A note on competing risks in survival data analysis.

Survival analysis encompasses investigation of time to event data. In most clinical studies, estimating the cumulative incidence function (or the probability of experiencing an event by a given time) is of primary interest. When the data consist of patients who experience an event and censored individuals, a nonparametric estimate of the cumulative incidence can be obtained using the Kaplan-Meier method. Under this approach, the censoring mechanism is assumed to be noninformative. In other words, the survival time of an individual (or the time at which a subject experiences an event) is assumed to be independent of a mechanism that would cause the patient to be censored. Often times, a patient may experience an event other than the one of interest which alters the probability of experiencing the event of interest. Such events are known as competing risk events. In this setting, it would often be of interest to calculate the cumulative incidence of a specific event of interest. Any subject who does not experience the event of interest can be treated as censored. However, a patient experiencing a competing risk event is censored in an informative manner. Hence, the Kaplan-Meier estimation procedure may not be directly applicable. The cumulative incidence function for an event of interest must be calculated by appropriately accounting for the presence of competing risk events. In this paper, we illustrate nonparametric estimation of the cumulative incidence function for an event of interest in the presence of competing risk events using two published data sets. We compare the resulting estimates with those obtained using the Kaplan-Meier approach to demonstrate the importance of appropriately estimating the cumulative incidence of an event of interest in the presence of competing risk events.

Poorly differentiated insular thyroid carcinoma. A case report with identification of intact insulae with fine needle aspiration biopsy.

BACKGROUND: Subsequent to the publication of a report in 1984 entitled "Poorly Differentiated ("Insular") Carcinoma: A Reinterpretation of Langhans "wuchernde Struma," poorly differentiated insular thyroid carcinoma (PDITC) has become recognized as a distinct thyroid neoplasm. It is classified morphologically and biologically as an intermediate entity between well-differentiated (papillary and follicular) and undifferentiated (anaplastic) thyroid carcinomas. Only a few publications have addressed the findings with fine needle aspiration biopsy (FNAB). CASE: A 67-year-old female presented for evaluation of a massively enlarged thyroid gland. Fine needle aspiration biopsy of the thyroid with a 22-gauge needle showed many large, multilayered, round to oval nests of tumor cells, 0.2-0.4 mm in diameter. Rosettelike configurations of 8-15 cells, 0.025-0.050 mm in diameter, were also observed. Nests of neoplastic cells in the histologic sections were virtually identical to those in the fine needle aspiration biopsy specimens. When the patient developed metastatic cervical adenopathy one year later, a microfollicular pattern was seen on both the FNAB and histologic sections. CONCLUSION: When nests of tumor cells, 0.2-0.4 mm in diameter, are identified in a thyroid FNAB specimen, PDITC should be included in the differential diagnosis. A microfollicular pattern in a metastatic lymph node does not exclude the possibility that the primary tumor is a PDITC.

Transgenic mice bearing a human mutant thyroid hormone beta 1 receptor manifest thyroid function anomalies, weight reduction, and hyperactivity.

BACKGROUND: Resistance to thyroid hormone (RTH) is a syndrome characterized by refractoriness of the pituitary and/or peripheral tissues to the action of thyroid hormone. Mutations in the thyroid hormone receptor beta (TR beta) gene result in TR beta 1 mutants that mediate the clinical phenotype by interfering with transcription of thyroid hormone-regulated genes via a dominant negative effect. In this study, we developed transgenic mice harboring PV, a potent dominant negative human mutant TR beta 1 devoid of thyroid hormone binding and transcriptional activation, as an animal model to understand the molecular basis of this human disease. MATERIALS AND METHODS: Standard molecular biology approaches were used to obtain a cDNA fragment containing mutant PV which was injected into the pronucleus of fertilized egg. Founders were identified by Southern analysis and the expression of PV in tissues was determined by RNA and immunohistochemistry. Thyroid function was determined by radioimmunoassays of the hormones and the behavior of mice was observed using standard methods. RESULTS: The expression of mutant PV was directed by the beta-actin promoter. Mutant PV mRNA was detected in all tissues of transgenic mice, but the levels varied with tissues and with different lines of founders. Thyroid function tests in transgenic mice with high expression of mutant PV showed a significantly (approximately 1.5-fold) higher mean serum total of L-thyroxine levels (p < 0.01) than those of nontransgenic mice. Moreover, thyroid-stimulating hormone levels were not significantly different from those of nontransgenic mice. In addition, these mice displayed decreased weights and a behavioral phenotype characterized by hyperactivity. CONCLUSIONS: These mice have phenotypic features consistent with the commonly observed clinical features of RTH and could be used as a model system to better understand the action of mutant TR beta 1 in a physiological context, which could lead to better treatment for this disease.

Bacterial concentration and blood volume required for a positive blood culture.

We attempted to define the minimum blood volume and bacterial concentration required to obtain a positive blood culture with the use of placental blood and an in vitro technique. Known amounts of either Escherichia coli or group B beta-hemolytic streptococci were added to heparinized placental blood specimens. Blood samples of 0.25, 0.5, and 1.0 ml containing bacteria were inoculated into 30 ml of a commercially available broth culture medium, incubated for 24 hours, and examined for bacterial growth. Samples of at least 0.25 ml blood containing more than 10 colony-forming units of bacteria per milliliter resulted in a positive blood culture for 131 of 132 samples. On the basis of these data, we suggest that if 0.25 ml of blood is sampled and the specimen contains more than 10 colony-forming units per milliliter of E. coli or group B beta-hemolytic streptococci, the blood culture is almost certain to be positive.