Handling underlying discrete variables with bivariate mixed hidden Markov models in NONMEM.

Non-linear mixed effects models typically deal with stochasticity in observed processes but models accounting for only observed processes may not be the most appropriate for all data. Hidden Markov models (HMMs) characterize the relationship between observed and hidden variables where the hidden variables can represent an underlying and unmeasurable disease status for example. Adding stochasticity to HMMs results in mixed HMMs (MHMMs) which potentially allow for the characterization of variability in unobservable processes. Further, HMMs can be extended to include more than one observation source and are then multivariate HMMs. In this work MHMMs were developed and applied in a chronic obstructive pulmonary disease example. The two hidden states included in the model were remission and exacerbation and two observation sources were considered, patient reported outcomes (PROs) and forced expiratory volume (FEV1). Estimation properties in the software NONMEM of model parameters were investigated with and without random and covariate effect parameters. The influence of including random and covariate effects of varying magnitudes on the parameters in the model was quantified and a power analysis was performed to compare the power of a single bivariate MHMM with two separate univariate MHMMs. A bivariate MHMM was developed for simulating and analysing hypothetical COPD data consisting of PRO and FEV1 measurements collected every week for 60 weeks. Parameter precision was high for all parameters with the exception of the variance of the transition rate dictating the transition from remission to exacerbation (relative root mean squared error [RRMSE] > 150%). Parameter precision was better with higher magnitudes of the transition probability parameters. A drug effect was included on the transition rate probability and the precision of the drug effect parameter improved with increasing magnitude of the parameter. The power to detect the drug effect was improved by utilizing a bivariate MHMM model over the univariate MHMM models where the number of subject required for 80% power was 25 with the bivariate MHMM model versus 63 in the univariate MHMM FEV1 model and > 100 in the univariate MHMM PRO model. The results advocates for the use of bivariate MHMM models when implementation is possible.

Reduced and optimized trial designs for drugs described by a target mediated drug disposition model.

Monoclonal antibodies against soluble targets are often rich and include the sampling of multiple analytes over a lengthy period of time. Predictive models built on data obtained in such studies can be useful in all drug development phases. If adequate model predictions can be maintained with a reduced design (e.g. fewer samples or shorter duration) the use of such designs may be advocated. The effect of reducing and optimizing a rich design based on a published study for Omalizumab (OMA) was evaluated as an example. OMA pharmacokinetics were characterized using a target-mediated drug disposition model considering the binding of OMA to free IgE and the subsequent formation of an OMA-IgE complex. The performance of the reduced and optimized designs was evaluated with respect to: efficiency, parameter uncertainty and predictions of free target. It was possible to reduce the number of samples in the study by 30% while still maintaining an efficiency of almost 90%. A reduction in sampling duration by two-thirds resulted in an efficiency of 75%. Omission of any analyte measurement or a reduction of the number of dose levels was detrimental to the efficiency of the designs (efficiency ≤ 51%). However, other metrics were, in some cases, relatively unaffected, showing that multiple metrics may be needed to obtain balanced assessments of design performance.

Population pharmacokinetics of plasma-derived factor IX: procedures for dose individualization.

BACKGROUND: Population pharmacokinetic (POPPK) models describing factor IX (FIX) activity levels in plasma, in combination with individual FIX measurements, may be used to individualize dosing in the treatment of hemophilia B. OBJECTIVES: The aim was to reevaluate a previously developed POPPK model for FIX activity and to explore the number and timing of FIX samples required in pharmacokinetic (PK) dose individualization. METHODS: The POPPK model was reevaluated using an extended data set. Several sampling schedules, varying with respect to the timing and number of samples, were evaluated in a simulation study with relative dose errors compared between schedules. The performance of individually calculated doses was compared with commonly prescribed FIX doses with respect to the number of patients with a trough FIX activity > 0.01 U mL(-1) . RESULTS AND CONCLUSIONS: A three-compartment PK model best described the FIX activity levels. The number and timing of samples greatly influenced imprecision in dose prediction. Schedules with single samples taken on both day 2 and day 3 were identified as being convenient schedules with an acceptable performance level. Individually calculated doses performed better with respect to patient target attainment than a fixed 40 U kg(-1) dose regardless of how many samples were available to calculate individual doses. The results of this study suggest that PK dose tailoring with limited sampling may be applicable for plasma-derived FIX products.

Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis.

OBJECTIVES: Smokers have an increased incidence of rheumatoid factor (RF) and rheumatoid arthritis (RA) and one report has also indicated that smoking may also adversely influence the severity of RA. METHODS: Sixty-three women with advanced RA answered a structured questionnaire that included detailed information about their smoking history. The women were also evaluated clinically and radiologically. RESULTS: Heavy smoking (>/= 20 pack-yr) was associated with rheumatoid nodules (P: = 0.01), a higher HAQ score (P: = 0.002) and a lower grip strength (P: = 0.01). Smoking was also associated with more radiological joint damage (P: = 0.02). A positive correlation was observed between smoking and RF levels, in particular IgA RF and a combined elevation of IgM and IgA RF. CONCLUSIONS: Smoking has an adverse effect on disease progression in patients with RA. An association was also observed between smoking and those RF types that predispose to RA and have the highest diagnostic specificity for this disease.

[Telemedicine. Information technology and health-care planning.].

The purpose of this article is to demonstrate how the development of telemedicine has been in close context with the rapid development of information technology. The increased use of telemedicine has resulted in strategic planning by health authorities of how to increase access to specialist consultation. Overview is given of existing and coming telemedicine projects in Iceland. An important issue to be discussed further is to find telemedicine place in routine clinical service in the healthcare system.

[Telemedicine in iceland.].

The aim of this survey is to consider the evolution and historical background of telemedicine, as well as reviewing the present status, globally, and locally. General definitions and aims of telemedicine are mentioned and discussed, examples of successful telemedicine implementations in various areas are presented, especially mentioning Canada, Australia and Norway. In Iceland only a few projects within telemedicine have been tried so far; the most extensive one being the successful establishment of a few teleradiology links. Various other projects are in preparation, and the importance of telemedicine as a tool for facilitation of equity to services as well as a powerful educational medium is stressed.

Hypermobility associated with osteoarthritis of the thumb base: a clinical and radiological subset of hand osteoarthritis.

OBJECTIVES: To study the impact of articular hypermobility on the clinical and radiological features of hand osteoarthritis (OA) and to investigate whether hand osteoarthritis associated with hypermobility should be considered a separate subset of hand OA. METHODS: Fifty consecutive female patients with clinical hand OA and thumb base symptoms were examined for hypermobility according to the Beighton criteria. RESULTS: Thirty one of the 50 patients had hypermobility features (Beighton score > or = 2) and 17 patients fulfilled four or more Beighton criteria. Corresponding figures for 94 control patients were 30 (p < 0.05) and nine (p < 0.001) respectively. Patients with hypermobility features were characterised clinically and radiologically by fewer and less severely involved interphalangeal joints. Radiologically, two fairly distinct subsets could be identified: Severe interphalangeal OA in which the prevalence of hypermobility was similar to controls, and patients with predominant involvement of the first carpometacarpal joint (CMC 1), most of whom had evidence of hypermobility. CONCLUSION: A causal relation exists between articular hypermobility and development of thumb base OA, and hypermobility associated hand OA constitutes a definite clinical and radiological subset of hand OA. In the clinical setting, the easily applied hypermobility criterion of passive dorsiflexion of the fifth finger > or = 90 degrees is useful in identifying most patients with hand OA and hypermobility.

Use of X-rays in family practice. A multicentre study.

Practicing physicians, faced with pressure to control health care costs, are increasingly being asked to incorporate considerations of cost into their decisions regarding the care they offer their patients. Accordingly, it is of importance to know how the money is spent. The use and cost of X-rays in family practice, and what factors influence it, is not well known. The aim of this study is to analyse the use and the cost of X-ray requests in family practice. A prospective practice study from 16 Icelandic community health centres (HC) with computerised contact data and their target populations, 12 rural and four urban, was carried out. The X-ray requests, numbers, types and cost were analysed. Patient and practice characteristics were used to assess variation in X-ray practices. A total of 5173 X-ray requests were recorded, which comprised 3.2% of all office visits. The mean number of X-ray requests was 24.7 and 14.7/1000 contacts in rural and urban HCs respectively, and 123.1/1000 inhabitants in rural HCs. The X-ray request rate per individual increased with age, but per contact it was highest among young males. Extremity and chest X-rays were the most common requests. For every 1000 individuals added to a practice population, the likelihood of having an X-ray requested decreased by 18%. The use of X-ray examinations in family practices represents approximately 17% of all ambulatory X-ray use in Iceland. The calculated cost of X-rays requested in this study was $6157/1000 inhabitants per year as of October 1993.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiographic predictors of new coronary occlusions.

To determine whether coronary angiography is predictive of the future site of coronary occlusion, we analyzed the coronary angiograms of 246 consecutive patients having two or more angiograms without therapeutic invasive intervention in the interval between angiograms. The average interval between studies was 46 months. Of 2183 normal segments at the first angiogram, 51 (2.3%) were occluded at the second angiogram, whereas in segments with minimal disease (1% to 25% diameter stenosis) 33 (8%) of 411 were occluded (p < 0.05). There was a further stepwise increase in the occlusion ratio, with increasing stenosis reaching a 31% occlusion ratio in lesions with critical (91% to 99%) stenosis at the first angiogram. For any given degree of stenosis, the occlusion ratio of "long" lesions (5 to 20 mm) was on the average more than twice that of "short" lesions (< 5 mm, p < 0.01), except in lesions with critical stenosis (91% to 99%) where length was no longer important. Occlusion of segments judged free of disease on the first angiogram was highest in the right coronary artery, 4.7%, versus 2.7% in the left anterior descending and 0.6% in the circumflex artery (p < 0.01). History of recent myocardial infarction was a good clinical predictor of occlusion and deterioration of ventricular function.

[The commencement of radiology in Iceland: the pioneer.].

This essay deals with the pioneering work of Dr. Gunnlaugur Claessen (1881-1948), who introduced radiology into Iceland under very adverse conditions in 1914. His lifelong work and progress as a leader and teacher within that field is described. Dr Claessen was the founder and first chief of the Roentgen-Department of Landspitalinn University Hospital, from 1930 till his death.

[X-ray- and other medical imaging in Iceland 1993. Assessed and compared with earlier surveys.].

A country-wide survey of the use and utilization of medical imaging in Iceland was undertaken, by gathering of available information for the year 1993. The aim was primarily to assess the overall consumption of these services, with regard to radiation and the impact of other imaging modalities. Reference was made to earlier studies of the same kind adding a more specified break-down of information regarding age and sex as well as types of examination. The results are presented in tables and figures with accompanying text in English. The conclusions may be summed up as follows: 1: The average yearly increase in diagnostic imaging using ionizing radiation for the past 10 years was 1.7%, whereas the total average yearly increase of diagnostic imaging was 3.6%. This difference may be almost exclusively attributed to the increase in the use of ultrasound. 2: Although x-ray facilities are quite widely distributed, mainly due to geographic reasons, the main bulk of all examinations are made in a few specialised departments, and 92.8% of all examinations made are supervised by specialists in radiology, either directly or by consultation. 3: The overall number of examinations per 1000 population was 680, having increased from 555 in 1984. Comparable figures (1990) were 800 in the U.S. and 465 in the U.K.

Intraarticular ganglion between the cruciate ligaments of the knee. A case report.

Intraarticular ganglion cysts arising from the cruciate ligaments are rare. Only 9 cases have been described in the literature. Only in one case was the diagnosis suggested before operation by the appearance on MR imaging. We report a case of a patient presenting with a bone erosion in the proximal tibial epiphysis caused by an intraarticular ganglion cyst arising from the anterior cruciate ligament.

Methotrexate treatment of rheumatoid arthritis: effects on radiological progression.

Radiological progression was evaluated in 15 patients with rheumatoid arthritis (RA) treated with methotrexate (MTX). Prior to MTX treatment, all the patients had failed on other slow-acting agents and all showed radiological deterioration. For each patient, three sets of radiographs of hands and wrists were evaluated: prior to MTX treatment while on other slow-acting agents, at the beginning of MTX treatment, and at the most recent evaluation on MTX. Two experienced radiologists evaluated the radiographs independently. The rate of radiological progression was calculated by dividing the change in radiological score by the number of months between sets of radiographs. The mean time from film set one to two (period one) was 29.4 months and from set two to three (period two) 32.5 months. The mean rate of radiological progression for period one was 0.576 and for period two, 0.381. Eight patients showed decline in radiological progression during MTX treatment.

Relation between bone erosions and rheumatoid factor isotypes.

Total rheumatoid factor (RF) activity and individual RF isotypes were measured in 62 patients with rheumatic diseases. Retrospective analysis of available x rays showed an association between IgA RF and the occurrence of periarticular bone erosions in hands. In contrast, IgG RF and IgM RF did not show any significant association with erosions. Furthermore, a close correlation was observed between the RF isotype levels in simultaneously drawn serum and synovial fluid samples. The possible significance of IgA RF in the pathogenesis of bone erosions is discussed.

Mass screening for breast cancer.

Breast cancer is now the most common cancer in women. There is a certain correlation between the stage of the disease at diagnosis and outcome after treatment. Several studies have been initiated involving mammography with or without physical examination aimed at early detection of breast cancer in asymptomatic women. In order to review the results to date, a meeting was held in Reykjavík in April 1984 organized by international and Icelandic health agencies and attended by senior investigators of the ongoing screening studies. A summary of the available data is presented in this paper along with the conclusions of the meeting.

The penetration of metrizamide into the brain after routine lumbar myelography as shown by cerebral computed tomography and its effect on auditory brainstem transmission time.

Metrizamide is a widely used contrast medium with some well known adverse reactions. In a preliminary study, CT scans and brain stem evoked potentials (BAEP) were done before and 18 hours following lumbar myelography on 12 patients. A statistically significant prolongation of the BAEP was observed. Metrizamide therefore seems to be a potent substance in clinical use as indicated by its effect on BAEP. BAEP should not be done within the first few days after myelography with metrizamide.

Radiographic examination of the lumbosacral spine: an 'age-stratified' study.

Of a total of 99 922 radiological requests, 3.3% were for examinations of the lumbosacral spine. An 'age-stratified' study of 657 females aged 15-44 years referred for lumbosacral examination was carried out. 17.3% were referred because of trauma, with a total fracture incidence of 4.1% as compared with 9.5% in the other age-sex groups. Analysis of the other reasons for referral and the radiological diagnoses showed that 80% of all referrals were for more or less non-specific reasons, summarised as lower-back pain; an equal percentage of the radiological diagnoses indicated that there was either no lesion or a lesion which did not influence management.

Diagnostic sensitivity of X-ray examination of the large bowel in colorectal cancer.

All individuals subjected to x-ray examination of the large bowel at Borgarspitalinn, Reykjavik, over the 5-year period 1975-1979 were matched against the files of the Icelandic Cancer Registry, 1955-1980 inclusively. The diagnostic accuracy was 84.9% and with additional proctoscopy the diagnostic accuracy was 92.5%.