GWAB: a web server for the network-based boosting of human genome-wide association data.

During the last decade, genome-wide association studies (GWAS) have represented a major approach to dissect complex human genetic diseases. Due in part to limited statistical power, most studies identify only small numbers of candidate genes that pass the conventional significance thresholds (e.g. P ≤ 5 × 10-8). This limitation can be partly overcome by increasing the sample size, but this comes at a higher cost. Alternatively, weak association signals can be boosted by incorporating independent data. Previously, we demonstrated the feasibility of boosting GWAS disease associations using gene networks. Here, we present a web server, GWAB (www.inetbio.org/gwab), for the network-based boosting of human GWAS data. Using GWAS summary statistics (P-values) for SNPs along with reference genes for a disease of interest, GWAB reprioritizes candidate disease genes by integrating the GWAS and network data. We found that GWAB could more effectively retrieve disease-associated reference genes than GWAS could alone. As an example, we describe GWAB-boosted candidate genes for coronary artery disease and supporting data in the literature. These results highlight the inherent value in sub-threshold GWAS associations, which are often not publicly released. GWAB offers a feasible general approach to boost such associations for human disease genetics.

Prediction and validation of gene-disease associations using methods inspired by social network analyses.

Correctly identifying associations of genes with diseases has long been a goal in biology. With the emergence of large-scale gene-phenotype association datasets in biology, we can leverage statistical and machine learning methods to help us achieve this goal. In this paper, we present two methods for predicting gene-disease associations based on functional gene associations and gene-phenotype associations in model organisms. The first method, the Katz measure, is motivated from its success in social network link prediction, and is very closely related to some of the recent methods proposed for gene-disease association inference. The second method, called Catapult (Combining dATa Across species using Positive-Unlabeled Learning Techniques), is a supervised machine learning method that uses a biased support vector machine where the features are derived from walks in a heterogeneous gene-trait network. We study the performance of the proposed methods and related state-of-the-art methods using two different evaluation strategies, on two distinct data sets, namely OMIM phenotypes and drug-target interactions. Finally, by measuring the performance of the methods using two different evaluation strategies, we show that even though both methods perform very well, the Katz measure is better at identifying associations between traits and poorly studied genes, whereas Catapult is better suited to correctly identifying gene-trait associations overall [corrected].

Prioritizing candidate disease genes by network-based boosting of genome-wide association data.

Network "guilt by association" (GBA) is a proven approach for identifying novel disease genes based on the observation that similar mutational phenotypes arise from functionally related genes. In principle, this approach could account even for nonadditive genetic interactions, which underlie the synergistic combinations of mutations often linked to complex diseases. Here, we analyze a large-scale, human gene functional interaction network (dubbed HumanNet). We show that candidate disease genes can be effectively identified by GBA in cross-validated tests using label propagation algorithms related to Google's PageRank. However, GBA has been shown to work poorly in genome-wide association studies (GWAS), where many genes are somewhat implicated, but few are known with very high certainty. Here, we resolve this by explicitly modeling the uncertainty of the associations and incorporating the uncertainty for the seed set into the GBA framework. We observe a significant boost in the power to detect validated candidate genes for Crohn's disease and type 2 diabetes by comparing our predictions to results from follow-up meta-analyses, with incorporation of the network serving to highlight the JAK-STAT pathway and associated adaptors GRB2/SHC1 in Crohn's disease and BACH2 in type 2 diabetes. Consideration of the network during GWAS thus conveys some of the benefits of enrolling more participants in the GWAS study. More generally, we demonstrate that a functional network of human genes provides a valuable statistical framework for prioritizing candidate disease genes, both for candidate gene-based and GWAS-based studies.

[Kawasaki disease]. / Kawasakis syndrom.

Kawasaki syndrome was first described in 1967. The diagnosis is based on clinical criteria including fever for more than five days, conjunctivitis, lymph node enlargement and changes in the oral mucosa as well as in the palms and soles. Coronary complications including aneurysmal dilatation have been reported in 20-25% of untreated patients. Kawasaki syndrome is now the most common cause of acquired heart disease in children. Six patients were seen in our department during the period 1980-99. Five were treated with intravenous immunoglobulin. All of them showed immediate improvement of their general condition and were afebrile after 24-48 hours. One patient had a coronary aneurysm of moderate size, and four patients had signs of coronary vasculitis. All coronary changes were normalized after a maximum of 17 months. An update on Kawasaki disease is presented.

Natural killer activity of blood lymphocytes in patients with primary intracranial tumors. Correlation to histological tumor type and anatomical site.

The possible relationship between the natural killer (NK) activity of blood lymphocytes and the histological tumor type or anatomical location of the lesions was examined in 116 patients with primary intracranial tumors. The patients had not undergone any surgical intervention or received any treatment with ionizing radiation or cytotoxic drugs. However, some of them had received corticosteroid medication. Regardless of the histological type of tumor, there was no significant difference in the NK activity of the non-corticosteroid treated patients and the healthy control subjects. However, there was a trend towards an increased NK-activity in patients with low-grade gliomas, in particular oligodendrogliomas. The NK-activity was reduced in patients who were treated with corticosteroids. There was no relationship between the NK-activity in non-steroid treated patients and the anatomical location of the tumor. The latter finding contrasts to a recent observation showing a strong relationship between tumor site and PPD-reactivity of blood lymphocytes in patients with intracranial tumors.

Blood lymphocyte subsets in patients with primary intracranial tumours. Correlation to histological tumour type and anatomical site.

The blood lymphocyte population of 118 patients with primary intracranial tumours and healthy volunteers was examined with respect to its size and cellular composition using various rosette tests. The patients had not undergone any surgical intervention or received any treatment with ionizing irradiation or cytotoxic drugs. However, some of them were treated with corticosteroids. It was observed that non-steroid treated patients with oligodendrogliomas, but not patients with other histological types of tumours, had a significantly reduced proportion of "active" T-lymphocytes forming rosettes with sheep erythrocytes (a type of T-lymphocyte which is activated by foetal calf serum). These patients as well as those with astrocytomas, malignant gliomas (anaplastic astrocytomas and glioblastomas) or miscellaneous tumours (mainly meningiomas) had normal proportions of lymphocytes with receptors for the Fc-part of IgG or C'3 and cells forming rosettes with sheep erythrocytes under more conventional conditions. Patients who were treated with corticosteroids had an increased frequency of lymphocytes with the above Fc-receptor. An association between site of the lesions and cellular composition of the blood lymphocyte population was not detected. The results give further support for the view that the immunological system may be changed in patients with oligodendrogliomas.

Relation between the site of primary intracranial tumors and mitogenic responses of blood lymphocytes.

The possible relation between the site of primary intracranial tumors and mitogenic responses of blood lymphocytes was analyzed in 115 patients who had not undergone surgery or received any radiation or chemotherapy. Some of the patients had however received corticosteroid treatment. PHA responses were impaired in nonsteroid treated patients with tumors affecting the left cerebral hemisphere. They were normal in patients with tumors affecting the right cerebral hemisphere or central structures of the brain or tumors growing in the posterior fossa of the skull. Lymphocyte responses to PPD were normal in patients with hemispheric or posterior fossa tumors. However, the PPD response was sharply reduced in patients with central tumors. The results could not be explained by different histological tumor types or anticonvulsant medication in the various patient groups. In addition, the capacity of sera to promote mitogen stimulation of lymphocytes did not differ significantly between the patient groups. It is speculated that intracranial tumors may interfere with the function of certain centers in the brain which are involved in the regulation of lymphocyte responses.

Capacity of sera from patients with primary intracranial tumors to support mitogen stimulation of blood lymphocytes. Correlation to histological tumor type.

Sera from 125 untreated patients with various histological types of primary intracranial tumors were examined for the capacity to support proliferative responses of lymphocytes to PHA and PPD in vitro. It was observed that sera obtained from groups of non-corticosteroid treated patients with astrocytomas, malignant gliomas (anaplastic astrocytomas and glioblastomas), and miscellaneous tumors (mainly meningiomas) did not differ significantly from sera obtained from a group of healthy subjects. However, sera from a group of patients with oligodendrogliomas exhibited a significantly reduced capacity to support PHA- and PPD-responses of both autologous and allogeneic lymphocytes. Corticosteroid treated patients seemed to have reduced serum activities regardless of histological tumor type. It is not known whether sera from patients with oligodendrogliomas contain increased amounts of factors which inhibit mitogen responses of lymphocytes, or whether they contain reduced amounts of factors which support stimulations in vitro.

Mitogen stimulation of blood lymphocytes from patients with primary intracranial tumors. Correlation to histological tumor type.

Blood lymphocytes from 125 patients with primary intracranial tumors were examined for proliferative responses to PHA and PPD in parallel with lymphocytes from sex- and age-matched controls. The tests were performed prior to surgery, radiotherapy, or chemotherapy and a histological diagnosis was obtained in all cases. Depending on tumor type, patients were divided into the following four histological groups: astrocytomas, oligodendrogliomas, malignant gliomas (anaplastic astrocytomas and glioblastomas), and miscellaneous tumors (mainly meningiomas). PHA-responses were approximately 10% lower in patients with malignant gliomas not receiving corticosteroids in comparison to corresponding controls. No significant differences were observed in the other groups of patients if not being treated with steroids. PPD-responses were largely similar in all groups of non-steroid treated patients. In the corticosteroid treated groups PHA-responses were significantly reduced in patients with oligodendrogliomas and malignant gliomas, but this was not true of those with astrocytomas or those in the group with miscellaneous tumors. The mean steroid doses given at the time of testing were similar in all four patient groups. The treatment period was longest in malignant gliomas but reasonably similar in the other three groups. It is speculated that PHA-responses of lymphocytes from patients with oligodendrogliomas may exhibit an increased steroid sensitivity.