The analysis of disease biomarker data using a mixed hidden Markov model (Open Access publication)

A mixed hidden Markov model (HMM) was developed for predicting breeding values of a biomarker (here, somatic cell score) and the individual probabilities of health and disease (here, mastitis) based upon the measurements of the biomarker. At a first level, the unobserved disease process (Markov model) was introduced and at a second level, the measurement process was modeled, making the link between the unobserved disease states and the observed biomarker values. This hierarchical formulation allows joint estimation of the parameters of both processes. The flexibility of this approach is illustrated on the simulated data. Firstly, lactation curves for the biomarker were generated based upon published parameters (mean, variance, and probabilities of infection) for cows with known clinical conditions (health or mastitis due to Escherichia coli or Staphylococcus aureus). Next, estimation of the parameters was performed via Gibbs sampling, assuming the health status was unknown. Results from the simulations and mathematics show that the mixed HMM is appropriate to estimate the quantities of interest although the accuracy of the estimates is moderate when the prevalence of the disease is low. The paper ends with some indications for further developments of the methodology

Genetic management of infectious diseases: a heterogeneous epidemio-genetic model illustrated with S. aureus mastitis

Given that individuals are genetically heterogeneous in their degree of resistance to infection, a model is proposed to formulate appropriate choices that will limit the spread of an infectious disease. The model is illustrated with data on S. aureus mastitis and is based on parameters characterizing the spread of the disease (contact rate, probability of infection after contact, and rate of recovery after infection), the demography (replacement and culling rates) and the genetic composition (degree of relationship and heritability of the disease trait) of the animal population. To decrease infection pressure, it is possible to apply non-genetic procedures that increase the culling (e.g., culling of chronically infected cows) and recovery (e.g., antibiotic therapy) rates of infected cows. But the contribution of the paper is to show that genetic management of infectious disease is also theoretically possible as a control measure complementary to non-genetic actions. Indeed, the probability for an uninfected individual to become infected after contact with an infected one is partially related to their degree of kinship: the more closely they are related, the more likely they are to share identical genes like those associated to the non-resistance to infection. Different prospective genetic management procedures are proposed to decrease the contact rate between infected and uninfected relatives and keep the number of secondary cases generated by one infected animal below 1

Genetic study of immunological parameters in periparturient Holstein cows

Immunological assays were evaluated in 137 Holstein cows during the periparturient period. Results for all immune assays were altered around calving time. Heritability estimates were obtained before, at, and after immunosuppression. Significant genetic variability was found in the periparturient changes for neutrophil chemokinesis, assays measuring neutrophil respiratory burst (cytochrome C reduction, chemiluminescence, and iodination), serum concentration in IgG[subscript]1, IgG[subscript]2, and IGM, and serum hemolytic complement activity;Genetic factors affecting mastitis indicators (somatic cell score, clinical cases, bacteriological status) and retroviral infections (bovine leukosis virus, bovine immunodeficiency virus) were studied. Heritabilities for all mastitis indicators averaged 0.10, but differences were seen among mastitis indicators. Heritability estimates for retroviral infections were close to zero. The genetic correlation between the number of quarters infected with minor and major pathogens was negative;We examined the genetic effects on the disease indicators of our immunological assays and of the alleles at the BoLA-DRB3 locus, at the IgG[subscript] 2a locus, and at the locus for the mutation responsible for the bovine leukocyte adhesion deficiency syndrome. Negative genetic associations were found between all mastitis indicators and the presence of BoLA-DRB3 alleles b12 and b11, various neutrophil assays, the number of blood mononuclear cells, and the presence of IgG[subscript] 2a allele A1. BoLA-DRB3 allele b3 was negatively associated with infection with bovine immunodeficiency virus. No genetic effect of any of the immunological parameters on infection with bovine leukosis virus could be demonstrated

Clinical evaluation of cardiac effects of experimental doxycycline overdosing in healthy calves

Background Cardiac morphologic and functional changes consistent with cardiomyopathy have been reported in field cases of calves with accidental doxycycline overdosing. The purpose of this study was to evaluate clinically the cardiac effects of an experimentally-induced doxycycline overdosing in healthy calves. Twelve 2 months-old healthy Belgian Blue calves were studied. Six of them (group 1) received the normal dose (5 mg/kg, BID) and the six others (group 2) received five times the normal dose (25 mg/kg, BID) of oral doxycycline for five consecutive days (D1 to D5). Each calf was clinically examined daily. Measurement of serum AST, CK, Iso-CKs and LDH activities and an echocardiographic examination were performed before (D0) and one day after (D6) the last doxycycline administration. An ECG tracing was recorded at D0, D4, and D6. Results In both groups, no clinical, blood, echocardiographic or electrocardiographic changes suggestive of a cardiomyopathy were observed. Only a decreased appetite was observed in the calves of the group 2 between D3 and D6. Conclusions This trial failed to reproduce cardiac changes reported in accidental doxycycline-poisoning in calves, suggesting that high doses of doxycycline may not be the only etiologic factor of the cardiomyopathy reported in the field cases.Mise en place d’un laboratoire cardiovasculaire chez les grands animaux pour le développement de modèles chroniques de pathologies cardiaques

Utilisation par les praticiens des données et des outils issus du projet LAECEA

La santé mammaire et la production laitière sont des enjeux capitaux pour le secteur de l'élevage en région wallonne, et donc pour la fonction du médecin vétérinaire rural. Les enjeux modernes de la production laitière tels que la course à la productivité, la réduction des coûts de production et la maîtrise de la qualité des denrées alimentaire d'origine animale, amènent le vétérinaire du 21ème siècle à être confronté simultanément à ses rôles curatifs, préventifs et de partenaire économique. En outre, la mammite devient la première cause du recours aux antibiotiques en médecine bovine laitière, et l'avenir nous demande d'avantage de réflexion sur l'utilisation de ces thérapeutiques en élevage. Le lancement du projet LAECEA en 2010 a été une opportunité fédératrice, plusieurs praticiens ont été impliqués dans la récolte de données et dans la mise en ouvre, le testage et l'évaluation de nouveaux outils au travers du dossier de santé mammaire (DSM). Les résultats issus du projet LAECEA sont en outre des témoins du quotidien de la santé mammaire dans les élevages participants. L'étude de ces résultats peut orienter le diagnostic présomptif du clinicien en éditant l'épidémiologie loco-régionale de la mammite en Wallonie. Cette approche pourra permettre de cibler plus précisément le diagnostic mammaire, d'en tirer les conclusions en terme de fréquence, de moment d'apparition, d'étiologie. Ainsi, seront abordés les tendances épidémiologiques moyennes, l'impact économique de la variation des indicateurs générés, ainsi que les leviers préventifs associés à ces tendances. Le corollaire évident est une gestion plus précise des substances antimicrobienne, de part un diagnostic plus pré Le moment est venu, lors de ce forum d'été du RTVOL, de partager l'expérience de ces praticiens et de faire état des données rassemblées et de l'utilisation qui peut en être faite. Par la suite, tous les praticiens pourront utiliser ces outils dans leur pratique quotidienne

Getting insights on bovine mastitis treatment efficacy based on tissular indicators with an integrated udder health management file: Project LAECEA.

Mastitis is the most “antibiotic consuming” pathology in dairy medicine. Though antibiotics and antibiograms are known to vets since the early fifties, our practices did not evolved a lot from empiric antibiotic therapy. Indeed, the need for a treatment, the cost and the delay for an antibiogram are most of the time incoherent with a routine practice. Nevertheless, there is a surge for rational use of antibiotics. Our study was based on 1100 mastitis events from 30 Belgian farms collected between January 2011 and June 2012. We chose to compare tissular cure (TC) based on the threshold of 200.000 somatic cells/ml in milk at milk control at least 60 days after the clinical mastitis event. Regarding the mastitis event, severity (according 3 grades: alteration of milk as grade 1, alteration of quarter as grade 2 and alteration of general state as grade 3), quarter, treatments were recorded. We also assessed a chronicity status based on previous somatic cell count (SCC) of the cow. It was considered a new case a cow which at least 15 days before had an SCC <200.000 cells/ml, other were marked as chronic cases. In our distribution, we see a seasonal rise of incidence between January and May. This period would represent twice as many mastitis as the summer period. Overall TC reaches 46% of all mastitis events, which is quite poor. Rear quarters had significantly lower TC (p<0,05%). Grade 3 mastitis had lower TC, 42,6% (p<0.05%) versus 48,9 % for grade 2 and 44,2% for grade 1. Almost 49% of all mastitis was considered as chronic cases, which TC was 33% on average, whereas new cases reached 55,3% TC. Study of treatment was frustrating given the high number of different combinations of treatments. It was underlined that 4th generation cephalosporins (C4G) were the most used in our cohort, followed by aminopenicillin/methicillin association (PENA/PENM) and 1st generation cephalosporins/aminoglycosids (C1G/AG) association. Of these intramammary treatments, 20% of the cases were submitted to a second intramammary drug, mostly C1G or C1G/AG. One third of the cases were treated parenterally with antimicrobials, mostly macrolids, fluoroquinolones and penethacillin. Finally, 10% of mastitis was treated with anti-inflammatory drugs, mostly tolfenamic acid and flunixin-meglumin. Comparing mastitis without use of a secondary intramammary drug, only PENA and C1G/AG reached more than 60% TC. Considering new cases, then C1G/AG, PENA/PENM and Prednisolone containing specialties were above 60% TC. Use of a parenteral injections increased TC only on new cases (+12%), but not on chronic cases. Refining by severity, TC improved with a parenteral on new cases, mainly in grade 1 (+20%). Regarding associated factors, TC was negatively affected by chronicity, parity and lactation stage. Indeed, TC was lower on cases from more than 4 month in milk, third lactation (OR = 2.8 for no cure) compared with previous, and chronic cases (OR=2,6). Seemingly, chronicity was positively associated with parity and season. The 3rd parity cases had higher chances to be chronic ones (OR = 1,7), as well as cases from April to September (OR = 1,6). This evaluation of cure is rather simple and has a good variability which allows several questions about the real match between antimicrobial treatment for mastitis and the udder inflammation. Based on our epidemiological data, we can modify routine management of mastitis, as some cases might not worth the antimicrobial treatment.LAECE

Speed of sound measurements in the evaluation of bone properties in Holstein

peer reviewe

Cost-Effectiveness Assessment of Different Glucosamines in Patients with Knee Osteoarthritis: A Simulation Model Adapted to Germany

peer reviewedAbstract: Background: The use of symptomatic slow-acting drugs for osteoarthritis (OA) (e.g., glucosamine, chondroitin) is largely debated in the scientific literature. Indeed, multiple formulations of these agents are available, both as pharmaceutical-grade products and as nutritional supplements, but while all preparations may claim to deliver a therapeutic effect, not all are supported by clinical evidence. Moreover, few data are available regarding the cost-effectiveness of all these formulations. Usually, access to individual patient data is required to perform economic evaluations of treatments, but it can be challenging to obtain. We previously developed a model to simulate individual health utility scores from aggregated data obtained from published OA trials. Objective: In the present study, using our new simulation model, we investigated the costeffectiveness of different glucosamines used in Germany. Methods: We used our validated model to simulate the utility scores of 10 published trials that used different glucosamine preparations. Using the simulated utility scores, the quality-adjusted life years (QALYs) were calculated using the area-under-the-curve method. We used the 2018 public costs of glucosamine products available in Germany to calculate the Incremental Cost/Effectiveness Ratio (ICER). We performed analyses for pharmaceutical-grade Crystalline Glucosamine Sulfate (pCGS) and other formulations of glucosamine (OFG). A cost-effectiveness cut-off of 30,000 €/QALY was considered. Results: Of 10 studies in which utility was simulated, four used pCGS, and six used OFG. The ICER analyses showed that pCGS was cost-effective compared to a placebo, with an ICER of 4489 €/QALY at month 3, 4112 €/QALY at month 6, and 9983 €/QALY at year 3. The use of OFG was not cost-effective at any of the time points considered. Conclusion: Using our previously published model to simulate the individual health utility scores of patients, we showed that, in the German context, the use of pCGS could be considered costeffective, while the use of OFG could not. These results highlight the importance of the formulation of glucosamine

Relationships Between Changes in Bone Mineral Density or Bone Turnover Markers and Vertebral Fracture Incidence in Patients Treated with Bazedoxifene

Abstract We analyzed the relationships between bone mineral density (BMD) or bone turnover marker (BTM) changes and vertebral fracture incidence in women treated with bazedoxifene using a post hoc analysis from a 3-year randomized, placebo-controlled study evaluating the effect of bazedoxifene (20 or 40 mg) on fracture risk reduction. BMD was assessed at baseline and every 6 months for 3 years. Osteocalcin and C-telopeptide of type I collagen were assessed at baseline and at 3, 12, and 36 months. Vertebral fractures were assessed with a semiquantitative visual assessment. Data were available for 5,244 women, of whom 3,476 were treated with bazedoxifene. Using a logistic regression analysis and the classical Li approach, the proportion of fracture incidence explained by BMD change after 3 years of bazedoxifene treatment was 29 % for the total hip and 44 % for the femoral neck. The proportion of treatment explained by lumbar BMD change could not be quantified accurately because of the significant interaction between treatment and change in BMD. With the same model, the 12-month BTM changes explained up to 29 % of the fracture risk reduction observed with the two forms of bazedoxifene. In women treated with bazedoxifene, changes in femoral neck BMD, hip BMD, or BTMs explained a moderate proportion of the fracture risk reduction observed during the 3 years of follow-up. However, BMD or BTM changes cannot be recommended for individual monitoring of women treated with bazedoxifene

Mixture model for inferring susceptibility to mastitis in dairy cattle: a procedure for likelihood-based inference

A Gaussian mixture model with a finite number of components and correlated random effects is described. The ultimate objective is to model somatic cell count information in dairy cattle and to develop criteria for genetic selection against mastitis, an important udder disease. Parameter estimation is by maximum likelihood or by an extension of restricted maximum likelihood. A Monte Carlo expectation-maximization algorithm is used for this purpose. The expectation step is carried out using Gibbs sampling, whereas the maximization step is deterministic. Ranking rules based on the conditional probability of membership in a putative group of uninfected animals, given the somatic cell information, are discussed. Several extensions of the model are suggested