Accounting for incomplete testing in the estimation of epidemic parameters.

As the COVID-19 pandemic spreads across the world, it is important to understand its features and responses to public health interventions in real-time. The field of infectious diseases epidemiology has highly advanced modeling strategies that yield relevant estimates. These include the doubling time of the epidemic and various other representations of the numbers of cases identified over time. Crude estimates of these quantities suffer from dependence on the underlying testing strategies within communities. We clarify the functional relationship between testing and the epidemic parameters, and thereby derive sensitivity analyses that explore the range of possible truths under various testing dynamics. We derive the required adjustment to the estimates of interest for New York City. We demonstrate that crude estimates that assume stable testing or complete testing can be biased.

Nonidentifiability in the presence of factorization for truncated data.

A time to event, [Formula: see text], is left-truncated by [Formula: see text] if [Formula: see text] can be observed only if [Formula: see text]. This often results in oversampling of large values of [Formula: see text], and necessitates adjustment of estimation procedures to avoid bias. Simple risk-set adjustments can be made to standard risk-set-based estimators to accommodate left truncation when [Formula: see text] and [Formula: see text] are quasi-independent. We derive a weaker factorization condition for the conditional distribution of [Formula: see text] given [Formula: see text] in the observable region that permits risk-set adjustment for estimation of the distribution of [Formula: see text], but not of the distribution of [Formula: see text]. Quasi-independence results when the analogous factorization condition for [Formula: see text] given [Formula: see text] holds also, in which case the distributions of [Formula: see text] and [Formula: see text] are easily estimated. While we can test for factorization, if the test does not reject, we cannot identify which factorization condition holds, or whether quasi-independence holds. Hence we require an unverifiable assumption in order to estimate the distribution of [Formula: see text] or [Formula: see text] based on truncated data. This contrasts with the common understanding that truncation is different from censoring in requiring no unverifiable assumptions for estimation. We illustrate these concepts through a simulation of left-truncated and right-censored data.

Hypothesis Tests for Neyman's Bias in Case-Control Studies.

Survival bias is a long-recognized problem in case-control studies, and many varieties of bias can come under this umbrella term. We focus on one of them, termed Neyman's bias or "prevalence-incidence bias." It occurs in case-control studies when exposure affects both disease and disease-induced mortality, and we give a formula for the observed, biased odds ratio under such conditions. We compare our result with previous investigations into this phenomenon and consider models under which this bias may or may not be important. Finally, we propose three hypothesis tests to identify when Neyman's bias may be present in case-control studies. We apply these tests to three data sets, one of stroke mortality, another of brain tumors, and the last of atrial fibrillation, and find some evidence of Neyman's bias in the former two cases, but not the last case.

Gain of chromosome arm 1q in atypical meningioma correlates with shorter progression-free survival.

AIMS: Atypical (World Health Organization grade II) meningiomas have moderately high recurrence rates; even for completely resected tumours, approximately one-third will recur. Post-operative radiotherapy may aid local control and improve survival, but carries the risk of side effects. More accurate prediction of recurrence risk is therefore needed for patients with atypical meningioma. Previously, we used high-resolution array comparative genomic hybridization to identify genetic variations in 47 primary atypical meningiomas and found that approximately 60% of tumours show gain of 1q at 1q25.1 and 1q25.3 to 1q32.1 and that 1q gain appeared to correlate with shorter progression-free survival. This study aimed to validate and extend these findings in an independent sample. METHODS: Eighty-six completely resected atypical meningiomas (with 25 recurrences) from two neurosurgical centres in Ireland were identified and clinical follow-up was obtained. Utilizing a dual-colour interphase fluorescence in situ hybridization assay, 1q gain was assessed using Bacterial Artificial Chromosome probes directed against 1q25.1 and 1q32.1. RESULTS: The results confirm the high prevalence of 1q gain at these loci in atypical meningiomas. We further show that gain at 1q32.1 and age each correlate with progression-free survival in patients who have undergone complete surgical resection of atypical meningiomas. CONCLUSIONS: These independent findings suggest that assessment of 1q copy number status can add clinically useful information for the management of patients with atypical meningiomas.

Urinary biomarkers in the early diagnosis of acute kidney injury.

A change in the serum creatinine is not sensitive for an early diagnosis of acute kidney injury. We evaluated urinary levels of matrix metalloproteinase-9 (MMP-9), N-acetyl-beta-D-glucosaminidase (NAG), and kidney injury molecule-1 (KIM-1) as biomarkers for the detection of acute kidney injury. Urine samples were collected from 44 patients with various acute and chronic kidney diseases, and from 30 normal subjects in a cross-sectional study. A case-control study of children undergoing cardio-pulmonary bypass surgery included urine specimens from each of 20 patients without and with acute kidney injury. Injury was defined as a greater than 50% increase in the serum creatinine within the first 48 h after surgery. The biomarkers were normalized to the urinary creatinine concentration at 12, 24, and 36 h after surgery with the areas under the receiver-operating characteristic curve compared for performance. In the cross-sectional study, the area under the curve for MMP-9 was least sensitive followed by KIM-1 and NAG. Combining all three biomarkers achieved a perfect score diagnosing acute kidney injury. In the case-control study, KIM-1 was better than NAG at all time points, but combining both was no better than KIM-1 alone. Urinary MMP-9 was not a sensitive marker in the case-control study. Our results suggest that urinary biomarkers allow diagnosis of acute kidney injury earlier than a rise in serum creatinine.

Predicting short-term disability in multiple sclerosis.

OBJECTIVE: To develop covariate specific short-term disability curves to demonstrate the probability of progressing by Expanded Disability Status Scale (EDSS) at semiannual visits. METHODS: Semiannual EDSS scores were prospectively collected in 218 relapsing-remitting (RR) and clinically isolated syndrome (CIS) patients as part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study. Baseline brain parenchymal fraction (BPF) and T2 lesion volume were available on 205 patients. A partial proportional odds model determined the influence of covariates on the change in EDSS score at subsequent visits. A discrete second order Markov transitional model was fit and generated a probability matrix for each subject; the 6-month probabilities of EDSS change were graphically represented. RESULTS: The univariate analysis demonstrated the lowest baseline BPF quartile (OR 1.99; p = 0.0203) and the highest T2 lesion volume quartile (OR 2.19; p = 0.0130) were associated with progression in EDSS. Covariate specific disability curves demonstrated the effect of BPF and T2 lesion volume on short-term progression. In subjects with a 6-month EDSS of 2, the probability of a sustained progression of an EDSS of 3 within 3 years was 0.277 for a subject with low BPF and a high T2 lesion volume vs 0.055 for a subject with high BPF and a low T2 lesion volume. CONCLUSIONS: Markov transitional models allow for the comparison of covariate specific short-term disability changes among groups of patients with multiple sclerosis.

Outcomes in a series of 103 retroperitoneal sarcomas.

AIMS: To report the effect on outcome of selection in patients receiving intra-operative electron beam radiation (IOERT) and external beam radiation therapy (EBRT). METHODS: One hundred and three patients treated for primary RS were studied. Median follow-up was 27 months. Clinical presentation, tumor characteristics, and treatment methods were analyzed to determine impact on survival and recurrence and if selection was occurring. RESULTS: Mean age was 55+/-17 years. Mean tumor size was 15+/-6cm and 88 were high-grade. Complete gross tumor resection (CR) occurred in 62 patients and improved survival vs. both debulking (p=0.0005) and biopsy (p<0.0001). The 5- and 10-year survival rates were 62% and 52% for those with CR vs. 29% and 20% after incomplete resection. Among the 62 CR patients, there was selection to receive additional EBRT+/-IOERT in patients with high-grade tumors (p=0.005) and/or microscopically positive margins (p=0.011). In these high-risk patients there was a trend for IOERT to further augment survival vs. EBRT alone and to increase the time to both local and distant recurrences (p=0.036). CONCLUSIONS: Complete gross resection is the primary form of curative treatment for retroperitoneal sarcomas. Selection led to patients with high-risk tumors receiving additional radiation therapy. There appears to be a beneficial effect of IOERT plus EBRT in these high-risk patients after complete tumor resection.

C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the notch3 epidermal growth factor-like repeats. A Colombian kindred carries a novel C455R mutation located in the predicted ligand-binding domain. Stroke occurred in the patients at an unusually early age (median age: 31 years) in comparison to the more frequent onset in the fourth decade of life in other CADASIL populations, including a second Colombian kindred with an R1031C mutation.

Tumor location and growth pattern correlate with genetic signature in oligodendroglial neoplasms.

Molecular genetic subsets of anaplastic oligodendroglioma behave in biologically distinct ways, in both their rates of growth and their responses to standard therapies. In a series of 64 cases, we evaluated whether allelic loss of chromosomal arms 1p and 19q, an early molecular event in the genesis of chemosensitive oligodendrogliomas, is related to tumor location and extent of tumor spread in the brain. We observed that tumor genotype was closely associated with tumor location (P < 0.001). Anaplastic oligodendrogliomas located in the frontal, parietal, and occipital lobes were significantly more likely to harbor allelic loss of chromosomal arms 1p and 19q than histologically indistinguishable tumors arising in the temporal lobe, insula, and diencephalon (P < 0.001). In addition, loss of heterozygosity for 1p and 19q was significantly associated with a bilateral pattern of growth (P = 0.037); all seven bilaterally distributed anaplastic oligodendrogliomas had 1p and 19q allelic loss. We conclude, therefore, that molecular subtypes of oligodendrogliomas may arise preferentially in certain lobes of the brain and have differential patterns of growth, with tumors having allelic loss of chromosomes 1p and 19q occurring most frequently in the frontal lobes and having a tendency for widespread growth across the midline. These findings encourage inquiries into the biological basis of such marked differences and already have implications for the current management of these neoplasms.

alpha-Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids, and shows homology to the fatty acid-binding proteins.

alpha-Synuclein (alphaS) is a 140-residue neuronal protein that forms insoluble cytoplasmic aggregates in Parkinson's disease (PD) and several other neurodegenerative disorders. Two missense mutations (A53T and A30P) are linked to rare forms of familial PD. The normal function of alphaS is unknown, and cultured cell systems that model its modification from soluble monomers to aggregated forms have not been reported. Through a systematic centrifugal fractionation of mesencephalic neuronal cell lines and transgenic mouse brains expressing wild-type or A53T human alphaS, we observed unusual, previously unrecognized species of alphaS that migrate well above the 17-kDa monomeric form in denaturing gels. Incubation at 65 degrees C of high-speed cytosols from cells or brains revealed a modified alphaS species migrating at approximately 36 kDa and an extensive higher molecular mass alphaS-reactive smear. Extraction of the cytosols with chloroform/methanol or with a resin (Lipidex 1000) that binds fatty acids resulted in a similar pattern of higher molecular mass alphaS forms. On the basis of this effect of delipidation, we reexamined the primary structure of alphaS and detected a motif at the N and C termini that is homologous to a fatty acid-binding protein signature. In accord, we found that purified human alphaS binds oleic acid, with an apparent K(d) of 12.5 microM. We also observed an enhanced association of A53T alphaS with microsomal membranes in both mesencephalic cells and transgenic mouse brains. We conclude that alphaS has biochemical properties and a structural motif that suggest it is a novel member of the fatty acid-binding protein family and may thus transport fatty acids between the aqueous and membrane phospholipid compartments of the neuronal cytoplasm.

PTEN is a target of chromosome 10q loss in anaplastic oligodendrogliomas and PTEN alterations are associated with poor prognosis.

Allelic loss of 10q is a common genetic event in malignant gliomas, with three 10q tumor suppressor genes, ERCC6, PTEN, and DMBT1, putatively implicated in the most common type of malignant glioma, glioblastoma. Anaplastic oligodendroglioma, another type of malignant glioma, provides a unique opportunity to study the relevance of particular genetic alterations to chemosensitivity and survival. We therefore analyzed these three genes in 72 anaplastic oligodendrogliomas. Deletion mapping demonstrated 10q loss in 14 of 67 informative cases, with the PTEN and DMBT1 regions involved in all deletions but with the ERCC6 locus spared in two cases. Seven tumors had PTEN gene alterations; two had homozygous DMBT1 deletions, but at least one reflected unmasking of a germline DMBT1 deletion. No mutations were found in ERCC6 exon 2. Chemotherapeutic response occurred in two of the seven tumors with PTEN alterations, but with unexpected short survival times. PTEN gene alterations were not associated with poor therapeutic response in multivariate analysis, but were independently predictive of poor prognosis even after multivariate adjustment for both 10q and 1p loss. In anaplastic oligodendroglioma, therefore, PTEN is a target of 10q loss, and PTEN alterations are associated with poor prognosis, even in chemosensitive cases.

Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis.

PURPOSE: In a prior study of anaplastic oligodendrogliomas treated with chemotherapy at diagnosis or at recurrence after radiotherapy, allelic loss of chromosome 1p correlated with better chemotherapeutic response and overall survival. However, in this group of patients in whom therapeutic management was not uniform, loss of 1p did not identify all chemosensitive tumors, nor did all patients whose tumors harbor a 1p loss have long survival. EXPERIMENTAL DESIGN: To clarify the clinical relevance of molecular genetic testing at the time of diagnosis for patients with anaplastic oligodendrogliomas, we studied a larger, more homogeneous group of 50 patients with histologically defined anaplastic oligodendrogliomas treated with a chemotherapeutic regimen as the principal initial therapy. RESULTS: We demonstrate that these tumors can be divided genetically into four therapeutically and prognostically relevant subgroups. Patients whose tumors have combined but isolated losses of 1p and 19q have marked and durable responses to chemotherapy associated with long survival, with or without postoperative radiation therapy. Other tumors with chromosome 1p alterations also respond to chemotherapy, but with shorter duration of response and patient survival. Tumors lacking 1p loss can also be divided into two subgroups: those with TP53 mutations, which may also respond to chemotherapy but recur quickly, and those without TP53 mutations, which are poorly responsive, aggressive tumors that are clinically and genotypically similar to glioblastomas. CONCLUSIONS: These data raise the possibility, for the first time, that therapeutic decisions at the time of diagnosis might be tailored to particular genetic subtypes of anaplastic oligodendroglioma.

Nonparametric estimation in a cure model with random cure times.

Acute respiratory distress syndrome (ARDS) is a life-threatening acute condition that sometimes follows pneumonia or surgery. Patients who recover and leave the hospital are considered to have been cured at the time they leave the hospital. These data differ from typical data in which cure is a possibility: death times are not observed for patients who are cured and cure times are observed and vary among patients. Here we apply a competing risks model to these data and show it to be equivalent to a mixture model, the more common approach for cure data. Further, we derive an estimator for the variance of the cumulative incidence function from the competing risks model, and thus for the cure rate, based on elementary calculations. We compare our variance estimator to Gray's (1988, Annals of Statistics 16, 1140-1154) estimator, which is based on counting process theory. We find our estimator to be slightly more accurate in small samples. We apply these results to data from an ARDS clinical trial.

A computationally simple test of homogeneity of odds ratios for twin data.

It is of interest to compare measures of association of binary traits among samples of bivariate data. One example is the comparison of association within a sample of monozygotic (MZ) twins to that within a sample of dizygotic (DZ) twins. A larger association in the MZ twins suggests that the trait of interest may have a genetic component. The Bivariate data in this example are binary traits for the twins in each pair. Another example is the comparison of a measure of Hardy-Weinberg disequilibrium across several populations. The bivariate data in this example are the two alleles comprising the genotype of interest. We propose using derived logistic regression equations from the full exponential model for the bivariate outcomes to test for homogeneity. We adjust for correlation among outcomes via generalized estimating equations. This modeling approach allows for adjustment for individual-level and pair-level covariates and thereby allows for testing for gene x environment interactions. Further, we extend the model to allow for simultaneous analysis of two diseases, which allows for testing for a genetic component to the coaggregation of two diseases. In contrast to approaches proposed by previous authors, no special software is required; our approach can be easily implemented in standard software packages. We compare our results to those of other methods proposed in the literature for data from the Vietnam Era Twins Study. We apply our methods also to the Anqing Twin Study and to data on major depression and generalized anxiety disorder from the Virginia Twin Register.

Multivariate logistic regression for familial aggregation of two disorders. I. Development of models and methods.

The question of whether two disorders cluster together, or coaggregate, within families often arises. This paper considers how to analyze familial aggregation of two disorders and presents two multivariate logistic regression methods that model both disorder outcomes simultaneously. The first, a proband predictive model, predicts a relative's outcomes (the presence or absence of each of the two disorders) by using the proband's disorder status. The second, a family predictive model derived from the quadratic exponential model, predicts a family member's outcomes by using all of the remaining family members' disorder statuses. The models are more realistic, flexible, and powerful than univariate models. Methods for estimation and testing account for the correlation of outcomes among family members and can be implemented by using commercial software.

Multivariate logistic regression for familial aggregation of two disorders. II. Analysis of studies of eating and mood disorders.

Family studies have suggested that eating disorders and mood disorders may coaggregate within families. Previous studies, however, have been limited by use of univariate modeling techniques and failure to account for the correlation of observations within families. To provide a more efficient analysis and to illustrate multivariate logistic regression models for familial aggregation of two disorders, the authors analyzed pooled data from two previously published family studies (conducted in Massachusetts in 1984-1986 and 1986-1987) by using multivariate proband predictive and family predictive models. Both models demonstrated a significant familial aggregation of mood disorders and familial coaggregation of eating and mood disorders. The magnitude of the coaggregation between eating and mood disorders was similar to that of the aggregation of mood disorders. Similar results were obtained with alternative models, including a traditional univariate proband predictive model. In comparison with the univariate model, the multivariate models provided greater flexibility, improved precision, and wider generality for interpreting aggregation effects.

Approximating the distribution of maximally selected McNemar's statistics.

It is common in epidemiologic analyses to summarize continuous outcomes as falling above or below a threshold. With paired data and with a threshold chosen without reference to the outcomes, McNemar's test of marginal homogeneity may be applied to the resulting dichotomous pairs when testing for equality of the marginal distributions of the underlying continuous outcomes. If the threshold is chosen to maximize the test statistic, however, referring the resulting test statistic to the nominal chi 2 distribution is incorrect; instead, the p-value must be adjusted for the multiple comparisons. Here the distribution of a maximally selected McNemar's statistic is derived, and it is shown that an approximation due to Durbin (1985, Journal of Applied Probability 22, 99-122) may be used to estimate approximate p-values. The methodology is illustrated by an application to measurements of insulin-like growth factor-I (IGF-I) in matched prostate cancer cases and controls from the Physicians' Health Study. The results of simulation experiments that assess the accuracy of the approximation in moderate sample sizes are reported.

Shipment impairs lymphocyte proliferative responses to microbial antigens.

Lymphocyte proliferation assays (LPAs) are widely used to assess T-lymphocyte function of patients with human immunodeficiency virus infection and other primary and secondary immunodeficiency disorders. Since these assays require expertise not readily available at all clinical sites, specimens may be shipped to central labs for testing. We conducted a large multicenter study to evaluate the effects of shipping on assay performance and found significant loss of LPA activity. This may lead to erroneous results for individual subjects and introduce bias into multicenter trials.

Using conditional logistic regression to fit proportional odds models to interval censored data.

An easily implemented approach to fitting the proportional odds regression model to interval-censored data is presented. The approach is based on using conditional logistic regression routines in standard statistical packages. Using conditional logistic regression allows the practitioner to sidestep complications that attend estimation of the baseline odds ratio function. The approach is applicable both for interval-censored data in settings in which examinations continue regardless of whether the event of interest has occurred and for current status data. The methodology is illustrated through an application to data from an AIDS study of the effect of treatment with ZDV+ddC versus ZDV alone on 50% drop in CD4 cell count from baseline level. Simulations are presented to assess the accuracy of the procedure.

Multiple imputation for simple estimation of the hazard function based on interval censored data.

A data augmentation algorithm is presented for estimating the hazard function and pointwise variability intervals based on interval censored data. The algorithm extends that proposed by Tanner and Wong for grouped right censored data to interval censored data. It applies multiple imputation and local likelihood methods to obtain smooth non-parametric estimates for the hazard function. This approach considerably simplifies the problem of estimation for interval censored data as it transforms it into the more tractable problem of estimation for right censored data. The method is illustrated for two real data sets: times to breast cosmesis deterioration and times to HIV-1 infection for individuals with haemophilia. Simulations are presented to assess the effects of various parameters on the estimates and their variances.