Program Affiliations

Stanford Advisors

All Publications

  • The Network Zoo: a multilingual package for the inference and analysis of gene regulatory networks. Genome biology Ben Guebila, M., Wang, T., Lopes-Ramos, C. M., Fanfani, V., Weighill, D., Burkholz, R., Schlauch, D., Paulson, J. N., Altenbuchinger, M., Shutta, K. H., Sonawane, A. R., Lim, J., Calderer, G., van IJzendoorn, D. G., Morgan, D., Marin, A., Chen, C., Song, Q., Saha, E., DeMeo, D. L., Padi, M., Platig, J., Kuijjer, M. L., Glass, K., Quackenbush, J. 2023; 24 (1): 45


    Inference and analysis of gene regulatory networks (GRNs) require software that integrates multi-omic data from various sources. The Network Zoo (netZoo; is a collection of open-source methods to infer GRNs, conduct differential network analyses, estimate community structure, and explore the transitions between biological states. The netZoo builds on our ongoing development of network methods, harmonizing the implementations in various computing languages and between methods to allow better integration of these tools into analytical pipelines. We demonstrate the utility using multi-omic data from the Cancer Cell Line Encyclopedia. We will continue to expand the netZoo to incorporate additional methods.

    View details for DOI 10.1186/s13059-023-02877-1

    View details for PubMedID 36894939

  • Psammomatoid Ossifying Fibroma Is Defined by SATB2 Rearrangement. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Cleven, A. H., Szuhai, K., van IJzendoorn, D. G., Groen, E., Baelde, H., Schreuder, W. H., Briaire-de Bruijn, I. H., van der Meeren, S. W., Kleijwegt, M. C., Furth, W. R., Kroon, H. M., Suurmeijer, A. J., Savci-Heijink, D. C., Baumhoer, D., Bovee, J. V. 2023; 36 (1): 100013


    Psammomatoid ossifying fibroma (PsOF), also known as juvenile PsOF, is a benign fibro-osseous neoplasm predominantly affecting the extragnathic bones, particularly the frontal and ethmoid bones, with a preference for adolescents and young adults. The clinical and morphologic features of PsOF may overlap with those of other fibro-osseous lesions, and additional molecular markers would help increase diagnostic accuracy. Because identical chromosomal breakpoints at bands Xq26 and 2q33 have been described in 3 cases of PsOF located in the orbita, we aimed to identify the exact genes involved in these chromosomal breakpoints and determine their frequency in PsOF using transcriptome sequencing and fluorescence in situ hybridization (FISH). We performed whole RNA transcriptome sequencing on frozen tissue in 2 PsOF index cases and identified a fusion transcript involving SATB2, located on chromosome 2q33.1, and AL513487.1, located on chromosome Xq26, in one of the cases. The fusion was validated using reverse transcription (RT)-PCR and SATB2 FISH. The fusion lead to a truncated protein product losing most of the functional domains. Subsequently, we analyzed an additional 24 juvenile PsOFs, 8 juvenile trabecular ossifying fibromas (JTOFs), and 11 cemento-ossifying fibromas (COFs) for SATB2 using FISH and found evidence of SATB2 gene rearrangements in 58% (7 of 12) of the evaluable PsOF cases but not in any of the evaluable JTOF (n= 7) and COF (n= 7) cases. A combination of SATB2 immunofluorescence and a 2-color SATB2 FISH in our index case revealed that most tumor cells harboring the rearrangement lacked SATB2 expression. Using immunohistochemistry, 65% of PsOF, 100% of JTOF, and 100% of COF cases showed moderate or strong staining for SATB2. In these cases, we observed a mosaic pattern of expression with >25% of the spindle cells in between the bone matrix, with osteoblasts and osteocytes being positive for SATB2. Interestingly, 35% (8 of 23) of PsOFs, in contrast to JTOFs and COFs, showed SATB2 expression in <5% of cells. To our knowledge, this is the first report that shows the involvement of SATB2 in the development of a neoplastic lesion. In this study, we have showed that SATB2 rearrangement is a recurrent molecular alteration that appears to be highly specific for PsOF. Our findings support that PsOF is not only morphologically and clinically but also genetically distinct from JTOF and COF.

    View details for DOI 10.1016/j.modpat.2022.100013

    View details for PubMedID 36788065

  • Identification of stable housekeeping genes for induced pluripotent stem cells and -derived endothelial cells for drug testing. Scientific reports Ong, S. L., Baelde, H. J., van IJzendoorn, D. G., BovĂ©e, J. V., Szuhai, K. 2022; 12 (1): 16160


    There are no validated housekeeping genes in induced pluripotent stem cells (iPSC) and derived endothelial iPSC (iPSC-EC). Thus a comparison of gene expression levels is less reliable, especially during drug treatments. Here, we utilized transcriptome sequencing data of iPSC and iPSC-EC with or without CRISPR-Cas9 induced translocation to identify a panel of 15 candidate housekeeping genes. For comparison, five commonly used housekeeping genes (B2M, GAPDH, GUSB, HMBS, and HPRT1) were included in the study. The panel of 20 candidate genes were investigated for their stability as reference genes. This panel was analyzed and ranked based on stability using five algorithms, delta-Ct, bestkeeper, geNorm, Normfinder, and Reffinder. Based on the comprehensive ranking of Reffinder, the stability of the top two genes-RPL36AL and TMBIM6, and the bottom two genes-UBA1 and B2M, were further studied in iPSC-EC with and without genetic manipulation, and after treatment with telatinib. Using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), it was shown that gene expression of the top two housekeeping genes, RPL36AL and TMBIM6, remained stable during drug treatment. We identified a panel of housekeeping genes that could be utilized in various conditions using iPSC and iPSC-derived endothelial cells as well as genetically modified iPSC for drug treatment.

    View details for DOI 10.1038/s41598-022-20435-w

    View details for PubMedID 36171445

    View details for PubMedCentralID PMC9519970

  • Interactions in CSF1-driven Tenosynovial Giant Cell Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research van IJzendoorn, D. G., Matusiak, M., Charville, G. W., Spierenburg, G., Varma, S., Colburg, D. R., van de Sande, M. A., van Langevelde, K., Mohler, D. G., Ganjoo, K. N., Bui, N. Q., Avedian, R. S., Bovee, J. V., Steffner, R., West, R. B., van de Rijn, M. 2022


    A major component of cells in Tenosynovial Giant Cell Tumor (TGCT) consists of bystander macrophages responding to CSF1 that is overproduced by a small number of neoplastic cells with a chromosomal translocation involving the CSF1 gene. An autocrine loop was postulated where the neoplastic cells would be stimulated through CSF1R expressed on their surface. Here we use single cell RNA sequencing to investigate cellular interactions in TGCT.A total of 18,788 single cells from three TGCT and two Giant Cell Tumor of Bone (GCTB) samples underwent singe cell RNAseq. The three TGCTs were additionally analyzed using long read RNA sequencing. Immunofluorescence and immunohistochemistry for a range of markers was used to validate and extend the scRNAseq findings.Two recurrent neoplastic cell populations were identified in TGCT that are highly similar to non-neoplastic synoviocytes. We identified GFPT2 as a marker that highlights the neoplastic cells in TCGT. We show that the neoplastic cells themselves do not express CSF1R. We identified overlapping features between the giant cells in TGCT and GCTB.The neoplastic cells in TGCT are highly similar non-neoplastic synoviocytes. The lack of CSF1R on the neoplastic cells indicates they may be unaffected by current therapies. High expression of GFPT2 in the neoplastic cells is associated with activation of the YAP1/TAZ pathway. In addition, we identified expression of the PDGF receptor in the neoplastic cells. These findings suggest two additional pathways to target in this tumor.

    View details for DOI 10.1158/1078-0432.CCR-22-1898

    View details for PubMedID 36007098

  • Juvenile Psammomatoid Ossifying Fibroma is Defined by SATB2 Rearrangement Cleven, A., Szuhai, K., van IJzendoorn, D., Groen, E., Baelde, H., Schreuder, P., Briaire-de Bruijn, I., Genders, S., Kleijwegt, M., Kroon, H., Suurmeijer, A., Savci-Heijink, D., Baumhoer, D., Bovee, J. SPRINGERNATURE. 2022: 866
  • Juvenile Psammomatoid Ossifying Fibroma is Defined by SATB2 Rearrangement Cleven, A., Szuhai, K., van IJzendoorn, D., Groen, E., Baelde, H., Schreuder, P., Bruijn, I., Genders, S., Kleijwegt, M., Kroon, H., Suurmeijer, A., Savci-Heijink, D., Baumhoer, D., Bovee, J. SPRINGERNATURE. 2022: 866
  • Analysis of 567,758 randomized controlled trials published over 30 years reveals trends in phrases used to discuss results that do not reach statistical significance. PLoS biology Otte, W. M., Vinkers, C. H., Habets, P. C., van IJzendoorn, D. G., Tijdink, J. K. 2022; 20 (2): e3001562


    The power of language to modify the reader's perception of interpreting biomedical results cannot be underestimated. Misreporting and misinterpretation are pressing problems in randomized controlled trials (RCT) output. This may be partially related to the statistical significance paradigm used in clinical trials centered around a P value below 0.05 cutoff. Strict use of this P value may lead to strategies of clinical researchers to describe their clinical results with P values approaching but not reaching the threshold to be "almost significant." The question is how phrases expressing nonsignificant results have been reported in RCTs over the past 30 years. To this end, we conducted a quantitative analysis of English full texts containing 567,758 RCTs recorded in PubMed between 1990 and 2020 (81.5% of all published RCTs in PubMed). We determined the exact presence of 505 predefined phrases denoting results that approach but do not cross the line of formal statistical significance (P < 0.05). We modeled temporal trends in phrase data with Bayesian linear regression. Evidence for temporal change was obtained through Bayes factor (BF) analysis. In a randomly sampled subset, the associated P values were manually extracted. We identified 61,741 phrases in 49,134 RCTs indicating almost significant results (8.65%; 95% confidence interval (CI): 8.58% to 8.73%). The overall prevalence of these phrases remained stable over time, with the most prevalent phrases being "marginally significant" (in 7,735 RCTs), "all but significant" (7,015), "a nonsignificant trend" (3,442), "failed to reach statistical significance" (2,578), and "a strong trend" (1,700). The strongest evidence for an increased temporal prevalence was found for "a numerical trend," "a positive trend," "an increasing trend," and "nominally significant." In contrast, the phrases "all but significant," "approaches statistical significance," "did not quite reach statistical significance," "difference was apparent," "failed to reach statistical significance," and "not quite significant" decreased over time. In a random sampled subset of 29,000 phrases, the manually identified and corresponding 11,926 P values, 68,1% ranged between 0.05 and 0.15 (CI: 67. to 69.0; median 0.06). Our results show that RCT reports regularly contain specific phrases describing marginally nonsignificant results to report P values close to but above the dominant 0.05 cutoff. The fact that the prevalence of the phrases remained stable over time indicates that this practice of broadly interpreting P values close to a predefined threshold remains prevalent. To enhance responsible and transparent interpretation of RCT results, researchers, clinicians, reviewers, and editors may reduce the focus on formal statistical significance thresholds and stimulate reporting of P values with corresponding effect sizes and CIs and focus on the clinical relevance of the statistical difference found in RCTs.

    View details for DOI 10.1371/journal.pbio.3001562

    View details for PubMedID 35180228