Cut points and contexts Busch, Evan L.
Cancer,
December 1, 2021, Letnik:
127, Številka:
23
Journal Article
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Odprti dostop
In research, policy, and practice, continuous variables are often categorized. Statisticians have generally advised against categorization for many reasons, such as loss of information and precision ...as well as distortion of estimated statistics. Here, a different kind of problem with categorization is considered: the idea that, for a given continuous variable, there is a unique set of cut points that is the objectively correct or best categorization. It is shown that this is unlikely to be the case because categorized variables typically exist in webs of statistical relationships with other variables. The choice of cut points for a categorized variable can influence the values of many statistics relating that variable to others. This essay explores the substantive trade‐offs that can arise between different possible cut points to categorize a continuous variable, making it difficult to say that any particular categorization is objectively best. Limitations of different approaches to selecting cut points are discussed. Contextual trade‐offs may often be an argument against categorization. At the very least, such trade‐offs mean that research inferences, or decisions about policy or practice, that involve categorized variables should be framed and acted upon with flexibility and humility.
Lay Summary
In research, policy, and practice, continuous variables are often turned into categorical variables with cut points that define the boundaries between categories. This involves choices about how many categories to create and what cut‐point values to use.
This commentary shows that different choices about which cut points to use can lead to different sets of trade‐offs across multiple statistical relationships between the categorized variable and other variables.
These trade‐offs mean that no single categorization is objectively best or correct. This context is critical when one is deciding whether and how to categorize a continuous variable.
In practical settings, the choice of cut points for categorizing a continuous variable is likely to entail trade‐offs across multiple statistical relationships between the categorized variable and other variables. These trade‐offs mean that no single categorization is objectively best or correct.
Epithelial-mesenchymal transition (EMT) is thought to be an important mechanism of cancer cell metastasis. Clinical measurement of EMT markers in primary tumors could improve risk stratification and ...treatment decisions by identifying patients who potentially have metastatic disease. To evaluate the potential of EMT markers that could be used for risk stratification for patients with colorectal cancer, we conducted a systematic review of studies (N = 30) that measured at least one of a selection of EMT markers in primary tumors and patient outcomes. Fifteen of 30 studies (50%) reported at least one statistically significant result supporting a role for one of the selected EMT markers in identifying patients at risk for worse outcomes. Importantly, however, we identified design inconsistencies that limited inferences and prevented meta-analysis of data. We offer a number of recommendations to make future studies more informative and standardized, including consistent sampling of different parts of the primary tumor, larger sample sizes, and measurement of both protein and RNA expression of a given EMT marker in the same tumors. Strengthening the literature per our recommendations could facilitate translating EMT markers to clinical use.
Sensitive assays are essential for the accurate identification of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we report a multiplexed assay for the ...fluorescence-based detection of seroconversion in infected individuals from less than 1 µl of blood, and as early as the day of the first positive nucleic acid test after symptom onset. The assay uses dye-encoded antigen-coated beads to quantify the levels of immunoglobulin G (IgG), IgM and IgA antibodies against four SARS-CoV-2 antigens. A logistic regression model trained using samples collected during the pandemic and samples collected from healthy individuals and patients with respiratory infections before the first outbreak of coronavirus disease 2019 (COVID-19) was 99% accurate in the detection of seroconversion in a blinded validation cohort of samples collected before the pandemic and from patients with COVID-19 five or more days after a positive nasopharyngeal test by PCR with reverse transcription. The high-throughput serological profiling of patients with COVID-19 allows for the interrogation of interactions between antibody isotypes and viral proteins, and should help us to understand the heterogeneity of clinical presentations.
Endometrial tumors arise from a hormonally responsive tissue. Defining subtypes by hormone receptor expression might better inform etiology and prediction of patient outcomes. We evaluated the ...potential role of tumor estrogen receptor (ER) and progesterone receptor (PR) expression to define endometrial cancer subtypes.
We measured semi-continuous ER and PR protein expression in tissue specimens from 360 endometrial primary tumors from the Nurses' Health Study. To explore the impact of different definitions of marker positivity, we dichotomized ER and PR expression at different cut points in increments of 5% positive cells. Logistic regression was used to estimate associations between endometrial cancer risk factors, such as body mass index, with dichotomous ER or PR status. Reclassification statistics were used to assess whether adding dichotomous ER or PR status to standard prognostic factors of stage, grade, and histologic type would improve endometrial cancer-specific mortality prediction.
Compared with not being obese, obesity increased the odds of having an ER-positive tumor at cut points of 0% to 20% maximum OR, 2.92; 95% confidence interval (CI), 1.34-6.33 as well as the odds of having a PR-positive tumor at cut points of 70% to 90% (maximum OR, 2.53; 95% CI, 1.36-4.68). Adding dichotomous tumor ER or PR status to the panel of standard predictors did not improve both model discrimination and calibration.
Obesity may be associated with greater endometrial tumor expression of ER and PR. Adding either marker does not appear to improve mortality prediction beyond the standard predictors.
Body mass index might explain some of the biological variation among endometrial tumors.
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Fat transfer is an increasingly popular method for refining postmastectomy breast reconstructions. However, concern persists that fat transfer may promote disease recurrence. Adipocytes are derived ...from adipose-derived stem cells and express adipocytokines that can facilitate active breast cancer cells in laboratory models. The authors sought to evaluate the association between fat transfer to the reconstructed breast and cancer recurrence in patients diagnosed with local or regional invasive breast cancers.
A multicenter, case-cohort study was performed. Eligible patients from four centers (Memorial Sloan Kettering, M. D. Anderson Cancer Center, Alvin J. Siteman Cancer Center, and the University of Chicago) were identified by each site's institutional tumor registry or cancer data warehouse. Eligibility criteria were as follows: mastectomy with immediate breast reconstruction between 2006 and 2011, age older than 21 years, female sex, and incident diagnosis of invasive ductal carcinoma (stage I, II, or III). Cases consisted of all recurrences during the study period, and controls consisted of a 30 percent random sample of the study population. Cox proportional hazards regression was used to evaluate for association between fat transfer and time to recurrence in bivariate and multivariate models.
The time to disease recurrence unadjusted hazard ratio for fat transfer was 0.99 (95 percent CI, 0.56 to 1.7). After adjustment for age, body mass index, stage, HER2/Neu receptor status, and estrogen receptor status, the hazard ratio was 0.97 (95 percent CI, 0.54 to 1.8).
In this population of breast cancer patients who had mastectomy with immediate reconstruction, fat transfer was not associated with a higher risk of cancer recurrence.
Therapeutic, III.
SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, plays a vital role in the regulation of metabolism, stress responses, and genome stability. However, the role of SIRT1 in the ...multi-step process leading to transformation and/or tumorigenesis, as either a tumor suppressor or tumor promoter, is complex and may be dependent upon the context in which SIRT1 activity is altered, and the role of SIRT1 in tumor metabolism is unknown. Here, we demonstrate that SIRT1 dose-dependently regulates cellular glutamine metabolism and apoptosis, which in turn differentially impact cell proliferation and cancer development. Heterozygous deletion of Sirt1 induces c-Myc expression, enhancing glutamine metabolism and subsequent proliferation, autophagy, stress resistance, and cancer formation. In contrast, homozygous deletion of Sirt1 triggers cellular apoptotic pathways, increases cell death, diminishes autophagy, and reduces cancer formation. Consistent with the observed dose dependence in cells, intestine-specific Sirt1 heterozygous mice have enhanced intestinal tumor formation, whereas intestine-specific Sirt1 homozygous knockout mice have reduced development of colon cancer. Furthermore, SIRT1 reduction, but not deletion, is associated with human colorectal tumors, and colorectal cancer patients with low protein expression of SIRT1 have a poor prognosis. Taken together, our findings indicate that the dose-dependent regulation of tumor metabolism and possibly apoptosis by SIRT1 mechanistically contribute to the observed dual roles of SIRT1 in tumorigenesis. Our study highlights the importance of maintenance of a suitable SIRT1 dosage for metabolic and tissue homeostasis, which will have important implications in SIRT1-small-molecule-activator/inhibitor-based therapeutic strategies for cancers.
•Haploinsufficiency of SIRT1 promotes cancer development through glutamine metabolism•Haploinsufficiency of SIRT1 modulates glutamine metabolism through c-Myc•SIRT1 regulates murine colon cancer formation in a dose-dependent manner•Colorectal cancer patients with low levels of SIRT1 have a poor prognosis
Ren et al. show that dose-dependent regulation of cancer development by SIRT1 through c-Myc signaling and glutamine metabolism mechanistically contributes to the observed dual roles of SIRT1 in tumorigenesis, which will have important implications for SIRT1-small-molecule-activator/inhibitor-based therapeutic strategies in human cancers.
Functional health literacy is essential for the self-management of chronic diseases and preventive health behaviors. Patients with cancer who have a low level of health literacy may be at greater ...risk for poor care and poor outcomes.
We assessed health literacy using the Short Test of Functional Health Literacy in Adults in 347 participants with colorectal cancer who were nested within a prospective observational study of system, health care provider, and participant characteristics influencing cancer outcomes.
Having adequate health literacy increased the likelihood that participants with stage 3/4 disease received chemotherapy (odds ratio, 3.29; 95% confidence interval, 1.23-8.80) but had no effect on cancer stage at diagnosis or vital status at last observation during postenrollment follow-up. No difference was seen in health literacy status regarding participant beliefs and preferences about chemotherapy among those with stage 3/4 disease, nor in participant roles in deciding whether to receive chemotherapy.
Patients with lower levels of health literacy were less likely to receive chemotherapy compared with participants with higher levels of health literacy. Therefore, clear communication related to key health care decisions may lead to fewer disparities due to a patient's level of health literacy.
Metastases play a role in about 90% of cancer deaths. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells might provide diagnostic information about the ...likelihood that cancer cells have detached from the primary tumor. Used together with established diagnostic tests of detachment-lymph node evaluation and radiologic imaging-EMT marker measurements might improve the ability of clinicians to assess the patient's risk of metastatic disease. Translation of EMT markers to clinical use has been hampered by a lack of valid analyses of clinically-informative parameters. Here, we demonstrate a rigorous approach to estimating the sensitivity, specificity, and prediction increment of an EMT marker to assess cancer cell detachment from primary tumors.
We illustrate the approach using immunohistochemical measurements of the EMT marker E-cadherin in a set of colorectal primary tumors from a population-based prospective cohort in North Carolina. Bayesian latent class analysis was used to estimate sensitivity and specificity in a setting of multiple imperfect diagnostic tests and no gold standard. Risk reclassification analysis was used to assess the extent to which addition of the marker to the panel of established diagnostic tests would improve mortality prediction. We explored how changing the latent class conditional dependence assumptions and definition of marker positivity would impact the results.
All diagnostic accuracy and prediction increment statistics varied with the choice of cut point to define marker positivity. When comparing different definitions of marker positivity to each other, numerous trade-offs were observed in terms of sensitivity, specificity, predictive discrimination, and prediction model calibration. We then discussed several implementation considerations and the plausibility of analytic assumptions.
The approaches presented here can be extended to any EMT marker, to most forms of cancer, and to different kinds of EMT marker measurements, such as RNA or gene methylation data. These methods provide valid, clinically-informative assessment of whether and how to use a given EMT marker to refine tumor staging and consequent treatment decisions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Metastases are involved in most cancer deaths. Evidence has suggested that cancer cell detachment from primary tumors might occur largely via the mechanism of epithelial-mesenchymal transition (EMT) ...activated by epigenetic events, but data addressing other possible triggers of detachment, particularly genetic mutations, have been limited. Using the Profile study of cancer genomics at Dana-Farber Cancer Institute, we examined somatic mutations in the EMT genes
in 5,106 primary carcinomas and
in 7,578 primary carcinomas across 13 anatomic sites: urinary bladder, breast, colon/rectum, endometrium, esophagus, kidney, lung, ovary, pancreas, prostate, skin (non-melanoma), stomach, and thyroid. For each gene and anatomic site, we calculated the prevalence of primary carcinomas with at least one mutation. Across all anatomic sites, 4% of carcinomas had at least one
mutation and 4% of carcinomas had at least one
mutation. By anatomic site, the observed prevalence of carcinomas with at least one mutation was less than 5% at 10 sites for
and 12 sites for
. Tumor stage data were available for a subset of breast, colorectal, lung, and prostate tumors. Among patients from this subset who were diagnosed with regional or distant disease, only 4% had a
mutation and 1% had a
mutation in the primary tumor. The low mutation prevalences, especially among those with diagnoses of regional or distant disease, suggest that somatic mutations in
and
are unlikely to explain a substantial proportion of cancer cell detachment from primary carcinomas originating at most anatomic sites.
Differences in tumor characteristics might partially account for mortality disparities between African American (AA) and European American (EA) colorectal cancer patients. We evaluated effect ...modification by race for exposure and patient-outcomes associations with colorectal tumor methylation among 218 AA and 267 EA colorectal cancer cases from the population-based North Carolina Colon Cancer Study. Tumor methylation was assessed in CACNA1G, MLH1, NEUROG1, RUNX3, and SOCS1. We used logistic regression to assess whether associations between several lifestyle factors-intake of fruits, vegetables, folate, and non-steroidal anti-inflammatory drugs-and tumor methylation were modified by race. Proportional hazards models were used to evaluate whether race modified associations between tumor methylation and time to all-cause mortality. Greater fruit consumption was associated with greater odds of high NEUROG1 methylation among EA at methylation cut points of 15-35% (maximum OR 3.44, 95% CI 1.66, 7.13) but not among AA. Higher folate intake was associated with lower odds of high CACNA1G methylation among EAs but not AAs. Tumor methylation was not associated with all-cause mortality for either group. Race might modify associations between lifestyle factors and colorectal tumor methylation, but in this sample did not appear to modify associations between tumor methylation and all-cause mortality.
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