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[Identification and prediction of responders to a therapy. A model and its preliminary application to hypertension].

The effect of a given treatment for a given disease may be estimated from randomized controlled clinical trials, expressed as a single treatment effect averaged over the trial population. However, in recent years there has been an increasing willingness to individualize therapeutic decisions. The method we report here identifies responders by assessing the individual probability of an event, according to the treatment group. We used a treatment-stratified Cox regression model including interaction between treatment and patient's covariates, with common regression coefficients for treated and untreated, except for the special case of a prognostic variable which has an interaction with treatment. Further, we used a discriminate function based on the final model, representing the absolute individual therapeutic effect, to identify the patients to be treated according to a given threshold of clinical efficacy. The model was explored on the INDANA database (which pools individual patient data from clinical trials of anti-hypertensive drug intervention). Data on 36,444 patients, from five randomized controlled trials were included. The results show the relationship between the proportion of avoided events among the avoidable ones, and the proportion of patients treated who were responders, as a function of the threshold of absolute benefit defining responders. The confidence intervals of the absolute therapeutic benefit for each individual were calculated, by using the Monte Carlo simulation method. A comparison of the survival of treated and controlled individuals, in both subgroups of responders and non responders, illustrated the relevance of the model. We conclude that the tools for predicting individual therapeutic benefit do exist. It will be important to assess the reproducibility of these results in other models or in other populations before widespread application. It will be necessary to have a properly computerized environment and to train doctors to use these tools.

Decision Support Techniques↗

Automatic and efficient R wave discrimination in the right atrium using a two-state hidden Markov model.

INTRODUCTION: Discrimination of far-field R waves from atrial events in atrial electrograms (EGMs) is problematic in present implantable pacing systems. Adjustments of atrial refractory periods and sensitivity settings are the only options, and they will not provide optimal performance in many patients. The reliable detection or rejection of R waves in atrial EGMs would avoid problems of atrial undersensing or oversensing, thus benefiting DDD patients by providing more reliable and specific atrial arrhythmia detection. In addition, detection of far-field R waves could allow a measurement of AV conduction time in AAI and aid in discrimination of supraventricular tachyarrhythmia from ventricular tachyarrhythmia. METHODS AND RESULTS: Both atrial and ventricular unipolar EGMs were collected from 25 patients undergoing pacemaker implant or replacement. An average of 141 seconds of intrinsic or VVI paced EGMs was recorded and post analyzed. A new two-state hidden Markov model (HMM) was developed specifically for far-field R wave and P wave discrimination in the atrium. The recorded patients' EGMs were analyzed using this model, and the sensitivity and positive predictivity of far-field R wave detection were evaluated. The collected atrial EGMs were visually examined and marked as the control for verification of the detection analysis. Far-field R wave detection using this model had an overall sensitivity of 94% +/- 9.4% and a positive predictivity of 98.3% +/- 4.4%; and the far-field R wave rejection using the same model had a sensitivity and a positive predictivity of 98.8% +/- 3.8% and 99.1% +/- 1.7%, respectively. CONCLUSION: Far-field R wave detection in the right atrium by the two-state HMM is reliable and accurate, and can significantly improve atrial arrhythmia management for patients.

Adolescent↗

Kinetic analysis of high affinity forms of interleukin (IL)-13 receptors: suppression of IL-13 binding by IL-2 receptor gamma chain.

Interleukin-13 (IL-13) is a pleiotropic cytokine that controls growth, differentiation, and apoptosis of immune and tumor cells. To understand the mechanisms of interaction between IL-13 and IL-13 receptors (IL-13R), and the role of the IL-2 receptor common gamma chain (gammac) in IL-13 binding and processing, we have examined IL-13 binding kinetics, dissociation/shedding, and internalization in renal cell carcinoma (RCC) cell lines. We observed a new phenomena in that the apparent rate of association, but not the dissociation, was strongly related to IL-13 concentration. We also observed cooperativity phenomena in IL-13 and IL-13R interaction in control RCC (MLneo) cells, but not in cells transfected with gammac chain (MLgammac). The number of IL-13 binding sites, the effective rate of ligand association, and the dissociation rate constants were reduced in gammac-transfected cells compared to control RCC cells. Two forms of IL-13R were detected in these cell lines, which differed in the kinetics of endocytosis and dissociation/exocytosis. Only a small fraction of bound receptors (14-24%) was rapidly internalized and the same fraction of the ligand-receptor complexes was shed and/or dissociated. The expression of gammac chain did not change any of these processes. A two independent high-affinity and moderate-affinity receptor model fit the kinetic observations in gammac-transfected cells. However, in control cells, the binding kinetics were more complicated. A mathematical model that fit a set of kinetic and steady state data in control cells was selected from a set of possible models. This best-fit model predicts that 1) two different IL-13R are expressed on the cell membrane, 2) a minor fraction of IL-13R exist as microclusters (homodimers and/or heterodimers) without exogenous IL-13, 3) high morphological complexity of the gammac-negative control cell membrane affects the cooperativity phenomena of IL-13 binding, and 4) a large number of co-receptor molecules is present, which helps keep the ligand on the cell surface for a long period of time after fast IL-13 binding and provides a negative control for ligand binding via production of the high affinity inhibitor bound to IL-13. Our data demonstrate that gammac exerts dramatic changes in the kinetic mechanisms of IL-13 binding.

Binding, Competitive↗

Schistosomiasis in the Mekong region: epidemiology and phylogeography.

An account is given of progress made over the last 20 years in the study of Mekong schistosomiasis, causative agent Schistosoma mekongi (Trematoda: Digenea). Emphasis is given to the discussion of work concerning the origin and subsequent dispersal of S. mekongi and related taxa, including relevant snails. The role of such phylogeographical data in schistosomiasis control and the prediction of areas at risk is examined. New palaeogeographical models are reviewed in relation to traditional explanations for the biogeographic deployment of Southeast Asian Schistosoma and their intermediate hosts. The demographics and molecular ecology of Neotricula aperta (Gastropoda: Pomatiopsidae), the snail host of S. mekongi, are reviewed with particular reference to new models for the life cycle of this species and their importance in snail control. The use of population genetic data in the limitation of N. aperta populations is evaluated and strategies suggested for schistosomiasis control efforts directed against the intermediate host. Developments in the taxonomy of N. aperta, and related taxa, and changes in nomenclature are covered. The direction of future investigations into the problem of Mekong schistosomiasis is also discussed.

Animals↗

Use of ELISA for detection of immunoglobulins G and M that recognize Salmonella dublin lipopolysaccharide for prediction of carrier status in cattle.

Immunoglobulin reactions to Salmonella dublin in serum and milk from 4 groups of lactating cows were measured by an indirect ELISA. The groups consisted of (1) cows that were natural carriers of S dublin in the mammary gland, (2) experimentally infected cows that did not become carriers, (3) cows inoculated with a commercial S dublin bacterin, and (4) cows used as S dublin-negative controls. Milk and serum samples were obtained at monthly intervals. Models for predicting carrier status were developed by use of stepwise logistic regression. Independent variables consisted of serum and milk IgG and IgM titers to S dublin lipopolysaccharide and a ratio of IgG to IgM. The utility of a single sample vs multiple samples obtained at 1-month or 2-month intervals was tested by comparison of goodness-of-fit chi 2 P values for 8 models predicting carrier status. Immunoglobulin reactions specific to S dublin were a significant predictor of carrier status (P less than 0.001). Serum IgG titers specific for S dublin were the most important variable for predicting carrier status. Two serum IgG titers to S dublin obtained 2 months apart was a better predictor of carrier status than measurement of the IgG:IgM ratio from a single serum sample. Immunoglobulin recognizing S dublin epitopes also were detected in milk samples. In milk, performing 2 ELISA 60 days apart to determine IgG and IgM reactions to S dublin appeared to be useful for the prediction of carrier status, but was not as accurate as models for serum immunoglobulin reactions.

Animals↗

Ultrasonic actuators for nanometre positioning

This paper deals with ultrasonic motors based on bimodal plate vibrations and their application to nanometre resolution stepper positioning systems. The concept of a linear ultrasonic motor drive capable of nanometric steps, long-range travel and reversible controlled motion is presented. The motor concept developed is based on the superposition of a longitudinal and bending vibrations of a rectangular resonator. The ultrasonic motor model based on system identification via discrete observations and prediction has been developed for control applications. The control algorithm for ultrasonic motors has been developed and theoretical investigations have been made. The open loop positioning system with designed stepper ultrasonic drive produced 10 nm resolution and 5% displacement repeatability. The system with computer controlled position feedback has shown 0.3 micron positioning accuracy over the 100 mm positioning range.

Journal Article↗

The relationship of behavioral inhibition to executive functions in young adults.

Barkley's hybrid model of executive functions (EFs) predicts that individuals with deficient inhibitory control should show impairment of EFs. Thirty-eight nonreferred young adults were administered tests of EFs and four laboratory measures of inhibitory control: Stop Signal (SS), Go No-Go, Competing Motor Program (CMP), and Stroop Color-Word tests. Behavioral ratings of impulsivity were collected using the Barratt Impulsivity Scale-11 (BIS-11). CMP and SS accounted for a significant proportion of variance in measures of EFs beyond that accounted for by IQ. Additionally, increased impulsivity, as measured by the BIS-11, was associated with poorer performance on some tests of EFs. These findings provide partial support for Barkley's theory in that effective executive functioning is associated with sufficient inhibitory control.

Adolescent↗

Experimental gingivitis studies: effects of triclosan and triclosan-containing dentifrices on dental plaque and gingivitis in three-week randomized controlled clinical trials.

A recently reported six-month gingivitis study demonstrated that in subjects with gingivitis, a triclosan/pyrophosphate dentifrice provided supragingival plaque control. The level of plaque reduction was comparable with that reported for other triclosan-containing dentifrices; however, no reductions in gingivitis were observed for triclosan/pyrophosphate relative to the negative control. One possible explanation of this result is that the Hawthorne effect in the study was too great to allow the detection of a treatment benefit for the triclosan product. In order to further explore the relevance of these results, three independent clinical studies were undertaken utilizing designs based on a 21-day experimental gingivitis model in which Hawthorne effects are minimized, in part due to the absence of toothbrushing. In each model, a pre-study prophylaxis was followed by a three-week period of oral hygiene instruction to establish optimum baseline gingival health in study participants. The studies varied in enrollment; 120, 33 and 32 subjects completed treatment on studies 1, 2, and 3, respectively. In study 1, test articles were dentifrice products (0.28% triclosan/5% pyrophosphate/0.145% sodium fluoride, 0.2% triclosan/0.5% zinc citrate/0.112% sodium fluoride, 0.145% sodium fluoride and 0.15% sodium monofluorophosphate) applied neat and undiluted via a performed tooth shield (that prevents mechanical tooth-brushing at the test sites in the oral cavity) in a partial mouth design. In study 2, test articles were also dentifrice products (0.28% triclosan/5% pyrophosphate/0.243% sodium fluoride, 0.3% triclosan/2% Gantrez copolymer/0.24% sodium fluoride and 0.243% sodium fluoride) but administered to subjects in the form of 1:3 aqueous slurry rinses. Lastly, in study 3, test articles were all mouthrinses (0.12% chlorhexidine, 0.045% triclosan in ethanol plus respective vehicle placebos). Clinical assessments to quantify the test articles' effects on the development of plaque and gingivitis were conducted at baseline (studies 1, 2 and 3), day 7 (studies 2 and 3), day 14 (studies 2 and 3) and day 21 (studies 1, 2 and 3). In study 1, no statistically significant treatment effects were observed between the test articles and controls for plaque or gingivitis development. In study 2, no statistically significant treatment effects were observed at any time point between test products for the development of gingivitis. At days 7 and 14, there were no significant differences between test products and control for plaque development as well. At day 21, the group rinsing with the triclosan/pyrophosphate/sodium fluoride slurry had significantly less plaque accumulation than the group rinsing with the triclosan/copolymer/sodium fluoride slurry (p < 0.05); however, neither of the groups using test products containing triclosan was significantly different for plaque development from the group using the sodium fluoride control test article. In addition, aspartate aminotransferase activity in gingival crevicular fluid was assayed at days 0 and 21; no between-group differences were found at either of these time points, though day 21 AST activities were higher than those at baseline. In study 3, statistically significant treatment differences in plaque regrowth and gingivitis were observed at day 21 for the chlorhexidine rinse versus all other rinses (p < 0.05). No other statistically significant treatment effects were observed between test compounds at any other time points. The results benchmark the anti-plaque and anti-gingivitis benefit for a range of triclosan-based product forms against positive and negative controls in a three different experimental gingivitis models, a design considered predictive of clinical efficacy in longer-term investigations. It is concluded that dentifrice products containing triclosan do not possess sufficient antimicrobial activity to suppress plaque and gingivitis development in the absence of normal oral hygiene, and that relative to chlorhexidine, triclosan itself offers only modest efficacy for the prevention of plaque accumulation and therefore the delayed onset of gingivitis.

Adolescent↗

DNA-aware evaluation and debiasing of sequence-to-function models.

MOTIVATION: Genome sequence-to-function (S2F) models are widely used to interpret base-resolution functional genomics assays. Most S2F models are trained and evaluated against observed counts and profile-shapes using statistical objectives and fidelity metrics. These choices are well motivated, but they are DNA-independent. At the same time, experimental measurements arise from DNA-dependent assays with distinct characteristics. This mismatch motivates a complementary DNA-aware evaluation of S2F-predicted and experimental functional genomic tracks. RESULTS: We study DNA-dependency of experimental and S2F-predicted tracks using track-conditional genome language models (cgLMs). cgLMs predict masked nucleotides from a conditioning track under controlled DNA visibility. Across ATAC-seq and TF ChIP-seq peaks from GM12878 and K562, cgLM-probing reveals a consistent masked DNA-decodability gap between many experimental and S2F-predicted tracks. In particular, single-task (e.g. BPNet) and multi-task (e.g. AlphaGenome) S2F-predicted tracks enabled cgLMs to recover masked nucleotides with significantly higher accuracy and confidence than matched experimental tracks. Analyses of nonpeak and dinucleotide-shuffled sequences show that this gap is not confined to peaks and is not captured by standard DNA-agnostic profile-shape fidelity metrics alone. ChromBPNet Tn5-denoised predictions were an exception and behaved closer to the experimental regime, suggesting that staged training may reduce the gap. We then convert this diagnostic into a critic-derived objective, DNA-dependency matching (DDM), using a frozen multi-headed cgLM critic. We introduce Critic-Guided Profile-Shape Editing (CGPSE), a preliminary post hoc debiasing framework for frozen S2F models. In GM12878 ATAC-seq, CGPSE partially reduces the masked DNA-decodability gap for AlphaGenome and BPNet predictions, while exposing a tradeoff with profile-shape fidelity. AVAILABILITY AND IMPLEMENTATION: https://github.com/li-lab-mcgill/dna-aware-s2f-eval.

DNA↗

Clinical characteristics of major depression that predict risk of depression in relatives.

BACKGROUND: Major depression (MD) is both clinically and etiologically heterogeneous. We attempt to relate clinical and etiologic heterogeneity by determining those features of MD that reflect a high familial liability to depressive illness. METHODS: Our sample, 3786 personally interviewed twin pairs from a population-based registry, contained 1765 people with a lifetime history of MD by DSM-III-R criteria, of whom 639 (36.2%) had affected co-twins. We examine, using Cox proportional hazard models, the clinical features of MD in affected twins that predicted the risk for MD in the co-twin. Control variables were zygosity, age at interview, and sex of the twin and co-twin. RESULTS: The best-fitting model contained 4 significant predictors: number of episodes, duration of longest episode, recurrent thoughts of death or suicide, and level of distress or impairment. These 4 clinical features were similarly predictive of the risk for MD in the co-twins of male and female twins and predicted risk of illness more strongly in monozygotic than in dizygotic twins. Variables that did not uniquely predict risk of MD in the co-twin included age at onset and number of depressive symptoms. For number of episodes, the best-fitting model indicated an inverted U-shaped function with greatest co-twin risk for MD with 7 to 9 lifetime episodes. CONCLUSIONS: The clinical features of MD in epidemiologic samples can be meaningfully related to the familial vulnerability to illness. Familial MD is best characterized by intermediate levels of recurrence, long duration of episodes, high levels of impairment, and recurrent thoughts of death or suicide. These clinical features probably reflect a high genetic liability to depressive illness.

Adult↗

An electrically modulated drug delivery device. II. Effect of ionic strength, drug concentration, and temperature.

The effects of various physicochemical parameters on the changes in drug delivery rate produced by an electrophoretic current are examined using a model system. It was shown that ionic strength has an inverse relationship with the change in delivery rate produced by a given current. Small changes in pH were measured during electrophoresis experiments which were considered to be insignificant. Drug reservoir concentration selection is critical in the design of an electrophoretic device and is based on achieving a balance between providing a suitable reservoir and allowing adequate electrophoretic control. Electrophoretic control is affected by temperature in a manner which can be predicted using the Arrhenius relationship. The low power requirements of the model system demonstrate the feasibility of using the principle of electrophoresis to control drug delivery rates in a therapeutic system.

Chemical Phenomena↗

Detection of malignant tumours by multivariate analysis of proton magnetic resonance spectra of serum.

Proton magnetic resonance spectra of blood serum have been subjected to multivariate data analysis to discriminate between samples from cancer patients and from controls. The main feature was the use of digitally defined resonance profiles. The methyl and methylene lipoprotein signals centred at 1.3 and 0.9 parts per million are non-lorentzian composite peaks that cannot be described properly by the line width at half-height. Instead 71 and 76 data points were used to describe the methylene and methyl peak profiles, respectively. These data points were used as input to a principal component analysis to distinguish between malignant (n = 29) and control samples (n = 55). At a probability level of 0.01 (F-test) modelling classified all patients except 2 correctly, while 1 control was slightly above the predictive level for malignancy.

Female↗

Prenatal predictors of cesarean section due to labor arrest.

Cesarean section due to labor arrest occurs because the fetus is too large for the maternal outlet tract. If these women could be identified prior to labor, patient management could be optimized for both the clinician and the woman. A case-control study was designed to identify predictors of Cesarean section due to labor arrest. A five year retrospective review identified 32 cases and 329 controls with complete data for the prenatal maternal variables. Both cases and controls were considered for the stepwise logistic regression model. The prenatal variables predicting Cesarean section due to labor arrest are parity, history of past macrosomia, maternal age, term fundal height and maternal height. This model can be considered a pilot model that can be tested in a large international/inter-ethnic population.

Adolescent↗

Metabolic engineering from a cybernetic perspective. 2. Qualitative investigation of nodal architechtures and their response to genetic perturbation

A cybernetic representation of the branch point development of Stephanopoulos and Vallino is formulated. The model systems are employed to translate the qualitative properties of the nodal control architectures characterized by Stephanopoulos and Vallino into a mathematical context. It is shown that a cybernetic model in which the objective is the independent maximization of the levels of branch point products is consistent with the characterization of a flexible node. In contrast, the rigid control architecture is shown to be equivalent to the maximization of the mathematical product of the branch point products. It has been demonstrated subsequently that cybernetic metabolic network models are capable of predicting the system response to enzymatic amplification. However, given the complicated nature of the subsequent models, a clear illustration of the basic mechanism by which such predictions are manifested is not forthwith. Thus, a second objective of the present work is the examination of the response of the flexible and rigid control architectures to genetic perturbation, specifically enzymatic overexpression, with the expressed aim of elucidating the mechanism by which a cybernetic model predicts metabolic network responsiveness. It is shown that the ramifications of genetic perturbation are transmitted through the cybernetic representation of a metabolic network via the resource allocation structure which acts as the conduit by which regulatory signals are transmitted to seemingly unconnected portions of the network. It is postulated that enzymatic overexpression under an artificial promoter represents, from the perspective of the microorganism, an uncontrollable resource drain that forces the metabolic network control architecture to reevaluate the standing resource allocation policy as implemented via the cybernetic control variables. In biological terms, the reevaluation of allocation policy implies a shift in the level and activity of network enzymes yielding, in some cases, qualitatively different network function. It is our position that, conceptually, this is equivalent to the conventional wisdom that genetic manipulation of a metabolic network is the impetus for shifts in the network functionality, i.e., enzyme levels as well as activity. Thus, this development provides a necessary intellectual precursor for the formulation and analysis of the model systems that follow.

Journal Article↗

A multifaceted intervention for infants with failure to thrive. A prospective study.

OBJECTIVE: To determine whether a multifaceted intervention decreased the incidence of failure to thrive (FTT) in a group of preterm infants with low birth weights and improved the 3-year intelligence, health, growth, and behavior status of the children with FTT. DESIGN: Three-year, prospective, randomized, clinical trial. SETTING: Eight large university hospital sites throughout the United States. SAMPLE: Nine hundred fourteen preterm infants with low birth weights who were born at the sites and met study criteria. INTERVENTION: Home visits weekly during the first year of life and biweekly thereafter until the age of 3 years to provide family support and implement two curricula; and attendance at a child development center from 12 months until 3 years of age, 5 days a week, to deliver an early childhood educational intervention. RESULTS: The incidence of FTT did not differ between the treatment and control groups (20% vs 22%). Overall, children with FTT in the treatment group were not different from children with FTT in the follow-up group on any of the outcome variables. However, after controlling for other factors, treatment group membership significantly contributed to the prediction model of 36-month IQ (P = .005) for the children with FTT. In addition, children with FTT in the intervention group with higher compliance demonstrated higher 3-year IQ and better behavior scores than the children with FTT in the low-compliance group. CONCLUSIONS: The intervention did not change the incidence of FTT or the 3-year outcomes in this low-birth-weight, preterm cohort. After controlling for multiple independent variables, marked effects on 3-year IQ were noted. In addition, these beneficial effects were most pronounced in families that were most complaint with the intervention.

Child Behavior↗

Untangling the health disparities of teen pregnancy.

PURPOSE: The purpose of this secondary analysis is to determine whether a developmental maturity model differentially predicts pregnancy for African American, Puerto Rican, and Mexican inner-city teens. DESIGN AND METHODS: This is a secondary analysis of data from a case control study that tested a model of developmental maturity and teen pregnancy with 183 pregnant and never-pregnant pairs of inner-city teens matched on age, ethnicity, and freshman cohort. RESULTS: The models differentially predict pregnancy for the separate ethnic groups, with sexual behaviors being the most important factors regardless of ethnicity. PRACTICE IMPLICATIONS: The health disparities of teen pregnancies may not decrease unless patterns of dating/sexual behaviors are reversed.

Adolescent↗

Differentiated intestinal epithelial cell lines as in vitro models for predicting the intestinal absorption of drugs.

The oral absorption of a compound is a critical factor for the future of the compound as a drug. This absorption is mainly controlled by the passage across the intestinal epithelium. Thus, the prediction of the intestinal absorption by means of an in vitro model may represent a powerful tool for the early selection of molecules during the process of drug development. In the present study, the differentiated human intestinal epithelial cell line HT29-18-C1, was grown on permeable filters in dual chambers. These cells formed tight monolayers that were used to measure in vitro the transepithelial permeability coefficient (Pc) of various molecules. The results were compared with in vivo data of oral absorption. A threshold value of in vitro permeability of 2 x 10(-6) cm/s was found. Molecules having a permeability coefficient higher than this value were absorbed orally more than 80%, while drugs with Pc values lower than 2 x 10(-6) cm/s were poorly absorbed. By mathematical simulation, it was found that this Pc value, when extrapolated to the surface area and volume of the small intestine, corresponds to an absorption of 80% for a compound with a transit time through the small intestine of 5 h. This demonstrates the predictive utility of the threshold value of the permeability coefficient derived from the in vitro model of intestinal epithelium.

Cell Line↗

Concepts and tools for predictive modeling of microbial dynamics.

Description of microbial cell (population) behavior as influenced by dynamically changing environmental conditions intrinsically needs dynamic mathematical models. In the past, major effort has been put into the modeling of microbial growth and inactivation within a constant environment (static models). In the early 1990s, differential equation models (dynamic models) were introduced in the field of predictive microbiology. Here, we present a general dynamic model-building concept describing microbial evolution under dynamic conditions. Starting from an elementary model building block, the model structure can be gradually complexified to incorporate increasing numbers of influencing factors. Based on two case studies, the fundamentals of both macroscopic (population) and microscopic (individual) modeling approaches are revisited. These illustrations deal with the modeling of (i) microbial lag under variable temperature conditions and (ii) interspecies microbial interactions mediated by lactic acid production (product inhibition). Current and future research trends should address the need for (i) more specific measurements at the cell and/or population level, (ii) measurements under dynamic conditions, and (iii) more comprehensive (mechanistically inspired) model structures. In the context of quantitative microbial risk assessment, complexity of the mathematical model must be kept under control. An important challenge for the future is determination of a satisfactory trade-off between predictive power and manageability of predictive microbiology models.

Bacteria↗