Comparing supervised and semi-supervised machine learning approaches in NTCP modeling to predict complications in head and neck cancer patients.

Background and purpose: Head and neck cancer (HNC) patients treated with radiotherapy often suffer from radiation-induced toxicities. Normal Tissue Complication Probability (NTCP) modeling can be used to determine the probability to develop these toxicities based on patient, tumor, treatment and dose characteristics. Since the currently used NTCP models are developed using supervised methods that discard unlabeled patient data, we assessed whether the addition of unlabeled patient data by using semi-supervised modeling would gain predictive performance. Materials and methods: The semi-supervised method of self-training was compared to supervised regression methods with and without prior multiple imputation by chained equation (MICE). The models were developed for the most common toxicity outcomes in HNC patients, xerostomia (dry mouth) and dysphagia (difficulty swallowing), measured at six months after treatment, in a development cohort of 750 HNC patients. The models were externally validated in a validation cohort of 395 HNC patients. Model performance was assessed by discrimination and calibration. Results: MICE and self-training did not improve performance in terms of discrimination or calibration at external validation compared to current regression models. In addition, the relative performance of the different models did not change upon a decrease in the amount of (labeled) data available for model development. Models using ridge regression outperformed the logistic models for the dysphagia outcome. Conclusion: Since there was no apparent gain in the addition of unlabeled patient data by using the semi-supervised method of self-training or MICE, the supervised regression models would still be preferred in current NTCP modeling for HNC patients.

Missing data is poorly handled and reported in prediction model studies using machine learning: a literature review.

OBJECTIVES: Missing data is a common problem during the development, evaluation, and implementation of prediction models. Although machine learning (ML) methods are often said to be capable of circumventing missing data, it is unclear how these methods are used in medical research. We aim to find out if and how well prediction model studies using machine learning report on their handling of missing data. STUDY DESIGN AND SETTING: We systematically searched the literature on published papers between 2018 and 2019 about primary studies developing and/or validating clinical prediction models using any supervised ML methodology across medical fields. From the retrieved studies information about the amount and nature (e.g. missing completely at random, potential reasons for missingness) of missing data and the way they were handled were extracted. RESULTS: We identified 152 machine learning-based clinical prediction model studies. A substantial amount of these 152 papers did not report anything on missing data (n = 56/152). A majority (n = 96/152) reported details on the handling of missing data (e.g., methods used), though many of these (n = 46/96) did not report the amount of the missingness in the data. In these 96 papers the authors only sometimes reported possible reasons for missingness (n = 7/96) and information about missing data mechanisms (n = 8/96). The most common approach for handling missing data was deletion (n = 65/96), mostly via complete-case analysis (CCA) (n = 43/96). Very few studies used multiple imputation (n = 8/96) or built-in mechanisms such as surrogate splits (n = 7/96) that directly address missing data during the development, validation, or implementation of the prediction model. CONCLUSION: Though missing values are highly common in any type of medical research and certainly in the research based on routine healthcare data, a majority of the prediction model studies using machine learning does not report sufficient information on the presence and handling of missing data. Strategies in which patient data are simply omitted are unfortunately the most often used methods, even though it is generally advised against and well known that it likely causes bias and loss of analytical power in prediction model development and in the predictive accuracy estimates. Prediction model researchers should be much more aware of alternative methodologies to address missing data.

Quantitative measurements of venous reflux by duplex scanning of the incompetent long saphenous vein before and after high ligation at the saphenofemoral junction.

OBJECTIVE: To assess the effect of high ligation of the saphenofemoral junction (SFJ) on the amount of reflux in the long saphenous vein using quantitative duplex scanning. DESIGN: Prospective study. SETTING: Teaching hospital, The Netherlands. SUBJECTS: 23 patients presented with 29 limbs showing signs of isolated insufficiency of the long saphenous vein. INTERVENTION: High ligation of the SFJ. MAIN OUTCOME MEASURES: Duration of reflux (s), peak velocity (m/s), mean velocity (m/s) and mean flow (ml/s) at the SFJ, and in the mid-thigh, the distal thigh and the proximal lower leg before and four weeks after high ligation. RESULTS: All variables except duration of reflux improved significantly at all levels in the 29 limbs studied. One limb showed no improvement in flow at the level of the SFJ, 9 in the mid-thigh, 13 in the distal thigh, and 15 in the proximal lower leg (just below the knee). CONCLUSION: High ligation was effective in reducing reflux at the SFJ, but in about half the limbs the distal reflux in the long saphenous vein remained.

[Experiences with outpatient laparoscopic cholecystectomy]. / Ervaringen met poliklinische laparoscopische cholecystectomie.

OBJECTIVE: To determine the feasibility and desirability of laparoscopic cholecystectomy in day care. DESIGN: Prospective, pilot study. SETTING: Academic Medical Centre, Amsterdam, the Netherlands. METHOD: Fifteen patients (ASA I/II according to the American Society of Anesthesiologists) with symptomatic gallstones underwent laparoscopic cholecystectomy with the intention to discharge them the same day. Data were collected about: pain (visual analogue scale); pain medication before and after discharge; (rc)admissions; consultations of general practitioner or day care centre; complications; satisfaction of the patients about this treatment modality. RESULTS: Fourteen patients could be discharged after 6.2 hour (standard deviation 1.2) of observation. The pain scores and medication use were low. Readmissions did not take place and there were no consultations of general practitioners or the day care centre. These patients had no complications. Thirteen of them preferred day care over admission in hospital. One patient was admitted because of colicky pains and a common bile duct stone was diagnosed, which was removed endoscopically. CONCLUSION: Laparoscopic cholecystectomy in day care appears feasible in patients with symptomatic gallstones and no functional incapacities if day care facilities are present.

[Treatment of tibial shaft fractures using plate osteosynthesis]. / Behandeling van tibiaschachtfracturen met plaatosteosynthese.

A retrospective study of 203 fractures of the tibial shaft, treated with ASIF-plate osteosynthesis between 1975 and 1986, revealed that the rate of osteitis and pseudarthrosis in closed and first-degree open fractures compares favourably with nationwide figures. The same applies to the duration of disability. Early treatment of osteitis, delayed union and pseudarthrosis in all cases led to complete recovery. Moving to modern hospital premises appears to have lowered the prevalence of infectious complications. Despite several negative prognostic factors, the results showed that ASIF-plate osteosynthesis if correctly performed on the right indication, is still the treatment of choice for a large group of patients with fractures of the tibial shaft.

The biotin-streptavidin system in a two-site ELISA for the detection of plasmodial sporozoite antigen in mosquitoes.

A two-site ELISA has been designed for the detection of sporozoite antigen in mosquitoes. Biotin-labelled monoclonal antibodies against sporozoites and a streptavidin-biotin-peroxidase complex were used to visualize the antigen. Evaluation of the sensitivity and specificity of the procedure was carried out and background levels of reactivity on the basis of negative mosquitoes were calculated. The test has been deliberately kept as simple as possible for use in the tropics and was designed using Anopheles stephensi infected with in vitro cultivated Plasmodium falciparum gametocytes. A minimum of about 100-350 sporozoites could be detected in mature salivary gland infections; in addition sporozoite antigen was detected in mosquitoes several days before the entry of sporozoites into the salivary glands. No reaction was demonstrable either with bloodstage or ookinete antigens of P. falciparum, or with mosquitoes carrying sporozoites of other plasmodial species. The number of sporozoites in positive mosquitoes and the generating capacity of a single oocyst could be assessed by the use of a calibration curve based on dilution data of a known sporozoite suspension. It was found that a single oocyst can produce about 10,000 sporozoite equivalents.

Tabernaemontana L. (Apocynaceae): a review of its taxonomy, phytochemistry, ethnobotany and pharmacology.

The taxonomy, phytochemistry, ethnobotany, and pharmacology of the genus Tabernaemontana L. (Apocynaceae) is reviewed. The genus is currently being revised taxonomically; most of the segregate genera are being reunited with it and the number of species that will ultimately be recognized will probably be about 100. All the names encountered in the chemical and ethnobotanical literature have been evaluated as far as possible, and a list is presented of the recognized species and their synonyms. The biogenesis and classification of the indole alkaloids found in Tabernaemontana species is set out and some problems in the determination of their stereochemistry are discussed. To facilitate access to the information, three lists have been compiled: the alkaloids in alphabetical order; the alkaloids in order of increasing molecular weight; and the alkaloids grouped according to their biogenetic classification, together with the species and plant part(s) in which they are known to occur. Biogenetic and chemotaxonomic aspects are briefly considered. A table of the non-alkaloidal constituents is also included. The ethnobotany of individual Tabernaemontana species is outlined and an overall assessment made. Likewise, information on the pharmacology of crude extracts and individual alkaloids from Tabernaemontana species has been assembled and appraised.

Cultivation of fertile Plasmodium falciparum gametocytes in semi-automated systems. 1. Static cultures.

A semi-automated cultivation apparatus for the in vitro culture of Plasmodium falciparum gametocytes is described. This apparatus has been designed to produce large numbers of fertile sexual stages for use in the development of a gamete vaccine or for the infection of suitable mosquitoes. These mosquitoes in turn may be used for the development of a possible sporozoite vaccine. Loss of red cells during medium change has been eliminated and the addition of warmed fresh medium simplified compared to similar systems described previously. Material harvested from this apparatus has been used for infecting mosquitoes. Up to 98% of Anopheles stephensi were infected with a mean oocyst count of 24 per positive gut (range one to 109). The importance of satisfactory presentation of gametocytes for mosquito infection is stressed. The possible presence of substances in normal human sera which inhibits exflagellation to a variable degree and reduces mosquito infectivity is also discussed.

The production of mature gametocytes of Plasmodium falciparum in continuous cultures of different isolates infective to mosquitoes.

In vitro gametocytogenesis of Plasmodium falciparum was observed in all 22 isolates established in this laboratory. Gametocytes were produced in variable numbers--up to 3% of red cells--for a limited period of time after which this stage was seen only very sporadically. Complete maturation of microgametocytes in vitro was obtained in all 14 of the isolates that were tested for exflagellation. Up to 88.2% of membrane-fed Anopheles stephensi were infected from material produced in culture. It was also possible to infect A. gambiae and A. freeborni. Addition of fresh red cells and serum to culture material promoted infectivity of gametocytes. Gametocyte infectivity declined rapidly with time in the membrane feeders held at 38 degrees C.

Chloroquine sensitivity of isolates of Plasmodium falciparum adapted to in vitro culture.

Thirteen isolates of Plasmodium falciparum obtained from cases of malaria imported into the Netherlands and established in culture were tested for their sensitivity to chloroquine. Reproducibility of the test results depended on the exposure of a standardized number of parasites in culture to the drug. The maximum activity of chloroquine was obtained when medium with the drug was added to parasite cultures twice at 24 hour intervals. The result of drug action over a period of 48 hours was estimated best when parasites were counted 72 hours after the commencement of the test. Sensitivity to chloroquine could not provide a basis for the characterisation of strains.

Parasitologic and serologic observations of infection with Pneumocystis in humans.

More than 500 specimens of lung tissue were examined for Pneumocystis. Of the 38 infections detected, most were in immunodeficient patients. Samples of serum from approximately 600 healthy normal subjects and 117 children with acute lymphatic leukemia were examined by an indirect fluorescent antibody test. The age-related data from the normal children suggested that nearly 100% of children are infected with Pneumocystis during the first two years of life. Groups of patients with leukemia who had symptoms of pneumocystis pneumonia had significantly higher titers of IgG antibody than groups of patients with leukemia who did not have clinical symptoms and normal subjects. Nevertheless, the diagnostic value of the indirect fluorescent antibody test is limited, but serologic follow-up study can be useful. Groups of children with leukemia had lower mean titers of IgM antibody regardless of their clinical condition.

Specificity of the indirect haemagglutination test with Plasmodium falciparum test cells. Comparison of indirect haemagglutination and fluorescent antibody tests on African sera.

The specificity of the indirect haemagglutination (IHA) test with Plasmodium falciparum placental antigen-sensitized test cells was examined with sera from healthy blood donors and from patients with diseases other than malaria. Only 1 nonspecific antibody reaction was seen in more than 700 tests. A comparison of IHA titres and indirect fluorescent antibody (IFA) titres with IgG and IgM conjugates on 503 sera from inhabitants of Mto Wa Mbu in Tanzania showed in successive age groups an increasing number of seropositive reactors with both tests. The increase in the proportion of positive reactions and in the mean titre levels started earlier but was more gradual in the IFA test than in the IHA test. Parasite carriers had higher antibody levels than people without an apparent parasitaemia. Parasite carriers in the younger age groups especially were more frequently seronegative in the IHA test than in the IFA test with anti-IgG conjugates. The reactivity of the IHA test with P. falciparum (Palo Alto/Aotus) antigen was higher than that with P. falciparum placental antigen and was thus closer to that of the IFA test with IgG conjugates.

Comparison of indirect haemagglutination and immunofluorescence tests for malaria antibody in Aotus monkeys infected with Plasmodium falciparum. Application of indirect haemagglutination tests for malaria.

Longitudinal observations were made on 6 Aotus monkeys repeatedly infected with Plasmodium falciparum (West African and Palo Alto strains). Immunofluorescence titres were higher than indirect haemagglutination titres in the primary phase of the infections. Both serological tests were consistently positive later in the infections. Precipitins were often not detectable even during episodes of parasitaemia.

Application of the indirect haemagglutination test for malaria: reproducibility with Plasmodium falciparum-sensitized cells.

The reproducibility of the IHA test was assessed. Two batches of glutaraldehyde-fixed sheep cells were used and the cells were sensitized with different batches of P. falciparum antigen obtained from 4 owl monkeys. At the individual level the IHA test appears to have a reproducibility of approximately 90%.