosis infection.
CONCLUSION: Sufficient scientific evidence is not yet available to propose screening for toxoplasmosis in pregnant women, and efforts should be made to provide such knowledge. Also, the magnitude of the negative impact of screening, such as induced abortion of healthy fetuses, anxiety in women with false positive screening tests, and side effects of treatment, has not been sufficiently examined.

Molecular screening of families affected by familial adenomatous polyposis (FAP).
I Gazzoli, C De Andreis, SM Sirchia, P Sala, C Rossetti, L Bertario, and G Colucci. J Med Screen 1996 3: 195-199.
OBJECTIVES: To assess the risk of developing familial adenomatous polyposis (FAP) in presymptomatic individuals using APC gene flanking and intragenic polymorphic markers.
SETTING: Twenty families enrolled in the Italian Registry of Polyposis comprising a total of 217 individuals, including 53 (24%) presymptomatic subjects with a 50% a priori risk of FAP, were analysed. Direct analysis techniques had previously failed to identify the FAP mutation in these families.
METHODS: DNA isolated from peripheral mononuclear blood cells and tissue sections was analysed by the polymerase chain reaction and a panel of seven highly polymorphic markers--YN5.64, CB83, CB26, LNS, APC1458.5, MBC, 37AB. Amplification products were separated by a modified denaturing gel electrophoresis method.
RESULTS: The haplotype associated with the disease was identified in 18 families (90%). The segregation of the FAP haplotype in these kindreds showed that 10 presymptomatic individuals had inherited the FAP mutation and carried a high risk of developing the disease. The remaining two families were not informative because of the lack of a sufficient number of probands or biological specimens.
CONCLUSIONS: These data indicate that indirect analysis with linked DNA markers has a high rate of success in defining the risk of FAP of presymptomatic subjects, provided that a sufficient number of probands or samples is available. Uninformative families accounted for 10% of the total, indicating that linkage analysis may still have higher sensitivity than direct mutation analysis techniques. The combined use of both approaches should be implemented, however, to enhance further the application of molecular genetics to the screening of families with FAP.

A comparison of two view and one view mammography in the detection of small invasive cancers: results from the National Health Service breast screening programme.
RG Blanks, SM Moss, and MG Wallis. J Med Screen 1996 3: 200-203.
OBJECTIVE: To examine the effect of using two view mammography in comparison with one view mammography in the detection of small (< 15 mm) invasive cancers.
SETTING: Screening programme data from National Health Service breast screening programme (NHSBSP).
METHODS: Data were collated from all screening programmes in the United Kingdom on standard "Korner" returns (KC62 forms) for the screening year 1 April 1994 to 31 March 1995. The comparison of invasive cancer detection rates by programmes using one and two view mammography with indirectly age standardised invasive cancer detection rates.
RESULTS: Programmes using two views for women attending their prevalent screen (first screen) in the NHSBSP detected 3% more non-invasive/microinvasive cancers, 7% more large invasive cancers (> or = 15 mm), and 42% more small invasive cancers (< 15 mm) than programmes using one view mammography.
CONCLUSIONS: The success of the screening programme depends largely on the ability of individual programmes to detect small invasive cancers. The results suggest that the benefit of using two view mammography is largely in the increased detection of these cancers.

Reasons for cervical cancer despite extensive screening.
B Stenkvist and J Soderstrom. J Med Screen 1996 3: 204-207.
OBJECTIVE: To explain an age adjusted incidence rate of cervical cancer of 10.1 and 10.5 per 100,000 women, despite extensive screening.
SETTING: The Swedish county of Gavleborg in 1986 and 1987.
METHODS: Thirty eight patients with "cervical cancer" reported to the central cancer registry in Sweden were investigated. The patients and their diagnoses were scrutinised in a double blind manner.
RESULTS: Eighteen per cent (7/38) of cases were shown to be mistakes in data transfer; 11% (4/38) of cases were endocervical adenocarcinomas; 13% (5/38) were histopathological misinterpretations and should have been reported as carcinoma in situ. Of the remaining 22 patients with invasive squamous cancer, 12 (55%) had not participated in the gynaecological health control programme. Of the 10 participants with invasive squamous cancer despite this participation, eight (80%) had repeatedly had abnormal Papanicolaou smears without further gynaecological/histopathological examination and treatment. There was no evidence of cases of carcinoma in situ or endometrial cancer diagnosed in 1986-87 being squamous cervix cancer. The true incidence of squamous cervical cancer among participants was 3.0 per 100,000 for the two years scrutinised. If all the patients with Papanicolaou smear abnormalities had been properly managed at the right time, and the treatment had been successful, the incidence of invasive squamous cancer would have been 0.8 per 100,000 women among participants as opposed to 38.2 per 100,000 among non-participants.
CONCLUSION: The evidence strongly suggests overascertainment of cervical cancer, which conceals the success of screening, and also suggests that much attention must be given to clinical management of detected lesions in cervical screening. Care is needed in applying accurate histopathological criteria when making a diagnosis of invasive squamous cancer, to separate squamous cancer from other malignant tumours of the cervix, and in data transfer to cancer registries.

Co-morbidity in patients with abdominal aortic aneurysm.
R Kanagasabay, H Gajraj, L Pointon, and RA Scott. J Med Screen 1996 3: 208-210.
OBJECTIVES: Selection for surgery of patients with abdominal aortic aneurysm (AAA) depends on an assessment of risk from operation compared with risk from aneurysm rupture. A study was performed to assess the levels of co-morbidity and to see whether co-morbidity was different in people with a normal aorta after ultrasonographic examination than in those with an aneurysmal aorta.
SETTING AND METHODS: Over a two year period 5392 people (2341 men, 3051 women) aged 65-80 were screened using B-mode linear ultrasound, with maximum measurements taken of transverse, anteroposterior diameters, or both. All subjects were given a questionnaire seeking a history of angina, stroke, claudication, myocardial infarct, respiratory problems, and diabetes.
RESULTS: 218 men and women were found to have an AAA of 3 cm or greater. The results of the questionnaire were analysed using logistic regression whereby all the co-morbid conditions were adjusted for each other and for smoking, sex, and age. The only conditions which were significantly associated with AAA in both sexes were myocardial infarction with an odds ratio (OR) of 1.66 (95% confidence interval (CI) 1.06 to 2.60) and claudication with an OR of 1.68 (95% CI 1.17 to 2.42). The association between angina and AAA was of borderline significance (OR = 1.52, 95% CI 1.00 to 2.30). Stroke was significantly associated only in women, with an OR of 3.71 (95% CI 1.42 to 9.69). Rates of diabetes and respiratory disease were not significantly different between people with AAA and normal aortas.
CONCLUSIONS: These findings show there is significantly higher co-morbidity in people with ultrasound detected AAA, which might influence outcome from surgery and long term survival.

Clinical Trial
Screening for cutaneous malignant melanoma: a feasibility study.
S Tornberg, E Mansson-Brahme, D Linden, U Ringborg, I Krakau, R Karnell, J Landegren, Y Brandberg, and T Hakulinen. J Med Screen 1996 3: 211-215.
OBJECTIVES: To study two different procedures for inviting subjects to screening for malignant melanoma, and to study the role of specially trained nurses as primary examiners.
METHODS: The study was carried out in Stockholm county and comprised 5000 randomly selected men and women aged 40 to 60, of whom 2,500 were invited with a personal invitation letter and with a set time of appointment and 2,500 were sent a questionnaire and instructions for self examination of the skin. To test the nurses' competence, a survey was made, comparing the judgments of skin examination between nurses and doctors.
RESULTS: 1654 (66%) of those invited for a skin examination took part. 1507 (60%) replied in the questionnaire group, of whom 1024 (41%) requested and attended a subsequent skin examination. Of the subjects attending from both groups, the nurses judged 9% v 11% as having skin lesions suggesting malignant melanoma, whereas the two doctors referred 4% v 3% of the subjects for surgical biopsy. Two malignant melanomas were detected, both of them in the questionnaire group. In the study of nurses' screening competence, both nurses and doctors equally judged one case out of 19 as having a lesion suspicious for malignant melanoma.
CONCLUSIONS: When the questionnaire method was used the results were achieved with one third fewer skin examinations, but it is difficult to conclude whether one of the procedures is better than the other. The results also indicate that nurses can be trained to be the primary examiners in a melanoma screening programme.

Letter
Maternal serum total activin A in pregnancies affected with fetal Down's syndrome.
GM Lambert-Messerlian, JA Canick, and GE Palomaki. J Med Screen 1996 3: 217.

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