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The human receptor for the complement cleavage fragments C3b and C4b (complement receptor type 1, CRl) is found on the surfaces of erythrocytes, most peripheral blood leukocytes, glomerular podocytes, and follicular dendritic cells, and in plasma (1-3). Besides the removal of C3b-or C4b-coated microorganisms or immune complexes (4), CRl also serves as an inhibitor of the C3 and the C5 convertases by dissociating C2b and Bb fragments and by acting as a cofactor for the factor I-mediated cleavage of C3b and C4b (5, 6) . This regulatory capacity is shared by the structurally related members of a supergene family, termed the regulator of complement activation (RCA)t region, located on chromosome 1 (7-13) .Human CRl is a single chain glycoprotein with four allotypic variants that differ in Mr on SDS-PAGE by increments of 40-50 kD (14-17). The two most common variants are termed F and S (or A and B allotypes) and exhibit Mr of 250 and 290 kD, respectively. These variations reflect differing lengths of the polypeptides and not posttranslational modifications, since distinct unglycosylated precursors have been described (18) and incremental differences of 1.3 to 1.5 kb were also observed in the CRl transcripts from various allotypes (19,20). The cDNA that encodes the entire F allotype of 2,039 amino acids (aa) has been sequenced and the extracellular portion of the molecule is found to comprise 30 short consensus repeats (SCR). A feature that distinguishes CR1 from the other proteins of this gene family is the organization of the NH2-terminal 28 SCRs into four tandem long homologous repeats (LHR) of about 450 aa, each containing seven SCRs . Extensive sequence homologies of 60 to 99% have been observed among the LHRs, suggesting that they have arisen by gene duplication (21,22).

As residential radon programmes of identification and remediation have proceeded, so questions have been raised about their costs and benefits. This study presents a generalizable model for estimating the cost-effectiveness of a radon mitigation programme using the methodological framework now considered appropriate in the economic evaluation of health interventions. Its use will help to inform future discussion of radon remediation and lung cancer prevention programmes. Data from Northamptonshire were analysed, resulting in a societal cost-effectiveness ratio of £13250 per life-year gained in 1997. The percentage of houses found to be over the action level, and the percentage of householders who decide to remediate are shown to be important parameters for the cost-effectiveness analysis. Questions are raised about the particular importance of perspective in this type of analysis and suggestions are made for future research directions. © 1999 Cancer Research Campaign

Human CR1 exhibits an unusual form of polymorphism in which allotypic variants differ in the molecular weight of their respective polypeptide chains. To address mechanisms involved in the generation of the CR1 allotypes, DNA from individuals having the F allotype (250,000 Mr), the S allotype (290,000 Mr), and the F' allotype (210,000 Mr) was digested by restriction enzymes, and Southern blots were hybridized with CR1 cDNA and genomic probes. With the use of Bam HI and Sac I, an additional restriction fragment was observed in 20 of 21 individuals having the S allotype with no associated loss of other restriction fragments. Southern blot analysis with a noncoding genomic probe derived from the S allotype-specific Bam HI fragment showed hybridization to this fragment and to two other fragments that were also present in FF individuals. Thus, an intervening sequence may be repeated twice in the F allele and three times in the S allele. A restriction fragment length polymorphism (RFLP) unique to two individuals expressing the F' allotype was seen with Eco RV, but the absence of persons homozygous for this rare allotype prevented further comparisons with the F and S allotypes. Analysis of the CR1 transcripts associated with the three CR1 allotypes indicated that these differed by 1.3-1.5 kb and had the same rank order as the corresponding allotypes. Taken together, these findings suggest that the S allele was generated from the F allele by the acquisition of additional sequences, the coding portion of which may correspond to a long homologous repeat of approximately 1.4 kb that has been identified in CR1 cDNA. We saw two other RFLPs with Hind III and Pvu II that were in linkage dysequilibrium with the Bam HI-Sac I RFLPs associated with the S allotype, and a third polymorphism was seen with Eco RI that was not in linkage dysequilibrium with the other polymorphisms. Thus, 10 commonly occurring CR1 alleles can be defined, making this locus a useful marker for the long arm of chromosome 1 to which the CR1 gene maps.

Prenatal/preconceptional and newborn screening programs have been a focus of recent policy debates that have included attention to ethical, legal, and social issues (ELSIs). In parallel, there has been an ongoing discussion about whether and how ELSIs may be addressed in health technology assessment (HTA). We conducted a knowledge synthesis study to explore both guidance and current practice regarding the consideration of ELSIs in HTA for prenatal/preconceptional and newborn screening. As the concluding activity for this project, we held a Canadian workshop to discuss the issues with a diverse group of stakeholders. Based on key workshop themes integrated with our study results, we suggest that population-based genetic screening programs may present particular types of ELSIs and that a public health ethics perspective is potentially highly relevant when considering them. We also suggest that approaches to addressing ELSIs in HTA for prenatal/preconceptional and newborn screening may need to be flexible enough to respond to diversity in HTA organizations, cultural values, stakeholder communities, and contextual factors. Finally, we highlight a need for transparency in the way that HTA producers move from evidence to conclusions and the ways in which screening policy decisions are made.

A critical discussion in the HTA literature considers the definition of ELSIs in HTA, highlighting the importance of thinking beyond ELSIs as impacts of technology. Existing HTA guidance on integrating ELSIs relates to three broad approaches: literature synthesis, involvement of experts, and consideration of stakeholder values. The thirteen key policy evaluation frameworks relating to disease screening and public health genomics identified a range of ELSIs relevant to genetic screening. Beyond straightforward impacts of screening, these ELSIs require consideration of factors such as the social and political context surrounding policy decisions. The three broad approaches to addressing ELSIs described above are apparent in the screening/genomics literatures. In integrating these findings we suggest that the method chosen for addressing ELSIs in HTA for genetic screening may determine which ELSIs are prioritized; and that an important challenge is the lack of guidance for evaluating such methods.

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