Electronic health records: new opportunities for clinical research.

Clinical research is on the threshold of a new era in which electronic health records (EHRs) are gaining an important novel supporting role. Whilst EHRs used for routine clinical care have some limitations at present, as discussed in this review, new improved systems and emerging research infrastructures are being developed to ensure that EHRs can be used for secondary purposes such as clinical research, including the design and execution of clinical trials for new medicines. EHR systems should be able to exchange information through the use of recently published international standards for their interoperability and clinically validated information structures (such as archetypes and international health terminologies), to ensure consistent and more complete recording and sharing of data for various patient groups. Such systems will counteract the obstacles of differing clinical languages and styles of documentation as well as the recognized incompleteness of routine records. Here, we discuss some of the legal and ethical concerns of clinical research data reuse and technical security measures that can enable such research while protecting privacy. In the emerging research landscape, cooperation infrastructures are being built where research projects can utilize the availability of patient data from federated EHR systems from many different sites, as well as in international multilingual settings. Amongst several initiatives described, the EHR4CR project offers a promising method for clinical research. One of the first achievements of this project was the development of a protocol feasibility prototype which is used for finding patients eligible for clinical trials from multiple sources.

Standardization of health informatics--results and challenges.

OBJECTIVES: This review article aims to highlight the importance of standards for effective communication and provides an overview of international standardization activities. METHODS: This article is based on the experience of the author of European standardization in CEN, which he leads, and the global work of ISO, where he is leading the security working group, and an overview of the work of DICOM, IEEE and HL7, partly using their web presentations. RESULTS: Health communication is highly dependent of the general development of information technology with standards coming from ISO/IEC JTCI, ITU and several other organizations e.g. IETF, the World Wide Web consortium and Open group. A number of standardization initiatives have been in progress for more than ten years with the aim to facilitate different aspects of the exchange of health information. Electronic record architecture, Message structures, Concept representation, Device communication including imaging and Security are the main areas. CONCLUSIONS: Important results have been achieved, and in some fields and parts of the world, standards are widely used today. Unfortunately, we are still facing the fact that most healthcare information systems cannot exchange information with all systems for which this would be desired. Either the existing standards are not sufficiently implemented, or the required standards and necessary national implementation guidelines do not yet exist. This causes unacceptable risks to patients, inefficient use of healthcare resources, and sub-optimal development of medical knowledge. Fortunately, the different bodies are now largely co-operating to achieve global consensus.

Anamnesis via the internet--prospects and pilot results.

A comprehensive computerized questionnaire was developed to obtain the anamnesis of patients seeking contact with a physician for any type of new problem. The purpose of this pilot study was to investigate if a structured questionnaire filled out by the patient and complementing an interview at the physician's office would contribute to a better quality of the total anamnesis and/or lead to savings in time at the visit. The results encourage further developments in this direction. The potential uses proposed are, in addition to being used to improve a visit, the correct assessment of the history for prioritization and scheduling of visits and in some situations, the anamnesis obtained over the net may be the basis for medical advice without a visit. This study emphasizes the great improvement of information captured by this type of questionnaire based on medical knowledge about associated symptoms and relevant questions depending on the problem presented compared to the results obtained by a simple open question used in many e-health services today.

Smart cards--a security tool for health information systems.

Expanding use of information technology in health care, both within and between the institutions, leads to additional security demands. The role is discussed that can be played by smart cards for healthcare professionals.

SEQ-ED: an interactive computer program for editing, analysis and storage of long DNA sequences.

The rapidly growing body of sequenced DNA demands efficient computer programs for its analysis and storage. The program described in this paper, SEQ-ED, has been designed to handle a large number of DNA sequences up to 200 kilobases [kb] long stored in a sequence library. In order to minimize the required storage space, the sequences are stored in a compressed format using three binary digits per base. In the development of this program, special care has been given to make it easy to use for molecular biologists without any previous computer experience.

Immune resistance of semisyngeneic F1 hybrid mice to lymphoma grafts differs from natural hybrid resistance in its genetic pattern.

Resistance of semisygeneic F1 hybrid mice immunized three times with irradiated tumor cells was compared to the genetic pattern of natural hybrid resistance to challenge with live tumor cells. Syngeneic mice responded equally well to immunization with all five hemopoietic tumor lines tested as the naturally much more highly resistant F1 hybrids. Natural hybrid resistance was found to be severely reduced by sublethal irradiation with 4 Gy, in contrast to hybrid resistance to parental bone marrow.

Genetic control of in vitro NK-activity and in vivo resistance to tumors.

Natural Killer (NK) cells are lymphocyte like cells which lack conventional B- and T-cell characteristics, and have the ability to rapidly kill certain tumor cells in vitro. Analysis of the genetic control of NK-activity in mice have provided several models to test the in vivo role of NK-cells in defence against neoplasia. Studies of certain F1-hybrid and backcross combinations have revealed a correlation between H-2 linked in vivo resistance and in vitro NK-activity against semisyngeneic transplantable tumors. The beige (bg) mutation in C57B1 mice causes a partial impairment of NK-activity, and can therefore serve to evaluate whether NK-cells can contribute to resistance against syngeneic tumors in the normal intact host. We have recently studied natural resistance against the ascitic lines of one chemically and two virally induced syngeneic leukemias in C57B1.bg/bg mice and their phenotypically normal heterozygous littermates. S.c. threshold inocula of all three leukemia lines grew faster and caused death earlier in bg/bg than in +/bg mice, and two of the lines were rejected completely at a significantly higher frequency in +/bg control animals. The +/bg mice also eliminated 125I-IdUrd-labelled leukemia cells at a faster rate than bg/bg mice, as measured by pulmonary, hepatic and splenic radioactivity retained 14-30 h after i.v. injection. The bg mutation was also possible to study in T-cell free mice, by combining it with the nu mutation on a C57B1 background. The NK-activity of such beige-nude mice was found to be partially impaired compared to nude (non-beige) or wild type animals, but higher than that of beige (non-nude) mice. Our results suggest that NK-cells may be responsible for elimination of small numbers of tumor cells in the intact syngeneic host. The further use of beige and beige-nude mice in studies of transplanted and primary, autochthonous tumors will be discussed.

Incidence and type of tumors induced by DMBA carcinogenesis in H-2 congenic strains on a B10 background.

Five congenic strains on B10 background (B10, B10.S, B10.G, B10.BR and B10.A) were investigated for their susceptibility to tumor induction by 9,10 dimethyl-1,2 benzanthracene (DMBA). The DMBA was administered via a stomach tube five times at weekly intervals (total 5 mg). Two types of malignancies predominated: diffuse lymphocytic lymphomas with or without thymic involvement, and epidermal tumors. B10 (H-2b) was the most resistant strain when total tumor incidences were compared. B10.S (H-2s) had the highest incidence of both lymphomas and epithelial tumors and B10.G was significantly more susceptible to thymic lymphomas than B10. In B10.S mice thymic lymphomas were more frequent in males than in females, the reverse being true for tumors of epithelial origin. No correlation between tumor incidence and in vitro NK activity was demonstrated.

Elevated antibody titers to Epstein-Barr virus and low natural killer cell activity in patients with Chediak-Higashi syndrome.

Four Venezuelan patients with the autosomal recessive Chediak-Higashi syndrome (CHS) were studied. The results confirm the severe reduction in natural killer (NK) cell activity, as previously described and showed also a decline in the activity of cells involved in antibody-dependent cellular cytotoxicity (ADCC). No defect was found in the production of immunoglobulins and of specific antibodies to measles, varicella, herpes simplex, and cytomegalo viruses. Two of the patients had extremely high antibody titers to the Epstein-Barr virus (EBV) specific viral capsid antigen (VCA), to the restricted (R) component of the EBV-induced early antigen complex, and to the EBV-associated nuclear antigen (EBNA). These two patients had enlarged livers, spleens, and lymph nodes indicative of the lymphoproliferative phase. The other two patients were initially negative for all EBV-associated antibodies but seroconverted subsequently and, in the course of a year, also developed high antibody titers to VCA and R. In one of these patients the primary infection was accompanied by moderate signs of infectious mononucleosis (IM) followed after more than 6 months by persistent hepatosplenomegaly. The other patient also developed signs of a lymphoproliferative syndrome with hepatosplenomegaly and jaundice and died 8 months later. Such high anti-R titers are seen frequently in Burkitt's lymphoma, but rarely in other conditions. It is likely that the high antibody titers reflect an increased production of VCA and R due to defective NK and ADCC cell activities so that productively infected B lymphocytes are no longer eliminated before they have synthesized maximal amounts of antigens. The high anti-EBNA titers suggest normal T lymphocyte function. The possibility that the accelerated, lymphoma-like phase of the CHS involves EBV-transformed cells is discussed.

Thymus independence of hybrid resistance against a panel of T-cell lymphomas of H-2b origin.

Adult thymectomy, followed by whole-body irradiation and reconstitution with fetal liver, was performed to study the T-cell dependence of F1 hybrid resistance to a panel of lymphomas of H-2b origin. Previously, the pattern of hybrid resistance against the same lymphomas was found to correlate with the pattern of NK-activity in a spectrum of F1 hybrids (Kiessling et al., 1975). We now show that hybrid resistance against three lymphomas of C57BL/6 origin, P-52-127-166, RBL-5 and EL-4 and against YLD, of C57L origin, is expressed in the absence of thymus. In another series of experiments, the effectors responsible for hybrid resistance to the transplanted lymphoma EL-4 were studied by reconstituting thymectomized and non-thymectomized C57BL mice with syngeneic bone marrow from NK-deficient beige mutant or wild-type C57BL donors. While the recipients of beige bone marrow had a clearly reduced tumor resistance, thymectomy did not decrease resistance further. This study supports the hypothesis that resistance to these lymphomas in F1 hybrids as well as in syngeneic mice is mainly mediated by natural killer cells.

Hybrid resistance against a natural killer (NK) cell-resistant lymphoma (YWA) is mediated by a T cell-dependent mechanism.

Rejection of the Moloney virus-induced YAC lymphoma of strain A origin by semisynegeneic F1 hybrids has previously been shown to correlate with the levels of natural killer (NK) cell activity in the same F1 hybrids against this target cell line in vitro. In the present study, YAC and another Moloney virus-induced lymphoma,, YWA, derived from the A congenic A.SW strain, were tested for F1 hybrid resistance after s.c. inoculation of small numbers of cells into syngeneic and semisyngeneic F1 mice. While YAC cells invariably grew progressively once they formed a palpable tumor, regression of YWA tumors was frequently observed in both susceptible and resistant genotypes. The hybrid resistance pattern for YAC and YWA differed in one important respect: outcross of the syngeneic host to the A-congenic A.BY strain introduced a strong H-2b-associated resistance factor against YWA, but not against YAC. Compared to YAC, which is highly NK-sensitive and rapidly eliminated from mice with high NK activity, YWA was insensitive to NK-mediated lysis in vitro and [125I] UdR-labelled YWA cells were not eliminated more efficiently from the highly resistant (A.SW X A.BY) F1 then from the parental strain in short-term (4-18h) in vivo rejection assays. It was therefore concluded that the H-2b-associated resistance against YWA was independent of NK cells or other rapidly acting effector mechanisms. Moreover, thymectomy, followed by irradiation and fetal liver reconstitution, completely abolished the resistance against YWA but left the resistance against YAC virtually intact. These data suggest that two lymphomas induced by the same agent can be rejected by different effectors. The NK-resistant YWA lymphoma is rejected by a T-dependent mechanism, while the resistance against the inoculation of the highly NK-sensitive YAC line is T-independent and, in all probability, mediated by NK cells.

Decreased sensitivity of immunoselected and NK-selected YAC lymphoma sublines to hybrid resistance in vivo.

Two sublines of the Moloney lymphoma YAC, selected by alternating in vitro exposure to anti-MCSA + complement and in vivo passage in preimmunized hosts, had a decreased or undetectable expression of MCSA. These 'immunoselected' sublines were compared with the original YAC line with regard to their ability to grow in a panel of semisyngeneic F1 hybrids. Natural hybrid resistance to YAC, previously found to be mediated by NK cells, affected the immunoselected sublines to a much smaller extent. This was further corroborated by the fact that the same sublines showed a decreased sensitivity to the in vitro lysis by NK cells from the same hybrid genotypes. Another set of YAC variants were produced by repeated in vitro exposure to NK cells and intermittent passage in highly NK-active F1 hosts. These 'NK-selected' sublines showed a permanently decreased sensitivity to NK lysis after 8-10 selections. When compared for in vivo growth with the parental YAC-1 tissue culture line in a spectrum of relatively resistant F1 hybrids, they had an increased frequency of takes. This is in line with recent findings which show a relationship between the target site for natural antibodies and anti-MCSA on the one hand, and between the natural antibody-binding site and the NK target site on the other.

Incidence and type of tumors induced in C57BL bg/bg mice and +/bg littermates by oral administration of DMBA.

As an attempt to study the effect of the beige (bg) mutation on chemical carcinogenesis, 65 C57Bl/bg/bg mice and 83 +/bg littermate controls received DMBA in five weekly intragastric doses. The incidence of tumors of different histological types was monitored through observation periods ranging between 165 and 500 days. By 165 days after the first DMBA feeding, 18% of the +/bg and 31% of the bg/bg mice had developed tumors. The beige mice had a higher incidence of epithelial and non-epithelial tumors arising in cutaneous or subcutaneous sites than the controls. The total incidence of lymphomas was similar in the two groups. However, lymphomas appeared somewhat earlier in beige than in control mice. Altogether 33 +/bg and 27 bg/bg mice were followed for 500 days. By this time, 73% of the +/bg and 78% of the bg/bg mice had developed tumors. The beige group showed a higher incidence of non-thymic lymphomas than the controls. In contrast, the incidence of thymic lymphoma, cutaneous epithelial tumors and bile-duct adenomas was similar in the two groups or higher in +/bg that in bg/bg mice. The results suggest that the bg mutation causes a certain defect in a mechanism that may prevent or delay the onset of non-thymic lymphomas and of epithelial and non-epithelial cutaneous tumors in DMBA-treated mice. The differences between the two groups were smaller than those previously reported in relation to the increased susceptibility of beige mice to certain transplanted tumors, attributed to the known defect in natural killer (NK) activity in the beige mice. The reduced differential in the DMBA system may be due to the partial reduction of NK activity, induced by the carcinogen, as reported previously (Ehrlich et al., 1980) and confirmed in the present study.

In vitro NK-activity and in vivo resistance to leukemia: studies of beige, beige//nude and wild-type hosts on C57BL background.

The bg mutation in C57BL mice causes a partial impairment of NK activity, and has therefore been proposed as a model to evaluate the in vivo function of NK cells. In the present report, we studied natural resistance against the ascitic lines of one chemically and two virally induced syngeneic leukemias in C57BL bg/bg mice and their phenotypically normal heterozygous +/bg littermates. S.c. threshold inocula of all three leukemia lines grew faster and caused death earlier in bg/bg than in +/bg mice, and two of the lines were rejected completely at a significantly higher frequency in +/bg control animals. The +/bg mice also eliminated [125I]-IdUrd-labelled leukemia cells at a faster rate than bg/bg mice, as measured by pulmonary, hepatic and splenic radioactivity retained 18-30 h after i.v. injection. Direct splenic killing of 51Cr-labelled leukemia cells was also studied in vitro, and was found to be severely depressed in bg/bg compared to +/bg. This natural killer activity was independent of adherent cells and showed a rapid, but transient, increase after inoculation of the tumor cell doses used in the transplantation tests. It was also possible to study the bg mutation in T-cell-free mice, by combining it with the nu mutation on a C57BL background. The NK activity of such beige-nude mice was found to be partially impaired compared to nude (non-beige) or wild-type animals, but higher than that of beige (non-nude) mice. Our results suggest that NK cells may be responsible for elimination of small numbers of tumor cells in the intact syngeneic host. The further use of beige and beige-nude mice in studies of transplanted and primary tumors is discussed.