A Knowledge-based System for Intelligent Support in Pharmacogenomics Evidence Assessment: Ontology-driven Evidence Representation, Retrieval, Classification and Interpretation

Thesis (Ph.D.)--University of Washington, 2016-06

Genetic and environmental sources of covariance between reading tests used in neuropsychological assessment and IQ subtests

In this study, we examined genetic and environmental influences on covariation among two reading tests used in neuropsychological assessment (Cambridge Contextual Reading Test [CCRT], [Beardsall, L., and Huppert, F. A. ( 1994). J. Clin. Exp. Neuropsychol. 16: 232 - 242], Schonell Graded Word Reading Test [SGWRT], [ Schonell, F. J., and Schonell, P. E. ( 1960). Diagnostic and attainment testing. Edinburgh: Oliver and Boyd.]) and among a selection of IQ subtests from the Multidimensional Aptitude Battery (MAB), [Jackson, D. N. (1984). Multidimensional aptitude battery, Ontario: Research Psychologists Press.] and the Wechsler Adult Intelligence Scale-Revised (WAIS-R) [Wechsler, D. (1981). Manual for the Wechsler Adult Intelligence Scale-Revised (WAIS-R). San Antonio: The Psychological Corporation]. Participants were 225 monozygotic and 275 dizygotic twin pairs aged from 15 years to 18 years ( mean, 16 years). For Verbal IQ subtests, phenotypic correlations with the reading tests ranged from 0.44 to 0.65. For Performance IQ subtests, phenotypic correlations with the reading tests ranged from 0.23 to 0.34. Results of Structural Equation Modeling (SEM) supported a model with one genetic General factor and three genetic group factors ( Verbal, Performance, Reading). Reading performance was influenced by the genetic General factor ( accounting for 13% and 20% of the variance for the CCRT and SGWRT, respectively), the genetic Verbal factor ( explaining 17% and 19% of variance for the CCRT and SGWRT), and the genetic Reading factor ( explaining 21% of the variance for both the CCRT and SGWRT). A common environment factor accounted for 25% and 14% of the CCRT and SGWRT variance, respectively. Genetic influences accounted for more than half of the phenotypic covariance between the reading tests and each of the IQ subtests. The heritabilities of the CCRT and SGWRT were 0.54 and 0.65, respectively. Observable covariance between reading assessments used by neuropsychologists to estimate IQ and IQ subtests appears to be largely due to genetic effects.

Assessment of volume depletion in children with malaria

Background The degree of volume depletion in severe malaria is currently unknown, although knowledge of fluid compartment volumes can guide therapy. To assist management of severely ill children, and to test the hypothesis that volume changes in fluid compartments reflect disease severity, we measured body compartment volumes in Gabonese children with malaria. Methods and Findings Total body water volume (TBW) and extracellular water volume (ECW) were estimated in children with severe or moderate malaria and in convalescence by tracer dilution with heavy water and bromide, respectively. Intracellular water volume (ICW) was derived from these parameters. Bioelectrical impedance analysis estimates of TBW and ECW were calibrated and bioelectrical impedance analysis measurements were taken daily against dilution methods, until discharge. Sixteen children had severe and 19 moderate malaria. Severe childhood malaria was associated with depletion of TBW (mean [SD] of 37 [33] ml/kg, or 6.7% [6.0%]) relative to measurement at discharge. This is defined as mild dehydration in other conditions. ECW measurements were normal on admission in children with severe malaria and did not rise in the first few days of admission. Volumes in different compartments (TBW, ECW, and ICW) were not related to hyperlactataemia or other clinical and laboratory markers of disease severity. Moderate malaria was not associated with a depletion of TBW. Conclusions Significant hypovolaemia does not exacerbate complications of severe or moderate malaria. As rapid rehydration of children with malaria may have risks, we suggest that fluid replacement regimens should aim to correct fluid losses over 12-24 h.

Oral glucose tolerance test in children and adolescents: Positives and pitfalls

Objectives: To describe the glycaemic status (assessed by an oral glucose tolerance test (OGTT)) and associated comorbidities in a cohort of Australian children and adolescents at risk of insulin resistance and impaired glucose homeostasis (IGH). Methods: Twenty-one children and adolescents (three male, 18 female) (18 Caucasian, one Indigenous, two Asian) (20 obese, one lipodystrophy) referred to the Paediatric Endocrinology and Diabetes Clinic underwent a 2-h OGTT with plasma glucose and insulin measured at baseline, + 60 and + 120 min. If abnormal, the OGTT was repeated. Results: The mean (SD) age was 14.2 (1.6) years, BMI 38.8 (7.0) kg/m(2) and BMI-SDS 3.6 (0.6). Fourteen patients had fasting insulin levels >21 mU/L. Type 2 diabetes mellitus was diagnosed in one patient, impaired glucose tolerance (IGT) in four patients and impaired fasting glycaemia (IFG) in one patient. Despite no weight loss, only one patient had a persistently abnormal OGTT on repeat testing. Three patients with IGH were medicated with risperidone at the time of the initial OGTT. One patient who had persistent IGT had continued risperidone. The other two patients had initial OGTT results of IGT and diabetes mellitus type 2. They both ceased risperidone between tests and repeat OGTT showed normal glycaemic status. Conclusions: Use of fasting glucose alone may miss cases of IGH. Diagnosis of IGT should not be made on one test alone. Interpretation of glucose and insulin responses in young people is limited by lack of normative data. Larger studies are needed to generate Australian screening recommendations. Further assessment of the potential adverse effects of atypical antipsychotic medication on glucose homeostasis in this at-risk group is important.

The performance of South African English first language child speakers on a "low linguistically loaded" central auditory processing test protocol

The lack of standardized tests of central auditory processing disorder (CAPD) in South Africa (SA) led to the formation of a SA CAPD Taskforce, and the interim development of a "low linguistically loaded" CAPD test protocol using test recordings from the 'Tonal and Speech Materials for Auditory Perceptual Assessment Disc 2.0'. This study inferentially compared the performance of 16 SA English first, and 16 SA English second, language adult speakers on this test protocol, and descriptively compared their performances to previously published American normative data. Comparisons between the SA English first and second language speakers showed a poorer right ear performance (p < .05) by the second language speakers on the two-pair dichotic digits test only. Equivalent performances (p < .05) were observed on the left ear performance on the two pair dichotic digits test, and the frequency patterns test, the duration patterns test, the low-pass filtered speech test, the 45% time compressed speech test, the speech masking level difference test, and the consonant vowel consonant (CVC) binaural fusion test. Comparisons between the SA English and the American normative data showed many large differences (up to 37.1% with respect to predicted pass criteria as calculated by mean-2SD cutoffs), with the SA English speakers performing both better and worse depending on the test involved. As a result, the American normative data was not considered appropriate for immediate use as normative data in SA. Instead, the preliminary data provided in this study was recommended as interim normative data for both SA English first and second language adult speakers, until larger scale SA normative data can be obtained.

Australian norms for a quantitative olfactory function test

Quantitative olfactory assessment is often neglected in clinical practice, although olfactory loss can assist diagnosis and leads to significant morbidity. The aim of this study was to develop normative data for the Australian population for the 'Sniffin' Sticks', an internationally established olfactory function test. As in other populations, Australian females performed better than males and both lost olfactory function with age. From the normative data, criterion test scores for males and females were established for clinical classifications ('normosmic', 'hyposmic', and 'anosmic'). These clinical classifications were assessed in Parkinson's patients: 81.1 % were anosmic or severely hyposmic and only 7.7% were normosmic. A new term ('prebyosmia') is introduced to describe age-related loss of olfactory capacity of unknown aetiology. With these norms, the Sniffin' Sticks can be used in the Australian population to compare an individual's olfactory function against the population of others of similar age and sex and to identify olfactory dysfunction. (C) 2003 Elsevier Ltd. All rights reserved.

Assessment of disease progression in motor neuron disease

Motor neuron disease (MND) is characterised by progressive deterioration of the corticospinal tract, brainstem, and anterior horn cells of the spinal cord. There is no pathognomonic test for the diagnosis of MND, and physicians rely on clinical criteria-upper and lower motor neuron signs-for diagnosis. The presentations, clinical phenotypes, and outcomes of MND are diverse and have not been combined into a marker of disease progression. No single algorithm combines the findings of functional assessments and rating scales, such as those that assess quality of life, with biological markers of disease activity and findings from imaging and neurophysiological assessments. Here, we critically appraise developments in each of these areas and discuss the potential of such measures to be included in the future assessment of disease progression in patients with MND.

Screening for physical activity in family practice - Evaluation of two brief assessment tools

Background: Physical activity (PA) is relevant to the prevention and management of many health conditions in family practice. There is a need for an efficient, reliable, and valid assessment tool to identify patients in need of PA interventions. Methods: Twenty-eight family physicians in three Australian cities assessed the PA of their adult patients during 2004 using either a two- (2Q) or three-question (3Q) assessment. This was administered again approximately 3 days later to evaluate test-retest reliability. Concurrent validity was evaluated by measuring agreement with the Active Australia Questionnaire, and criterion validity by comparison with 7-day Computer Science Applications, Inc. (CSA) accelerometer counts. Results: A total of 509 patients participated, with 428 (84%) completing a repeat assessment, and 415 (82%) accelerometer monitoring. The brief assessments had moderate test-retest reliability (2Q k = 58.0%, 95% confidence interval [CI] = 47.2-68.8%; 3Q k = 55.6%, 95% CI = 43.8-67.4%); fair to moderate concurrent validity (2Q k = 46.7%, 95% CI = 35.657.9%; 3Q k = 38.7%, 95% CI = 26.4-51.1%); and poor to fair criterion validity (2Q k = 18.2%, 95% CI = 3.9-32.6%; 3Q k = 24.3%, 95% CI = 11.6-36.9%) for identifying patients as sufficiently active. A four-level scale of PA derived from the PA assessments was significantly correlated with accelerometer minutes (2Q rho = 0.39, 95% CI = 0.28-0.49; 3Q rho = 0.31, 95% CI = 0.18-0.43). Physicians reported that the assessments took I to 2 minutes to complete. Conclusions: Both PA assessments were feasible to use in family practice, and were suitable for identifying the least active patients. The 2Q assessment was preferred by clinicians and may be most appropriate for dissemination.

Evaluation of random plasma cortisol and the low dose corticotropin test as indicators of adrenal secretory capacity in critically ill patients: A prospective study

It is unclear whether a random plasma cortisol measurement and the corticotropin (ACTH) test adequately reflect glucocorticoid secretory capacity in critical illness. This study aimed to determine whether these tests provide information representative of the 24 hour period. Plasma cortisol was measured hourly for 24 hours in 21 critically ill septic patients followed by a corticotropin test with 1 μ g dose administered intravenously. Serum and urine were analysed for ACTH and free cortisol respectively. Marked hourly variability in plasma cortisol was evident (coefficient of variation 8-30%) with no demonstrable circadian rhythm. The individual mean plasma cortisol concentrations ranged from 286 59 nmol/l to 796 &PLUSMN; 83 nmol/l. The 24 hour mean plasma cortisol was strongly correlated with both random plasma cortisol (r(2) 0.9, P< 0.0001) and the cortisol response to corticotropin (r(2) 0.72, P< 0.001). Only nine percent of patients increased their plasma cortisol by 250 nmol/l after corticotropin (euadrenal response). However, 35% of non-responders had spontaneous hourly rises > 250 nmol/l thus highlighting the limitations of a single point corticotropin test. Urinary free cortisol was elevated (865&PLUSMN; 937 nmol) in both corticotropin responders and non-responders suggesting elevated plasma free cortisol. No significant relationship was demonstrable between plasma cortisol and ACTH. We conclude that although random cortisol measurements and the low dose corticotropin tests reliably reflect the 24 hour mean cortisol in critical illness, they do not take into account the pulsatile nature of cortisol secretion. Consequently, there is the potential for erroneous conclusions about adrenal function based on a single measurement. We suggest that caution be exercised when drawing conclusions on the adequacy of adrenal function based on a single random plasma cortisol or the corticotropin test.

Ototoxicity and tolerance assessment of a TrisEDTA and polyhexamethylene biguanide ear flush formulation in dogs

Clinically healthy mixed breed dogs (n = 20) were used to determine if a Tris (tromethamine)-buffered test solution, Otinide((R)) (Trademark of Dermcare-Vet Pty-Ltd, Australia), containing disodium ethylenediamine tetraacetic acid (EDTA; 1.21 g/L) and polyhexamethylene biguanide (PHMB; 0.22 g/L) caused ototoxicity or vestibular dysfunction. The dogs were randomly assigned to either a control group (group A, n = 10) receiving saline, or a treatment group (group B, n = 10) receiving the test solution. Phase 1 of the study consisted of applying 5.0 mL of saline to both ears of the control group (group A) and 5 mL of test solution to both ears of the test group (group B), for 21 days. A bilateral myringotomy was then performed on each dog under deep sedation. Phase 2 of the study then consisted of applying 2.0 mL of the saline to both ears of the control group (group A) and 2.0 mL of the test solution to both ears of the test group (group B), for 14 days. Throughout the study, dogs were examined for clinical health, and underwent otoscopic, vestibular and auditory examinations. The auditory examinations included brainstem auditory evoked potential (BAEP) threshold and supra-threshold assessments using both click and 8 kHz tone burst stimuli. The absence of vestibular signs and effects on the BAEP attributable to the test solution suggested the test solution could be applied safely to dogs, including those with a damaged tympanic membrane.

Global assessment of coral bleaching and required rates of adaptation under climate change

Elevated ocean temperatures can cause coral bleaching, the loss of colour from reef-building corals because of a breakdown of the symbiosis with the dinoflagellate Symbiodinium. Recent studies have warned that global climate change could increase the frequency of coral bleaching and threaten the long-term viability of coral reefs. These assertions are based on projecting the coarse output from atmosphere-ocean general circulation models (GCMs) to the local conditions around representative coral reefs. Here, we conduct the first comprehensive global assessment of coral bleaching under climate change by adapting the NOAA Coral Reef Watch bleaching prediction method to the output of a low- and high-climate sensitivity GCM. First, we develop and test algorithms for predicting mass coral bleaching with GCM-resolution sea surface temperatures for thousands of coral reefs, using a global coral reef map and 1985-2002 bleaching prediction data. We then use the algorithms to determine the frequency of coral bleaching and required thermal adaptation by corals and their endosymbionts under two different emissions scenarios. The results indicate that bleaching could become an annual or biannual event for the vast majority of the world's coral reefs in the next 30-50 years without an increase in thermal tolerance of 0.2-1.0 degrees C per decade. The geographic variability in required thermal adaptation found in each model and emissions scenario suggests that coral reefs in some regions, like Micronesia and western Polynesia, may be particularly vulnerable to climate change. Advances in modelling and monitoring will refine the forecast for individual reefs, but this assessment concludes that the global prognosis is unlikely to change without an accelerated effort to stabilize atmospheric greenhouse gas concentrations.

Development and evaluation of the Clinician Suicide Risk Assessment Checklist

This paper describes the development and evaluation of a new instrument – the Clinician Suicide Risk Assessment Checklist (CSRAC). The instrument assesses the clinician’s competency in three areas: clinical interviewing, assessment of specific suicide risk factors, and formulating a management plan. A draft checklist was constructed by integrating information from 1) literature review 2) expert clinician focus group and 3) consultation with experts. It was utilised in a simulated clinical scenario with clinician trainees and a trained actor in order to test for inter-rater agreement. Agreement was calculated and the checklist was re-drafted with the aim of maximising agreement. A second phase of simulated clinical scenarios was then conducted and inter-rater agreement was calculated for the revised checklist. In the first phase of the study, 18 of 35 items had inadequate inter-rater agreement (60%>), while in the second phase, using the revised version, only 3 of 39 items failed to achieve adequate inter-rater agreement. Further evidence of reliability and validity are required. Continued development of the CSRAC will be necessary before it can be utilised to assess the effectiveness of risk assessment training programs.

Psychometric assessment of recovery from mild traumatic brain injury

The Rapid Screen of Concussion (RSC) is a brief psychometric test battery, designed to provide a functional criterion to aid clinical diagnosis of mild traumatic brain injury (mTBI). The present research aimed to examine the utility of this instrument for assessing recovery after mTBI. Three studies were conducted. In Study 1, Discriminant Function Analysis was performed to determine how well the RSC differentiated uninjured controls (N¼16), from mTBI patients (N¼22) and moderate to severe TBI patients (N¼14), several months post-injury. As predicted, moderate to severe TBI patients achieved lower scores than the mTBI and control groups. The RSC also successfully differentiated between each of the diagnostic groups, yielding an overall correct classification rate of 75%. Study 2 examined the predictive utility of the RSC in the mTBI sample (N¼22). Acute injury performance on the RSC was correlated with post-injury scores at an average of 5.5 months post-injury. Statistically significant partial correlation coefficients (r¼0.53r¼0.80) were found for each of the subtests, showing that low acute RSC scores were predictive of poor recovery scores on the RSC after mTBI. In the third study, Reliable Change Indices were calculated on the RSC subtests to examine individual patterns of recovery from mTBI. While 17 of the 23 participants made a significant improvement on their acute injury DSST scores (74%), only 13 of 25 made a significant improvement on the Rapid Sentence Judgement Test (52%), highlighting differential recovery of function, and challenging the notion of full recovery from mTBI within 3 months. These overall results offer support for the construct and predictive validity of the RSC and demonstrate that inexpensive tests of brain function may be useful for managing mTBI acutely for prognosis.

The application of numerical modelling to the assessment of the potential for, and the detection of, spontaneous combustion in coal mines

Numerical modelling has been used to examine the relationship between the results of two commonly used methods of assessing the propensity of coal to spontaneous combustion, the R70 and Relative Ignition Temperature tests, and the likely behaviour in situ. The criticality of various parameters has been examined and a method of utilising critical self-heating parameters has been developed. This study shows that on their own, the laboratory test results do not provide a reliable guide to in situ behaviour but can be used in combination to considerably increase the ability to predict spontaneous combustion behaviour.

The design and engineering of a reactor test facility for thermal processing of biomass

This thesis describes the design and engineering of a pressurised biomass gasification test facility. A detailed examination of the major elements within the plant has been undertaken in relation to specification of equipment, evaluation of options and final construction. The retrospective project assessment was developed from consideration of relevant literature and theoretical principles. The literature review includes a discussion on legislation and applicable design codes. From this analysis, each of the necessary equipment units was reviewed and important design decisions and procedures highlighted and explored. Particular emphasis was placed on examination of the stringent demands of the ASME VIII design codes. The inter-relationship of functional units was investigated and areas of deficiency, such as biomass feeders and gas cleaning, have been commented upon. Finally, plant costing was summarized in relation to the plant design and proposed experimental programme. The main conclusion drawn from the study is that pressurised gasification of biomass is far more difficult and expensive to support than atmospheric gasification. A number of recommendations have been made regarding future work in this area.