Protective immunity to malaria: studies with cloned lines of Plasmodium chabaudi and P. berghei in CBA/Ca mice. I. The effectiveness and inter-and intra-species specificity of immunity induced by infection

CBA/Ca mice were immunized by infection with cloned lines of Plasmodium berghei (isolates ANKA, KSP-11). Plasmodium chabaudi chabaudi (AS, CB) or Plasmodium chabaudi adami (DS) and then challenged with either homologous or heterologous parasites. Protective responses were assessed in immune mice relative to the controls by their ability to (i) extend the time taken for the mean parasitaemia to reach a predetermined level (1% or 0.1%) (ii) reduce peak parasitaemia (iii) resolve the parasitaemia sooner and/or (iv) control or eliminate recrudescences. At both the inter- and intra-species level, immunity appeared largely specific for the cloned line inducing it. At the interspecies level marginally effective cross-immunity was sometimes evident, thus P. berghei KSP-11 immune mice displayed some immunity against P.c. chabaudi AS, although immunity to this parasite was relatively ineffective against P. berghei ANKA or KSP-11. Cross-immunity was more apparent between the subspecies P.c. adami and P.c. chabaudi and between cloned lines of the latter parasite derived from the AS and CB isolates. These data reflect considerable inter- and intra-species structural and immunogenic differences in certain antigens of parasitized erythrocytes and merozoites, which have been identified in a number of murine malarias and associated with protective immunity. Similar differences recently identified in the equivalent antigens of the human parasite P. falciparum may therefore have important implications for protective immunity in man.     

The assessment of diagnostic tests

To determine whether improvements have occurred since a survey of the 1982 literature assessing diagnostic tests, the authors evaluated all English-language articles that assessed clinical diagnostic tests in abridged Index Medicus journals in 1985, and that had the terms sensitivity and specificity in the title, abstract, or key words. The 89 articles were assessed against seven methodologic criteria, including use of a well-defined “gold standard,” clearly defined test interpretation, blinding, clear data presentation, correct use of sensitivity and specificity, calculation of predictive values, and consideration of prevalence. In comparisons of 1985 vs. 1982 articles, there were significant improvements in five of the seven criteria. For example, the proportion of articles using a well-defined “gold standard” rose from 68% to 88%. Overall, the frequency of papers demonstrating five or more of the seven criteria increased from 26% to 47%. However, predictive values were discussed in only 54% of the articles without, necessarily, consideration of the influence of prevalence as well. This study raises the concern that while the concepts of sensitivity and specificity are now accepted, predictive values remain less well understood. Although there has been an improvement in the assessment of diagnostic tests in published research, attention to accepted methodologic standards is still needed on the part of researchers, reviewers, and editors. Received from the Department of Health Care and Epidemiology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. Supported by a National Health Scholar Award to Dr. Schechter from the Department of National Health and Welfare of Canada.     

The Cell‐CT 3‐dimensional cell imaging technology platform enables the detection of lung cancer using the noninvasive LuCED sputum test

The war against cancer has yielded important advances in the early diagnosis and treatment of certain cancer types, but the poor detection rate and 5‐year survival rate for lung cancer has changed little over the past 40 years. Early detection through emerging lung cancer screening programs promise the most reliable means of improving mortality. Sputum cytology has been tried without success because sputum contains few malignant cells that are difficult for cytologists to detect. However, research has shown that sputum contains diagnostic malignant cells and could serve as a means of lung cancer detection if those cells could be detected and correctly characterized. Recently, the National Lung Screening Trial reported that screening using 3 consecutive low‐dose x‐ray computed tomography scans provides a 20% reduction in lung cancer mortality compared with chest x‐ray. However, this reduction in mortality comes with an unacceptable false‐positive rate that increases patient risks and the overall cost of lung cancer screening. The LuCED test for detection of early lung cancer is reviewed in the current article. LuCED is based on patient sputum that is enriched for bronchial epithelial cells. The enriched sample is then processed on the Cell‐CT, which images cells in 3 dimensions with submicron resolution. Algorithms are applied to the 3‐dimensional cell images to extract morphometric features that drive a classifier to identify cells that have abnormal characteristics. The final status of these candidate abnormal cells is established by the pathologist's manual review. LuCED promotes accurate cell classification that could enable the cost‐effective detection of lung cancer. Cancer (Cancer Cytopathol) 2015;123:512–523. © 2015 American Cancer Society.     

Accuracy of ultrasound for predicting pathologic response during neoadjuvant therapy for breast cancer

Early assessment of response to neoadjuvant chemotherapy (NAC) for breast cancer allows therapy to be tailored; however, optimal response assessment methods have not been established. We estimated the accuracy of ultrasound (US) to predict pathologic complete response (pCR) using common response criteria and pCR definitions, and estimated incremental accuracy over known prognostic variables. Participants undergoing US after two cycles in the GeparTrio trial randomised to no change in NAC were eligible. US response by World Health Organisation (WHO) criteria (1D or 2D) and Response Evaluation Criteria In Solid Tumours (RECIST) was assessed. Four pCR definitions were applied. Sensitivity (correct prediction of pCR), specificity (correct prediction of no‐pCR) and diagnostic odds ratios (DORs) were calculated. Areas under the curve (AUCs) were derived from logistic regression including patient variables with and without US. In 832 patients, DORs decreased as pCR definitions became less stringent (p = 0.01). For WHO‐2D, DORs were as follows: 4.07 (ypT0,ypN0), 3.75 (ypT0/is,ypN0), 3.14 (ypT0/is,ypN+/?) and 2.65 (ypT0/is/1a,ypN+/?). DORs did not differ between US criteria (p = 0.60). High sensitivity and lower specificity were found for WHO‐2D and RECIST; WHO‐1D was highly specific with low sensitivity. Sensitivity was highest for WHO‐2D predicting ypT0,ypN0 (sensitivity = 81.7%, specificity = 47.6% vs. 42.3% and 80.4% for WHO‐1D). Adding US to models including patient variables (age, T‐stage, histology and subtype) improved AUCs for predicting pCR by 2–3%. In conclusion, US accuracy is highest for predicting ypT0,ypN0, shown to be most prognostic of long‐term survival. WHO‐2D and RECIST maximise sensitivity; WHO‐1D maximises specificity. US modestly improves the prediction of pCR by patient characteristics.     

Two-stage enrichment clinical trial design with adjustment for misclassification in predictive biomarkers

A two-stage enrichment design is a type of adaptive design, which extends a stratified design with a futility analysis on the marker negative cohort at the first stage, and the second stage can be either a targeted design with only the marker positive stratum, or still the stratified design with both marker strata, depending on the result of the interim futility analysis. In this paper, we consider the situation where the marker assay and the classification rule are possibly subject to error. We derive the sequential tests for the global hypothesis as well as the component tests for the overall cohort and the marker-positive cohort. We discuss the power analysis with the control of the type I error rate and show the adverse impact of the misclassification on the powers. We also show the enhanced power of the two-stage enrichment over the one-stage design and illustrate with examples of the recent successful development of immunotherapy in non–small-cell lung cancer.     

Optimal survival time‐related cut‐point with censored data

In biomedical research and practice, continuous biomarkers are often used for diagnosis and prognosis, with a cut‐point being established on the measurement to aid binary classification. When survival time is examined for the purposes of disease prognostication and is found to be related to the baseline measure of a biomarker, employing a single cut‐point on the biomarker may not be very informative. Using survival time‐dependent sensitivity and specificity, we extend a concordance probability‐based objective function to select survival time‐related cut‐points. To estimate the objective function with censored survival data, we adopt a non‐parametric procedure for time‐dependent receiver operational characteristics curves, which uses nearest neighbor estimation techniques. In a simulation study, the proposed method, when used to select a cut‐point to optimally predict survival at a given time within a specified range, yields satisfactory results. We apply the procedure to estimate survival time‐dependent cut‐point on the prognostic biomarker of serum bilirubin among patients with primary biliary cirrhosis. Copyright © 2014 John Wiley & Sons, Ltd.     

Efficient statistical tests to compare Youden index: accounting for contingency correlation

Youden index is widely utilized in studies evaluating accuracy of diagnostic tests and performance of predictive, prognostic, or risk models. However, both one and two independent sample tests on Youden index have been derived ignoring the dependence (association) between sensitivity and specificity, resulting in potentially misleading findings. Besides, paired sample test on Youden index is currently unavailable. This article develops efficient statistical inference procedures for one sample, independent, and paired sample tests on Youden index by accounting for contingency correlation, namely associations between sensitivity and specificity and paired samples typically represented in contingency tables. For one and two independent sample tests, the variances are estimated by Delta method, and the statistical inference is based on the central limit theory, which are then verified by bootstrap estimates. For paired samples test, we show that the estimated covariance of the two sensitivities and specificities can be represented as a function of kappa statistic so the test can be readily carried out. We then show the remarkable accuracy of the estimated variance using a constrained optimization approach. Simulation is performed to evaluate the statistical properties of the derived tests. The proposed approaches yield more stable type I errors at the nominal level and substantially higher power (efficiency) than does the original Youden's approach. Therefore, the simple explicit large sample solution performs very well. Because we can readily implement the asymptotic and exact bootstrap computation with common software like R, the method is broadly applicable to the evaluation of diagnostic tests and model performance. Copyright © 2015 John Wiley & Sons, Ltd.