Review of Medical Decision Support and Machine-Learning Methods.

Machine-learning methods can assist with the medical decision-making processes at the both the clinical and diagnostic levels. In this article, we first review historical milestones and specific applications of computer-based medical decision support tools in both veterinary and human medicine. Next, we take a mechanistic look at 3 archetypal learning algorithms-naive Bayes, decision trees, and neural network-commonly used to power these medical decision support tools. Last, we focus our discussion on the data sets used to train these algorithms and examine methods for validation, data representation, transformation, and feature selection. From this review, the reader should gain some appreciation for how these decision support tools have and can be used in medicine along with insight on their inner workings.

Not just for lymphoid cells: the role of the noncanonical NF-κB signaling pathway in early and late myelopoiesis with a focus on hypereosinophilic disorders.

The noncanonical NF-κB pathway is involved in lymphoid organ development, B-cell maturation, and cytokine production. However, new research has demonstrated that this pathway is also key for the orderly and sequential maturation of myeloid cells, including neutrophils and eosinophils. When this pathway is disrupted or constitutively activated, aberrations in hematopoietic stem and progenitor cell survival and proliferation, as well as subsequent granulopoiesis and eosinophilopoiesis, are affected. Disturbance of such a coordinated and delicate process can manifest in devastating clinical disease, including acute and chronic myeloid leukemias, preleukemic processes such as myelodysplastic syndrome, or hyperinflammatory conditions like hypereosinophilic syndrome. In this review, we discuss the molecular machinery within the noncanonical NF-κB pathway, crosstalk with the canonical NF-κB pathway, murine models of noncanonical signaling, and how aberrations in this pathway manifest in leukemic or hyperinflammatory disease with a focus on hypereosinophilic syndrome. Potential and promising drug therapies will also be discussed, emphasizing the noncanonical NF-κB pathway as a potential target for improved treatment for patients with leukemia or idiopathic hypereosinophilic syndrome. The hope is that review of such mechanisms and treatments may eventually result in findings that aid physicians in rapidly diagnosing and more accurately classifying patients with such complex and overlapping hematopoietic diseases.

Probable paraneoplastic leukocytosis in a dog with a gastrointestinal stromal tumor.

A 9-year-old female spayed Boston Terrier presented for diagnostic investigation of lethargy, poor appetite, weight loss, and a marked leukocytosis. Significant muscle wasting and a palpable abdominal mass were present on physical examination. Abdominal imaging revealed the mass to be of small intestinal origin; consequently, an intestinal resection and anastomosis were performed without complication. The histopathologic diagnosis was a gastrointestinal stromal tumor, verified by immunohistochemical positivity to CD117 (KIT). Two weeks after discharge, the leukocytosis had resolved. Though the exact molecular mediator of the severe leukocytosis was undetermined, resolution following tumor removal suggests a paraneoplastic cause. To the authors' knowledge, this is the first reported case of probable paraneoplastic leukocytosis secondary to a gastrointestinal stromal tumor in the dog. Gastrointestinal tract imaging should be performed when this uncommon hematologic abnormality is present.

Expression of vascular endothelial growth factor receptor-1 and -2 in normal and diseased canine eyes.

OBJECTIVE: To immunohistochemically evaluate expression of vascular endothelial growth factor receptor-1 (VEGFR1) and -2 (VEGFR2) in ocular tissue of healthy dogs and dogs affected with primary glaucoma, uveitic glaucoma, and intraocular neoplasia. SAMPLE POPULATION: Enucleated globes from five dogs with primary glaucoma, five dogs with uveitic glaucoma, six dogs with intraocular neoplasms and three ophthalmically normal control dogs. PROCEDURE: Ocular tissues were obtained from enucleated globes of clinical cases or immediately following euthanasia for control dogs. Tissue sections were stained immunohistochemically for VEGFR1 and VEGFR2 via standard techniques and vascular tissue was qualitatively evaluated. Vascular endothelial VEGFR1 and VEGFR2 expression patterns are reported for normal and diseased ocular tissues. In addition, VEGFR1 and VEGFR2 expression patterns are reported for all normal ocular tissues. RESULTS: A constitutive expression pattern was detected for VEGFR1 by ocular vascular endothelial cells as well as nonvascular cells in the cornea, uvea, lens, and retina. VEGFR2 demonstrated limited expression in normal ocular tissue, but was widely expressed in vascular endothelium of diseased eyes, particularly in pre-iridal fibrovascular membranes. CONCLUSIONS: The results of this study suggest a role for VEGF receptors in both physiologic and pathologic angiogenesis in canine ocular tissue. Manipulation of this pathway may be a rational consideration for therapeutic intervention in canine ocular disease exhibiting pathologic neovascularization.

Uses of informatics to solve real world problems in veterinary medicine.

Veterinary informatics is the science of structuring, analyzing, and leveraging information in an effort to advance animal health, disease surveillance, research, education, and business practices. Reference and terminology standards are core components of the informatics infrastructure. This paper focuses on three current activities that use reference standards in veterinary informatics: (1) the construction of a messaging standard in a national animal health laboratory network, (2) the creation of breed and species terminology lists for livestock disease surveillance, and (3) the development of a standardized diagnoses list for small animal practices. These and other endeavors will benefit from research conducted to identify innovative and superior tools, methods, and techniques. The authors believe there are many areas requiring study and special focus in order to advance veterinary informatics, and this paper highlights some of the needs and challenges surrounding these areas.

Hyperphosphatasemia and concurrent adrenal gland dysfunction in apparently healthy Scottish Terriers.

OBJECTIVE: To determine causes of hyperphosphatasemia (high serum alkaline phosphatase [ALP] activity) in apparently healthy Scottish Terriers. DESIGN: Prospective case-controlled study. ANIMALS: 34 apparently healthy adult Scottish Terriers (17 with and 17 without hyperphosphatasemia). PROCEDURES: Serum activities for 3 isoforms (bone, liver, and corticosteroid) of ALP were measured. Concentrations of cortisol, progesterone, 17-hydroxyprogesterone, androstenedione, estradiol, and aldosterone were measured before and after cosyntropin administration (ie, ACTH; 5 microg/kg [2.27 microg/lb], IM). Liver biopsy specimens from 16 dogs (11 with and 5 without hyperphosphatasemia) were evaluated histologically. RESULTS: In dogs with hyperphosphatasemia, the corticosteroid ALP isoform comprised a significantly higher percentage of total ALP activity, compared with the percentage in dogs without hyperphosphatasemia (mean +/- SE, 69 +/- 5.0% and 17 +/- 3.8%, respectively). In 6 dogs with hyperphosphatasemia, but none without, serum cortisol concentrations exceeded reference intervals after ACTH stimulation. Six dogs with and 15 without hyperphosphatasemia had increased concentrations of >or = 1 noncortisol steroid hormone after ACTH stimulation. Serum ALP activity was correlated with cortisol and androstenedione concentrations (r = 0.337 and 0.496, respectively) measured after ACTH stimulation. All dogs with and most without hyperphosphatasemia had abnormal hepatocellular reticulation typical of vacuolar hepatopathy. Subjectively, hepatocellular reticulation was more severe and widespread in hyperphosphatasemic dogs, compared with that in nonhyperphosphatasemic dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Hyperphosphatasemia in apparently healthy Scottish Terriers was most likely attributable to hyperadrenocorticism on the basis of exaggerated serum biochemical responses to ACTH administration and histologic hepatic changes, but none of the dogs had clinical signs of hyperadrenocorticism.

Diagnostic accuracy of stereotactic brain biopsy for intracranial neoplasia in dogs: Comparison of biopsy, surgical resection, and necropsy specimens.

BACKGROUND: Stereotactic brain biopsy (SBB) is a technique that allows for definitive diagnosis of brain lesions. Little information is available regarding the diagnostic utility of SBB in dogs with intracranial diseases. OBJECTIVE: To investigate the diagnostic accuracy (DA) of SBB in dogs with brain tumors. ANIMALS: Thirty-one client-owned dogs that underwent SBB followed by surgical resection or necropsy examinations. METHODS: Retrospective observational study. Two pathologists blinded to SBB and reference standard diagnoses reviewed histologic specimens and typed and graded tumors according to World Health Organization and revised canine glioma classification criteria. Agreement between tumor type and grade from SBB were compared to reference standards and assessed using kappa statistics. Patient and technical factors associated with agreement also were examined. RESULTS: Stereotactic brain biopsy specimens were obtained from 24 dogs with gliomas and 7 with meningiomas. Tumor type agreement between SBB and the reference standard was observed in 30/31 cases (κ = 0.95). Diagnostic concordance was perfect for meningiomas. Grade agreement among gliomas was observed in 18/23 cases (κ = 0.47). Stereotactic brain biopsy underrepresented the reference standard glioma grade in cases with disagreement. The DA of SBB was 81%, with agreement noted in 56/69 biopsy samples. Smaller tumors and fewer SBB specimens obtained were significantly associated with diagnostic discordance. CONCLUSIONS AND CLINICAL IMPORTANCE: The DA of SBB readily allows for the diagnosis of common brain tumors in dogs. Although glioma grade discordance was frequent, diagnoses obtained from SBB are sufficient to currently inform therapeutic decisions. Multiple SBB specimens should be collected to maximize DA.

Diagnostic equine serology.

This article is presented with two main goals: (1) to provide equine clinicians with a resource for identifying types of serum tests available and (2) to outline briefly the necessary sample type, assay principle, and relative strengths and weakness of the various methods. Specific etiologies are presented and grouped by clinical diagnosis categories, along with brief comments concerning each disorder and its relevant diagnostic assays. This organization provides an abstracted list of infectious disorders commonly considered for the various clinical presentations and a summary of available serologic tests for narrowing the differential diagnosis list. The reader is also provided with a list of specific laboratories that perform the diagnostic assay for the mentioned disorders.

Blood proteins and inflammation in the horse.

Activation of the host response to infection, the "acute-phase response," is a highly organized physiologic reaction that includes changes in concentrations of plasma acute-phase proteins (APPs). The APPs are increasingly being used as markers for prognosis and monitoring response to therapy along with general determinants of equine health. Use of APPs in veterinary medicine is becoming more widespread as more commercial diagnostic kits are being validated. This article reviews the salient features of APPs and examines their current application and potential utility in equine inflammatory disorders.

Immunosignature Differentiation of Non-Infectious Meningoencephalomyelitis and Intracranial Neoplasia in Dogs.

A variety of inflammatory conditions of unknown cause (meningoencephalomyelitis of unknown etiology-MUE) and neoplastic diseases can affect the central nervous system (CNS) of dogs. MUE can mimic intracranial neoplasia both clinically, radiologically and even in some cases, histologically. Serum immunosignature protein microarray assays have been used in humans to identify CNS diseases such as Alzheimer's and neoplasia, and in dogs, to detect lymphoma and its progression. This study evaluated the effectiveness of immunosignature profiles for distinguishing between three cohorts of dogs: healthy, intracranial neoplasia, and MUE. Using the learned peptide patterns for these three cohorts, classification prediction was evaluated for the same groups using a 10-fold cross validation methodology. Accuracy for classification was 100%, as well as 100% specific and 100% sensitive. This pilot study demonstrates that immunosignature profiles may help serve as a minimally invasive tool to distinguish between MUE and intracranial neoplasia in dogs.

Adrenocortical Challenge Response and Genomic Analyses in Scottish Terriers With Increased Alkaline Phosphate Activity.

Scottish terriers (ST) frequently have increased serum alkaline phosphatase (ALP) of the steroid isoform. Many of these also have high serum concentrations of adrenal sex steroids. The study's objective was to determine the cause of increased sex steroids in ST with increased ALP. Adrenal gland suppression and stimulation were compared by low dose dexamethasone (LDDS), human chorionic gonadotropin (HCG) and adrenocorticotropic hormone (ACTH) response tests. Resting plasma pituitary hormones were measured. Steroidogenesis-related mRNA expression was evaluated in six ST with increased ALP, eight dogs of other breeds with pituitary-dependent hyperadrenocorticism (HAC), and seven normal dogs. The genome-wide association of single nucleotide polymorphisms (SNP) with ALP activity was evaluated in 168 ST. ALP (reference interval 8-70 U/L) was high in all ST (1,054 U/L) and HAC (985 U/L) dogs. All HAC dogs and 2/8 ST had increased cortisol post-ACTH administration. All ST and 2/7 Normal dogs had increased sex steroids post-ACTH. ST and Normal dogs had similar post-challenge adrenal steroid profiles following LDDS and HCG. Surprisingly, mRNA of hydroxysteroid 17-beta dehydrogenase 2 (HSD17B2) was lower in ST and Normal dogs than HAC. HSD17B2 facilities metabolism of sex steroids. A SNP region was identified on chromosome 5 in proximity to HSD17B2 that correlated with increased serum ALP. ST in this study with increased ALP had a normal pituitary-adrenal axis in relationship to glucocorticoids and luteinizing hormone. We speculate the identified SNP and HSD17B2 gene may have a role in the pathogenesis of elevated sex steroids and ALP in ST.

Evaluation of supervised machine-learning algorithms to distinguish between inflammatory bowel disease and alimentary lymphoma in cats.

Inflammatory bowel disease (IBD) and alimentary lymphoma (ALA) are common gastrointestinal diseases in cats. The very similar clinical signs and histopathologic features of these diseases make the distinction between them diagnostically challenging. We tested the use of supervised machine-learning algorithms to differentiate between the 2 diseases using data generated from noninvasive diagnostic tests. Three prediction models were developed using 3 machine-learning algorithms: naive Bayes, decision trees, and artificial neural networks. The models were trained and tested on data from complete blood count (CBC) and serum chemistry (SC) results for the following 3 groups of client-owned cats: normal, inflammatory bowel disease (IBD), or alimentary lymphoma (ALA). Naive Bayes and artificial neural networks achieved higher classification accuracy (sensitivities of 70.8% and 69.2%, respectively) than the decision tree algorithm (63%, p < 0.0001). The areas under the receiver-operating characteristic curve for classifying cases into the 3 categories was 83% by naive Bayes, 79% by decision tree, and 82% by artificial neural networks. Prediction models using machine learning provided a method for distinguishing between ALA-IBD, ALA-normal, and IBD-normal. The naive Bayes and artificial neural networks classifiers used 10 and 4 of the CBC and SC variables, respectively, to outperform the C4.5 decision tree, which used 5 CBC and SC variables in classifying cats into the 3 classes. These models can provide another noninvasive diagnostic tool to assist clinicians with differentiating between IBD and ALA, and between diseased and nondiseased cats.

Evaluation of endothelin-1 and MMPs-2, -9, -14 in cerebrospinal fluid as indirect indicators of blood-brain barrier dysfunction in chronic canine hypothyroidism.

Chronic canine hypothyroidism is associated with blood-brain barrier (BBB) disruption. We hypothesized that this change is mediated by endothelin-1(ET-1) and matrix metalloproteinases (MMP) -2, -9, and -14, as evidenced by increased concentrations of these proteins in cerebrospinal fluid (CSF) compared to controls. CSF from 18 dogs, 9 controls and 9 with experimentally induced hypothyroidism was collected before and 6, 12, and 18 months after induction of hypothyroidism. Concentrations of ET-1 using an ELISA kit, and for MMP-2, -9, and -14 using gelatinase zymography were measured in CSF. ET-1 was undetectable in CSF of control and hypothyroid dogs at all time-points. Constitutively expressed MMP-2 was detectable in CSF samples in all dogs at all time-points. No other MMPs were detectable in CSF. No differences in CSF concentrations of ET-1 and MMP-2, 9, and 14 were found between hypothyroid and euthyroid dogs. Therefore, ET-1 and MMP-2, 9, and 14 are unlikely to be primary mediators of BBB damage in chronically hypothyroid dogs.

Optic nerve astrocytoma in a dog.

Intracranial astrocytomas are relatively uncommon in dogs and optic nerve astrocytomas even more so. This neoplasm should be considered as differential in canine patients with vision loss, retinal detachment, ocular mass, and histopathologic findings of infiltrative fusiform to polygonal glial cells possibly associated with glomeruloid vascular proliferation.

SNOMED representation of explanatory knowledge in veterinary clinical pathology.

BACKGROUND: The Systematized Nomenclature of Medicine (SNOMED) is an established standard nomenclature for the expression of human and veterinary medical concepts. Nomenclature standards ease sharing of medical information, create common points of understanding, and improve data aggregation and analysis. OBJECTIVES: The objective of this study was to determine whether SNOMED adequately represented concepts relevant to veterinary clinical pathology. METHODS: Concepts were isolated from 3 different types of clinical pathology documents: 1) a textbook (Textbook), 2) the Results sections of industry pathology reports (Findings), and Discussion sections from industry pathology reports (Discussion). Concepts were matched (mapped) by 2 reviewers to semantically-equivalent SNOMED concepts. A quality score of 3 (good match), 2 (problem match), or 1 (no match) was recorded along with the SNOMED hierarchical location of each mapped concept. Results were analyzed using Cohen's Kappa statistic to assess reviewer agreement and chi-square tests to evaluate association between document type and quality score. RESULTS: The percentage of good matches was 48.3% for the Textbook, 45.4% for Findings, and 47.5% for Discussion documents, with no significant difference among documents. Of remaining concepts, 40% were partially expressed by SNOMED and 14% did not match. Mean reviewer agreement on quality score assignments was 76.8%. CONCLUSIONS: Although SNOMED representation of veterinary clinical pathology content was limited, missing and problem concepts were confined to a relatively small area of terminology. This limitation should be addressed in revisions of SNOMED to optimize SNOMED for veterinary clinical pathology applications.

Frame-Based Stereotactic Biopsy of Canine Brain Masses: Technique and Clinical Results in 26 Cases.

This report describes the methodology, diagnostic yield, and adverse events (AE) associated with frame-based stereotactic brain biopsies (FBSB) obtained from 26 dogs with solitary forebrain lesions. Medical records were reviewed from dogs that underwent FBSB using two stereotactic headframes designed for use in small animals and compatible with computed tomographic (CT) and magnetic resonance (MR) imaging. Stereotactic plans were generated from MR and CT images using commercial software, and FBSB performed both with (14/26) and without intraoperative image guidance. Records were reviewed for diagnostic yield, defined as the proportion of biopsies producing a specific neuropathological diagnosis, AE associated with FBSB, and risk factors for the development of AE. Postprocedural AE were evaluated in 19/26 dogs that did not proceed to a therapeutic intervention immediately following biopsy. Biopsy targets included intra-axial telencephalic masses (24/26), one intra-axial diencephalic mass, and one extra-axial parasellar mass. The median target volume was 1.99 cm(3). No differences in patient, lesion, or outcome variables were observed between the two headframe systems used or between FBSB performed with or without intraoperative CT guidance. The diagnostic yield of FBSB was 94.6%. Needle placement error was a significant risk factor associated with procurement of non-diagnostic biopsy specimens. Gliomas were diagnosed in 24/26 dogs, and meningioma and granulomatous meningoencephalitis in 1 dog each. AE directly related to FBSB were observed in a total of 7/26 (27%) of dogs. Biopsy-associated clinical morbidity, manifesting as seizures and transient neurological deterioration, occurred in 3/19 (16%) of dogs. The case fatality rate was 5.2% (1/19 dogs), with death attributable to intracranial hemorrhage. FBSB using the described apparatus was relatively safe and effective at providing neuropathological diagnoses in dogs with focal forebrain lesions.

Survival time following hospital discharge in dogs with palliatively treated primary brain tumors.

OBJECTIVE: To analyze survival time and identify prognostic factors associated with outcome following discharge in dogs with primary brain tumors treated palliatively. DESIGN: Prospective case series. ANIMALS: 51 dogs with 5 histopathologic types of brain tumors. PROCEDURES: Owners with dogs examined from 2004 to 2008 were invited to participate if dogs had CT or MRI evidence of a brain mass that was histopathologically confirmed as a neoplasm upon death, dogs survived for ≥ 48 hours after hospital discharge, and treatments following discharge were limited to administration of prednisone or phenobarbital. Prognostic factors, including signalment, clinical signs (including duration), tumor type, tumor location, degree of peritumoral edema, lesion burden, and prescribed treatment, were evaluated. Survival time was estimated and animal- and tumor-specific variables evaluated as potential prognostic factors. RESULTS: The median survival time in all dogs was 69 days (95% confidence interval [CI], 18 to 201 days). Multivariate analyses identified neuroanatomic location as the only significant prognostic variable, with the survival time of dogs with infratentorial tumors (n = 18) being significantly shorter (median, 28 days; 95% CI, 19 to 68 days) than survival time of dogs with supratentorial (33) tumors (median, 178 days; 95% CI, 119 to 270 days). Seizures were the most common clinical sign associated with supratentorial tumors (24/33 [73%]) and central vestibular dysfunction with infratentorial tumors (12/18). CONCLUSIONS AND CLINICAL RELEVANCE: Dogs with palliatively treated primary brain tumors, particularly those with tumors in the cerebellum, pons, or medulla, had a poor prognosis. However, dogs with supratentorial tumors had survival times > 3 months.

Leukocyte adhesion deficiency type I in a mixed-breed dog.

A 6-month-old, neutered male, mixed-breed dog was examined for a 2-month persistent fever, nonhealing dermal metacarpal area wound, and leukocytosis (47.0-198.0 × 10(3)/µl). Serum chemistry findings included hypoalbuminemia, hyperglobulinemia, hyperphosphatemia, and hyperphosphatasemia. Complete blood cell count results revealed a moderate microcytic, hypochromic nonregenerative anemia with a profound leukocytosis (198.5 × 10(3)/µl), characterized by neutrophilia with toxicity and hypersegmentation, and significant band cells. Tick-borne disease titers (genera Anaplasma, Ehrlichia, and Borrelia) were negative, as were polymerase chain reaction for other infectious agents (genera Hepatozoon, Mycobacterium, Mycoplasma; and Canine distemper virus). No agents were identified in a deep dermal biopsy (conventional and special histochemical stains) of the chronic draining, metacarpal region lesion. Cytology of the draining tract revealed numerous mixed bacteria and a surprising lack of neutrophils. Chronic occult blood loss with iron deficiency was considered a possible cause of the anemia. Differentials for the leukon were chronic established inflammation (occult infectious agent), chronic neutrophilic leukemia, paraneoplastic leukocytosis (neoplastic source of granulocyte colony-stimulating factor [CSF] or granulocyte-macrophage CSF), and leukocyte adhesion deficiency (LAD). The possibility of a LAD disorder was further investigated because of the noted hypersegmented neutrophils, absence of neutrophils in the cytology sample, the animal's young age, and persistence of clinical and laboratory signs. Flow cytometry of blood neutrophils showed a 60% reduction in surface expression of the ß2-integrin (CD18) subunit, whereas neutrophil function tests (oxidative burst and phagocytosis) were normal. Genetic testing revealed a homozygous missense mutation in the ß2-integrin subunit gene, previously recognized only in purebred Irish Setters, leading to a diagnosis of LAD type 1 disorder in this mixed-breed dog.

Role of TLRs in Brucella mediated murine DC activation in vitro and clearance of pulmonary infection in vivo.

Brucellosis is worldwide zoonoses affecting 500,000 people annually with no approved human vaccines available. Live attenuated Brucella abortus vaccine strain RB51 protects cattle through CD4 and CD8 T-cell mediated responses. However, limited information is known regarding how Brucella stimulate innate immunity. Although the most critical toll like receptors (TLRs) involved in the recognition of Brucella are TLR2, TLR4 and TLR9, it is important to identify the essential TLRs that induce DC activation/function in response to Brucella, to be able to upregulate both vaccine strain RB51-mediated protection, and clearance of pathogenic strain 2308. Furthermore, in spite of the importance of aerosol transmission of Brucella, no published studies have addressed the role of TLRs in the clearance of strain 2308 or strain RB51 from intranasally infected mice. Therefore, we used a (a) bone marrow derived dendritic cell model in TLRKO and control mice to assess the differential role of pathogenic and vaccine strains to induce DC activation and function in vitro, and (b) respiratory model in TLRKO and control mice to assess the critical roles for TLRs in clearance of strains in vivo. In support of the essential TLRs in clearance and protection, we performed challenge experiments to identify if these critical TLRs (as agonists) could enhance vaccine induced protection against pathogenic strain 2308 in a respiratory model. We determined: vaccine strain RB51 induced significant (p≤0.05) DC activation vs. strain 2308 which was not dependent on a specific TLR; strain RB51 induced TNF-α production was TLR2 and TLR9 dependent, and IL-12 production was TLR2 and TLR4 dependent; TLR4 and TLR2 were critical for clearance of vaccine and pathogenic Brucella strains respectively; and TLR2 (p<0.05), TLR4 (p<0.05) and TLR9 (p=0.075) agonists enhanced vaccine strain RB51-mediated protection against respiratory challenge with strain 2308 in the lung.