Malka Gorfine

Sensitivity analysis for complex ecological models - A new approach

A strategy for global sensitivity analysis of a multi-parameter ecological model was developed and used for the hydrodynamic-ecological model (DYRESM-CAEDYM, DYnamic REservoir Simulation Model-Computational Aquatic Ecosystem Dynamics Model) applied to Lake Kinneret (Israel). Two different methods of sensitivity analysis, RPART (Recursive Partitioning And Regression Trees) and GLM (General Linear Model) were applied in order to screen a subset of significant parameters. All the parameters which were found significant by at least one of these methods were entered as input to a GBM (Generalized Boosted Modeling) analysis in order to provide a quantitative measure of the sensitivity of the model variables to these parameters. Although the GBM is a general and powerful machine learning algorithm, it has substantial computational costs in both storage requirements and CPU time. Employing the screening stage reduces this cost. The results of the analysis highlighted the role of particulate organic material in the lake ecosystem and its impact on the over all lake nutrient budget. The GBM analysis established, for example, that parameters such as particulate organic material diameter and density were particularly important to the model outcomes. The results were further explored by lumping together output variables that are associated with sub-components of the ecosystem. The variable lumping approach suggested that the phytoplankton group is most sensitive to parameters associated with the dominant phytoplankton group, dinoflagellates, and with nanoplankton (Chlorophyta), supporting the view of Lake Kinneret as a bottom-up system. The study demonstrates the effectiveness of such procedures for extracting useful information for model calibration and guiding further data collection.

5-HT1A Receptor Function in Normal Subjects on Clinical Doses of Fluoxetine: Blunted Temperature and Hormone Responses to Ipsapirone Challenge

Serotonergic receptors of the 5-HT1A subtype have been suggested to play a pivotal role in the mechanism of action of antidepressant drugs, including specific serotonin reuptake inhibitors (SSRIs). We examined the effect of clinical doses of the SSRI, fluoxetine, on 5-HT1A receptor function in 15 normal volunteers. Hypothermic and hormone responses to the 5-HT1A receptor agonist, ipsapirone (0.3 mg per kg, per os) were examined after two weeks of placebo and again, after the subjects had been receiving fluoxetine for four weeks. On fluoxetine, the hypothermic response to ipsapirone was significantly blunted, as were ACTH, cortisol and growth hormone release. Ipsapirone plasma levels were significantly increased by fluoxetine but a pharmacokinetic effect could not have accounted for the observed blunting of 5-HT1A receptor mediated effects. These findings confirm and extend previous observations in rodents and humans and indicate that both post-synaptic 5-HT1A receptors in the hypothalamus, which mediate hormone responses to 5-HT1A agonists, and pre-synaptic 5-HT1A receptors which (putatively) mediate the hypothermic response, are rendered subsensitive by chronic SSRI administration. Since fluoxetine did not have significant effects on mood and other psychological variables in these subjects, alterations in 5-HT1A receptor function induced by SSRIs may have psychotropic relevance only in the context of existing perturbations of serotonergic function which underlie the psychopathological states in which these drugs are therapeutically effective.

A consistent multivariate test of association based on ranks of distances

We consider the problem of detecting associations between random vectors of any dimension. Few tests of independence exist that are consistent against all dependent alternatives. We propose a powerful test that is applicable in all dimensions and consistent against all alternatives. The test has a simple form, is easy to implement, and has good power. Copyright 2013, Oxford University Press.

Onset and time course of antidepressant action : psychopharmacological implications of a controlled trial of electroconvulsive therapy

Onset and time course of antidepressant effect were examined in 47 patients with major depressive disorder who had been randomly assigned to twice weekly bilateral, brief pulse electroconvulsive therapy plus one simulated treatment per week (ECT×2) or to a three times weekly schedule of administration (ECT×3). Rapid improvement was observed in the ECT×3 group in whom the number of real ECTs to 30% reduction on the Hamilton Depression Scale (HAM-D) was 3.2±1.90, administered over 7.3±4.43 days and to 60% reduction, 5.9±3.09 real ECTs over 13.7±7.21 days. Among the responders in both groups combined, 24.3±29.58% of the overall improvement in HAM-D was contributed by the first real ECT, 60.9±28.13% by the first four real ECTs and 91.6±25.82% by the first eight. Although 85.3% of the responders had reached 60% HAM-D improvement after eight ECTs, a clinically significant minority (14.7%) responded later in the course (ECT 9–12). However, response was predictable on the basis of symptomatic improvement (30% on the HAM-D) by the sixth real ECT. Thirty-three out of 34 responders would have been correctly identified by this criterion and only 2 out of 13 non-responders mis-identified (P<0.000001). Once achieved, the antidepressant effect was stable, without continuation pharmacotherapy, until 1 week after the last treatment and on lithium carbonate (Li) or Li plus clomipramine for a further 3 weeks. These findings confirm the clinical impression that ECT is a rapidly effective treatment for major depression with a shorter latency than generally reported for antidepressant drugs. Elucidation of its neurobiological mechanisms could contribute to the development of pharmacological agents with a similar profile.

Statistical concerns about the GSEA procedure.

To the editor: Mootha et al.1 propose a statistical method (Gene Set Enrichment Analysis; GSEA) to discern changes in expression levels of sets of genes selected a priori in transcriptional profiling experiments. Although consideration of groups of genes is an interesting strategy, the proposed test statistic may not necessarily determine “...if the members of a given gene set are enriched among the most differentially expressed genes between two classes”1. Situations will probably arise when using GSEA in which genes with the highest values of the difference metric will be ignored solely due to the size of the selected gene sets, unrelated to any biological context of the genes comprising the set. By way of illustration, consider the following hypothetical example. Assume that a given data set consists of three potentially interesting sets of genes S1, S2 and S3, of respective sizes n, 5n and 4n genes, where n is any integer. Assume also that all of the genes in S1 are ranked higher (i.e., they have greater differences in expression) than the genes in S2, which in turn are ranked higher than the genes in S3. The GSEA procedure yields enrichment scores (ES)1 of 3n, 4n and 0 for S1, S2 and S3, respectively. The maximum ES1 is 4n and is attributed to S2. S2 will therefore be singled out as the candidate for further investigation over S1, even though S1 comprises the highest ranked genes. This does not seem reasonable, because S2 has been chosen only by virtue of containing a larger number of genes. In other words, GSEA can be at odds with the picture suggested by the gene ranking. A second observation, using the same illustrative example as above, gives another counterintuitive result. In the absence of a defined third gene set (S3), the ES for S2 = 0 and the ES for S1 remains positive. Therefore, S1, and not S2, is chosen by GSEA, a result opposite to that of the previous scenario. An unusual situation has arisen in which a choice or preference between sets of high ranking is affected simply by the presence or absence of a lower ranking set. The behavior of GSEA can not be dismissed as one of the usual power issues encountered due to noise in data, small sample size or lack of robustness to model assumptions. The simple example outlined here indicates that the power of the test statistic is sensitive to the a priori definition of the hypotheses of interest. These limitations should be clearly understood in applying and interpreting the results of the approach.

Age-related changes in brain perfusion of normal subjects detected by 99mTc-HMPAO SPECT.

Abstract Previous functional imaging data generally show impairment in global cerebral blood flow (CBF) with age. Conflicting data, however, concerning age-related changes in regional CBF (rCBF) have been reported. We examined the relative rCBF in a sample of healthy subjects of various ages, to define and localize any age-related CBF reduction. Twenty-seven healthy subjects (17 male, 10 female; mean age 49 ± 15, range 26–71, median 47 years) were studied by 99mTc-HMPAO brain SPECT. The younger age group consisted of subjects below, the older group above 47 years of age, respectively. Analysis was performed by applying three preformed templates, each containing delineated regions of interest (ROIs), to three transaxial brain slices at approximately 4, 6, and 7 cm above the orbitomeatal line (OML). The average number of counts for each ROI was normalized to mean uptake of the cerebellum and of the whole brain slice. Globally, 99mTc-HMPAO uptake ratio normalized to cerebellum was significantly decreased in older subjects, affecting both hemispheres. A slight left-to-right asymmetry was observed in HMPAO uptake of the whole study group. It did not, however, change with age. Regionally, both cortical and subcortical structures of older subjects were involved: uptake ratio to cerebellum was significantly lower (after correction for multiple testing) in the left basal ganglia and in the left superior temporal, right frontal and bilateral occipital cortices at 4 cm above the OML. At 6 cm above the OML, reduced uptake ratios were identified in the left frontal and bilateral parietal areas. At 7 cm, reduced uptake was detected in the right frontal and left occipital cortices. Most of these differences were reduced when uptake was normalized to whole slice, whereas an increase in uptake ratios was observed in the cingulate cortex of the elderly. An inverse correlation between age and HMPAO uptake ratios normalized to cerebellum was observed in a number of brain regions. These findings suggest that advancing age has a differential effect on cerebral perfusion reflected in brain 99mTc-HMPAO uptake.

A novel host-proteome signature for distinguishing between acute bacterial and viral infections.

Bacterial and viral infections are often clinically indistinguishable, leading to inappropriate patient management and antibiotic misuse. Bacterial-induced host proteins such as procalcitonin, C-reactive protein (CRP), and Interleukin-6, are routinely used to support diagnosis of infection. However, their performance is negatively affected by inter-patient variability, including time from symptom onset, clinical syndrome, and pathogens. Our aim was to identify novel viral-induced host proteins that can complement bacterial-induced proteins to increase diagnostic accuracy. Initially, we conducted a bioinformatic screen to identify putative circulating host immune response proteins. The resulting 600 candidates were then quantitatively screened for diagnostic potential using blood samples from 1002 prospectively recruited patients with suspected acute infectious disease and controls with no apparent infection. For each patient, three independent physicians assigned a diagnosis based on comprehensive clinical and laboratory investigation including PCR for 21 pathogens yielding 319 bacterial, 334 viral, 112 control and 98 indeterminate diagnoses; 139 patients were excluded based on predetermined criteria. The best performing host-protein was TNF-related apoptosis-inducing ligand (TRAIL) (area under the curve [AUC] of 0.89; 95% confidence interval [CI], 0.86 to 0.91), which was consistently up-regulated in viral infected patients. We further developed a multi-protein signature using logistic-regression on half of the patients and validated it on the remaining half. The signature with the highest precision included both viral- and bacterial-induced proteins: TRAIL, Interferon gamma-induced protein-10, and CRP (AUC of 0.94; 95% CI, 0.92 to 0.96). The signature was superior to any of the individual proteins (P<0.001), as well as routinely used clinical parameters and their combinations (P<0.001). It remained robust across different physiological systems, times from symptom onset, and pathogens (AUCs 0.87-1.0). The accurate differential diagnosis provided by this novel combination of viral- and bacterial-induced proteins has the potential to improve management of patients with acute infections and reduce antibiotic misuse.

Complex effects of age and gender on hypothermic, adrenocorticotrophic hormone and cortisol responses to ipsapirone challenge in normal subjects

The effects of a challenge dose of the 5-HT1A agonist, ipsapirone (0.3 mg per kg body weight), or placebo on body temperature and on adrenocorticotrophic hormone (ACTH) and cortisol release, were examined in 30 normal subjects (14 males, 19–74 years and 16 females, 22–69 years) using a randomized, double blind design. Irrespective of age or gender, ipsapirone induced a significant reduction in body temperature relative to placebo and a significant increase in ACTH and cortisol release. Maximal temperature reduction by ipsapirone was significantly blunted in older subjects and was inversely related to age. There was no gender difference in the hypothermic response to ipsapirone. ACTH and cortisol responses showed an opposite impact of aging in males and females. Whereas both responses diminished with age in male subjects, they increased with age in females. The cortisol response of older females was significantly larger than that of all the other subjects. Adverse effects of ipsapirone were also more marked in elderly females and were correlated with ACTH and cortisol responses. These findings should be taken into consideration in the use of ipsapirone and other 5-HT1A agonists as challenge procedures for studying central serotonergic function in depression and other disorders. Careful matching of control and experimental subjects is indicated so as to avoid spurious results which reflect the effects of age and gender rather than the pathophysiology of the disorders being investigated.

Interrelationship of age, depression, and central serotonergic function: evidence from fenfluramine challenge studies.

The purpose of this study was to examine the relationship between age-associated changes in central serotonergic function and abnormalities associated with major depression. Under randomized double-blind conditions, prolactin and cortisol responses to the serotonin-releasing agent d,l-fenfluramine hydrochloride (60 mg orally) and placebo were examined in 30 normal subjects (15 men, 15 women; age range 21-84 years) and 39 patients with major depressive disorder, endogenous subtype (14 men, 25 women; age range 29-72 years). In the normal subjects, a significant Age x Challenge x Time interaction was observed in the prolactin response (p = .03). This was primarily due to the elevated prolactin responses of the younger healthy women. Peak minus baseline (delta) prolactin responses were negatively correlated with age (women, p = .004; men, p = .06). In the depressed patients there was no age-related decline in prolactin response to fenfluramine. When depressed and healthy younger subjects were compared, delta prolactin responses to fenfluramine were significantly blunted in young patients with depression (p = .003) irrespective of the significant effect of gender (p = .01), but not in older depressed patients. Cortisol responses to fenfluramine did not reveal consistent effects of age, gender, or diagnosis. Age-related decline in central serotonergic function may make older individuals more vulnerable to depression and possibly render depressive episodes more frequent, more severe, and less amenable to treatment.

Cerebral hypoperfusion in medication resistant, depressed patients assessed by Tc99m HMPAO SPECT

Functional imaging studies generally show decreased cerebral metabolism and perfusion in depressed patients relative to normal controls, although the location of the deficits varies. We used Tc99m HMPAO SPECT to compare cerebral blood flow in medication resistant, depressed patients and a normal control group. HMPAO uptake ratios (adjusted for age) were significantly lower in the depressed patients in the transaxial slices 4 cm and 6 cm above the orbitomeatal line (OML) on the left side. Examining individual regions of interest (corrected for age and multiple testing), we found significantly lower perfusion in the left superior temporal, right parietal and bilateral occipital regions in the patient group. These findings are in limited agreement with previous HMPAO SPECT studies. Methodological differences between studies, particularly variability in adjusting data for age, lead to a divergence in findings. Future research should seek to standardize protocols and data analysis in order to generate comparable results.