| 1. |
- Ekström, Joakim, 1982-
(författare)
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A generalized definition of the polychoric correlation coefficient
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We generalize the polychoric correlation coefficient to a large class of parametric families of bivariate distributions. The generalized definition agrees with the conventional definition on the family of bivariate normal distributions, and with the generalized tetrachoric correlation coefficient for dichotomous variables. Furthermore, we provide some suggestions for goodness-of-fit tests. The theory is illustrated with examples, which show that the distributional assumption can have a substantial impact on the conclusions of the association analysis.
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| 2. |
- Ekström, Joakim, 1982-
(författare)
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A generalized definition of the tetrachoric correlation coefficient
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We generalize the tetrachoric correlation coefficient to a large class of parametric families of bivariate distributions. We also show that the generalized definition agrees with the conventional definition on the family of bivariate normal distributions. Furthermore, we provide a necessary and sufficient condition for the generalized tetrachoric correlation coefficient to be well defined for a given family of distributions, and some sufficient criteria which can be useful for practical purposes. Moreover, we illustrate with examples how the distributional assumption can have a profound impact on the conclusions of the association analysis. Using S&P 100 stock data, we exemplify the fact that a correct distributional assumption is vitally important for the analysis. Consequently, it is concluded that the tetrachoric correlation coefficient is not robust to changes of the distributional assumption.
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| 3. |
- Ekström, Joakim, 1982-
(författare)
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An empirical polychoric correlation coefficient
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We propose a new measure of association for ordinal variables. The new measure of association, named the empirical polychoric correlation coefficient, builds upon the polychoric correlation coefficient, but relaxes its fundamental assumption so that an underlying distribution is only assumed to exist, not to be of a particular parametric family. The empirical polychoric correlation coefficient has properties that are superior to those of the polychoric correlation coefficient; it rests on weaker assumptions, it is well defined for every contingency table, and it converges almost surely to the correct theoretical polychoric correlation. Consequentially, the empirical polychoric correlation coefficient is theoretically robust to changes of the distributional assumption, unlike the polychoric correlation coefficient. A simulation study confirms that the empirical coefficient is considerably more robust than the polychoric correlation coefficient, and it also indicates that it has lower standard deviation.
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| 4. |
- Ekström, Joakim, 1982-
(författare)
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Contributions to the Theory of Measures of Association for Ordinal Variables
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, we consider measures of association for ordinal variables from a theoretical perspective. In particular, we study the phi-coefficient, the tetrachoric correlation coefficient and the polychoric correlation coefficient. We also introduce a new measure of association for ordinal variables, the empirical polychoric correlation coefficient, which has better theoretical properties than the polychoric correlation coefficient, including greatly enhanced robustness. In the first article, entitled ``On the relation between the phi-coefficient and the tetrachoric correlation coefficient'', we show that under given marginal probabilities there exists a continuous bijection between the two measures of association. Furthermore, we show that the bijection has a fixed point at zero for all marginal probabilities. Consequently, the choice of which of these measures of association to use is for all practical purposes a matter of preference only. In the second article, entitled ``A generalized definition of the tetrachoric correlation coefficient'', we generalize the tetrachoric correlation coefficient so that a large class of parametric families of bivariate distributions can be assumed as underlying distributions. We also provide a necessary and sufficient condition for the generalized tetrachoric correlation coefficient to be well defined for a given parametric family of bivariate distributions. With examples, we illustrate the effects on the polychoric correlation coefficient of different distributional assumptions. In the third article, entitled ``A generalized definition of the polychoric correlation coefficient'', we generalize the polychoric correlation coefficient to a large class of parametric families of bivariate distributions, and show that the generalized and the conventional polychoric correlation coefficients agree on the family of bivariate normal distributions. With examples, we illustrate the effects of different distributional assumptions on the polychoric correlation coefficient. In combination with goodness-of-fit p-values, the association analysis can be enriched with a consideration of possible tail dependence. In the fourth article, we propose a new measure of association for ordinal variables, named the empirical polychoric correlation coefficient. The empirical polychoric correlation coefficient relaxes the fundamental assumption of the polychoric correlation coefficient so that an underlying joint distribution is only assumed to exist, not to be of a particular parametric family. We also provide an asymptotical result, by which the empirical polychoric correlation coefficient converges almost surely to the true polychoric correlation under very general conditions. Thus, the proposed empirical polychoric correlation coefficient has better theoretical properties than the polychoric correlation coefficient.
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| 5. |
- Ekström, Joakim, 1982-, et al.
(författare)
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Exact Probability Distribution for the ROC Area under Curve
- 2023
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 15:6
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary This contribution allows for the computation of exact p-values and for conducting accurate statistical hypothesis tests of ROC AUC-values. As a result, the development of diagnostic tests is facilitated. This work is illustrated via simulated data and through the development of proteomic blood biomarkers for the early detection of cancer. The Receiver Operating Characteristic (ROC) is a de facto standard for determining the accuracy of in vitro diagnostic (IVD) medical devices, and thus the exactness in its probability distribution is crucial toward accurate statistical inference. We show the exact probability distribution of the ROC AUC-value, hence exact critical values and p-values are readily obtained. Because the exact calculations are computationally intense, we demonstrate a method of geometric interpolation, which is exact in a special case but generally an approximation, vastly increasing computational speeds. The method is illustrated through open access data, demonstrating superiority of 26 composite biomarkers relative to a predicate device. Especially under correction for testing of multiple hypotheses, traditional asymptotic approximations are encumbered by considerable imprecision, adversely affecting IVD device development. The ability to obtain exact p-values will allow more efficient IVD device development.
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| 6. |
- Ekström, Joakim, 1982-
(författare)
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On the relation between the phi-coefficient and the tetrachoric correlation coefficient
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We show existence of a continuous bijection between the tetrachoric correlation coefficient and the phi-coefficient under given marginal probabilities. Implications are that the tetrachoric correlation coefficient can be calculated using the assumptions of the phi-coefficient construction, and the phi-coefficient can be calculated using the assumptions of the tetrachoric correlation construction. As a consequence, whether to use the phi-coefficient or the tetrachoric correlation coefficient is a matter of preference only. The result can also be used to construct a numerical table of tetrachoric correlation coefficients, converted from the marginal probabilities and the phi-coefficient, which is easy to calculate by hand. Moreover, a mathematically rigorous definition of the tetrachoric correlation coefficient is provided, along with a proof that the coefficient is well defined.
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| 7. |
- Hammarström, Klara, et al.
(författare)
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A Comprehensive Evaluation of Associations Between Routinely Collected Staging Information and The Response to (Chemo)Radiotherapy in Rectal Cancer
- 2021
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Rectal cancer patients are often treated with radiotherapy, either alone or combined with chemotherapy, prior to surgery to enable radical surgery on a non-resectable tumor or to lower the recurrence risk. For some patients, the tumor disappears completely after preoperative treatment, while others experience little or no benefit. Accurate prediction of therapy response before treatment is of great importance for a personalized treatment approach and intentional organ preservation. We performed a comprehensive evaluation of the predictive capacity of all routinely collected staging information at diagnosis in a population-based, completely staged patient material of 383 patients representing a real-life clinical situation. Size or stage of the rectal tumor were independent predictors of excellent response irrespective of preoperative treatment, with small/early-stage tumors being significantly more likely to reach a complete response. Levels of the tumor marker carcinoembryonic antigen (CEA) above upper normal limit halved the chance of response. Radiotherapy (RT) or chemoradiotherapy (CRT) are frequently used in rectal cancer, sometimes resulting in complete tumor remission (CR). The predictive capacity of all clinical factors, laboratory values and magnetic resonance imaging parameters performed in routine staging was evaluated to understand what determines an excellent response to RT/CRT. A population-based cohort of 383 patients treated with short-course RT (5 x 5 Gy in one week, scRT), CRT, or scRT with chemotherapy (scRT+CT) and having either had a delay to surgery or been entered into a watch-and-wait program were included. Complete staging according to guidelines was performed and associations between investigated variables and CR rates were analyzed in univariate and multivariate analyses. In total, 17% achieved pathological or clinical CR, more often after scRT+CT and CRT than after scRT (27%, 18% and 8%, respectively, p < 0.001). Factors independently associated with CR included clinical tumor stage, small tumor size (<3 cm), tumor level, and low CEA-value (<3.8 mu g/L). Size or stage of the rectal tumor were associated with excellent response in all therapy groups, with small or early stage tumors being significantly more likely to reach CR (p = 0.01 (scRT), p = 0.01 (CRT) and p = 0.02 (scRT+CT). Elevated level of carcinoembryonic antigen (CEA) halved the chance of response. Extramural vascular invasion (EMVI) and mucinous character may indicate less response to RT alone.
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| 8. |
- Hammarström, Klara, et al.
(författare)
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Determining the use of preoperative (chemo)radiotherapy in primary rectal cancer according to national and international guidelines
- 2019
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Ingår i: Radiotherapy and Oncology. - : ELSEVIER IRELAND LTD. - 0167-8140 .- 1879-0887. ; 136, s. 106-112
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pre-operative radiotherapy (RT) or chemoradiotherapy (CRT) is frequently used prior to rectal cancer surgery to improve local control and survival. The treatment is administered according to guidelines, but these recommendations vary significantly between countries. Based on the stage distribution and risk factors of rectal cancers as determined by magnetic resonance imaging (MRI) in an unselected Swedish population, the use of RT/CRT according to 15 selected guidelines is described. Materials and methods: Selected guidelines from different countries and regions were applied to a wellcharacterized unselected population-based material of 686 primary non-metastatic rectal cancers staged by MRI. The fraction of patients assigned to surgery alone or surgery following pre-treatment with (C) RT was determined according to the respective guideline. RT/CRT administered to rectal cancer patients for other reasons, for example, for organ preservation or palliation, was not considered. Results: The fraction of patients with a clear recommendation for pre-treatment with (C) RT varied between 38% and 77% according to the different guidelines. In most guidelines, CRT was recommended to all patients who were not operated directly, and, in others, short-course RT was also recommended to patients with intermediate risk tumours. If only non-resectable or difficult to resect tumours were recommended pre-treatment, as stated in many Japanese publications, 9% would receive CRT followed by a delay to surgery. Conclusions: According to most guidelines, well over 50% of primary non-metastatic rectal cancer patients from a general population, in which screening for colorectal cancer is not practised, are recommended treatment with pre-operative/neo-adjuvant therapy. (C) 2019 Elsevier B. V. All rights reserved. Radiotherapy and Oncology
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| 9. |
- Mezheyeuski, Artur, et al.
(författare)
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An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 88
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression.Methods: Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations.Findings: By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy.Interpretation: Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types.
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| 10. |
- Mezheyeuski, Artur, et al.
(författare)
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The Immune Landscape of Colorectal Cancer
- 2021
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:21
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Tidskriftsartikel (refereegranskat)abstract
- We sought to provide a detailed overview of the immune landscape of colorectal cancer in the largest study to date in terms of patient numbers and analyzed immune cell types. We applied a multiplex in situ staining method in combination with an advanced scanning and image analysis pipeline akin to flow cytometry, and analyzed 5968 individual multi-layer images of tissue defining in a total of 39,078,450 cells. We considered the location of immune cells with respect to the stroma, and tumor cell compartment and tumor regions in the central part or the invasive margin. To the best of our knowledge, this study is the first comprehensive spatial description of the immune landscape in colorectal cancer using a large population-based cohort and a multiplex immune cell identification.While the clinical importance of CD8+ and CD3+ cells in colorectal cancer (CRC) is well established, the impact of other immune cell subsets is less well described. We sought to provide a detailed overview of the immune landscape of CRC in the largest study to date in terms of patient numbers and in situ analyzed immune cell types. Tissue microarrays from 536 patients were stained using multiplexed immunofluorescence panels, and fifteen immune cell subclasses, representing adaptive and innate immunity, were analyzed. Overall, therapy-naive CRC patients clustered into an 'inflamed' and a 'desert' group. Most T cell subsets and M2 macrophages were enriched in the right colon (p-values 0.046-0.004), while pDC cells were in the rectum (p = 0.008). Elderly patients had higher infiltration of M2 macrophages (p = 0.024). CD8+ cells were linked to improved survival in colon cancer stages I-III (q = 0.014), while CD4+ cells had the strongest impact on overall survival in metastatic CRC (q = 0.031). Finally, we demonstrated repopulation of the immune infiltrate in rectal tumors post radiation, following an initial radiation-induced depletion. This study provides a detailed analysis of the in situ immune landscape of CRC paving the way for better diagnostics and providing hints to better target the immune microenvironment.
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