Mary J. Lindstrom

Nonlinear Mixed Effects Models for Repeated Measures Data

We propose a general, nonlinear mixed effects model for repeated measures data and define estimators for its parameters. The proposed estimators are a natural combination of least squares estimators for nonlinear fixed effects models and maximum likelihood (or restricted maximum likelihood) estimators for linear mixed effects models. We implement Newton-Raphson estimation using previously developed computational methods for nonlinear fixed effects models and for linear mixed effects models. Two examples are presented and the connections between this work and recent work on generalized linear mixed effects models are discussed.

A large-scale study of the ultrawideband microwave dielectric properties of normal, benign and malignant breast tissues obtained from cancer surgeries

The development of microwave breast cancer detection and treatment techniques has been driven by reports of substantial contrast in the dielectric properties of malignant and normal breast tissues. However, definitive knowledge of the dielectric properties of normal and diseased breast tissues at microwave frequencies has been limited by gaps and discrepancies across previously published studies. To address these issues, we conducted a large-scale study to experimentally determine the ultrawideband microwave dielectric properties of a variety of normal, malignant and benign breast tissues, measured from 0.5 to 20 GHz using a precision open-ended coaxial probe. Previously, we reported the dielectric properties of normal breast tissue samples obtained from reduction surgeries. Here, we report the dielectric properties of normal (adipose, glandular and fibroconnective), malignant (invasive and non-invasive ductal and lobular carcinomas) and benign (fibroadenomas and cysts) breast tissue samples obtained from cancer surgeries. We fit a one-pole Cole-Cole model to the complex permittivity data set of each characterized sample. Our analyses show that the contrast in the microwave-frequency dielectric properties between malignant and normal adipose-dominated tissues in the breast is considerable, as large as 10:1, while the contrast in the microwave-frequency dielectric properties between malignant and normal glandular/fibroconnective tissues in the breast is no more than about 10%.

Newton-Raphson and EM Algorithms for Linear Mixed-Effects Models for Repeated-Measures Data

Abstract We develop an efficient and effective implementation of the Newton—Raphson (NR) algorithm for estimating the parameters in mixed-effects models for repeated-measures data. We formulate the derivatives for both maximum likelihood and restricted maximum likelihood estimation and propose improvements to the algorithm discussed by Jennrich and Schluchter (1986) to speed convergence and ensure a positive-definite covariance matrix for the random effects at each iteration. We use matrix decompositions to develop efficient and computationally stable implementations of both the NR algorithm and an EM algorithm (Laird and Ware 1982) for this model. We compare the two methods (EM vs. NR) in terms of computational order and performance on two sample data sets and conclude that in most situations a well-implemented NR algorithm is preferable to the EM algorithm or EM algorithm with Aitkens acceleration. The term repeated measures refers to experimental designs where there are several individuals and several...

A large-scale study of the ultrawideband microwave dielectric properties of normal breast tissue obtained from reduction surgeries.

The efficacy of emerging microwave breast cancer detection and treatment techniques will depend, in part, on the dielectric properties of normal breast tissue. However, knowledge of these properties at microwave frequencies has been limited due to gaps and discrepancies in previously reported small-scale studies. To address these issues, we experimentally characterized the wideband microwave-frequency dielectric properties of a large number of normal breast tissue samples obtained from breast reduction surgeries at the University of Wisconsin and University of Calgary hospitals. The dielectric spectroscopy measurements were conducted from 0.5 to 20 GHz using a precision open-ended coaxial probe. The tissue composition within the probes sensing region was quantified in terms of percentages of adipose, fibroconnective and glandular tissues. We fit a one-pole Cole-Cole model to the complex permittivity data set obtained for each sample and determined median Cole-Cole parameters for three groups of normal breast tissues, categorized by adipose tissue content (0-30%, 31-84% and 85-100%). Our analysis of the dielectric properties data for 354 tissue samples reveals that there is a large variation in the dielectric properties of normal breast tissue due to substantial tissue heterogeneity. We observed no statistically significant difference between the within-patient and between-patient variability in the dielectric properties.

Loss of local control with prolongation in radiotherapy.

Twelve published clinical results of radical radiotherapy of head and neck cancer have been reviewed, seven of them with fresh multivariate analyses, to determine the magnitude of time factors relating local control to overall time. In all but two of the data sets a significant loss of local control was observed with prolongation. The median rate of loss was 14% in only 1 week, the range 3 to 25%. This corresponds to a median loss of 26% in 2 weeks (5-42%). These results are comparable with other, less detailed information. Whether these significant losses are due to proliferation of tumor cells or to other causes such as physician selection, it is clear that modest prolongation is associated with a lower chance of local control.

Knee Joint: Comprehensive Assessment with 3D Isotropic Resolution Fast Spin-Echo MR Imaging—Diagnostic Performance Compared with That of Conventional MR Imaging at 3.0 T

PURPOSE To determine whether a three-dimensional isotropic resolution fast spin-echo sequence (FSE-Cube) has similar diagnostic performance as a routine magnetic resonance (MR) imaging protocol for evaluating the cartilage, ligaments, menisci, and osseous structures of the knee joint in symptomatic patients at 3.0 T. MATERIALS AND METHODS This prospective, HIPAA-compliant, institutional review board-approved study was performed with a waiver of informed consent. FSE-Cube was added to the routine 3.0-T MR imaging protocol performed in 100 symptomatic patients (54 male patients with a median age of 32 years and 46 female patients with a median age of 33 years) who subsequently underwent arthroscopic knee surgery. All MR imaging studies were independently reviewed twice by two musculoskeletal radiologists. During the first review, the routine MR imaging protocol was used to detect cartilage lesions, ligament tears, meniscal tears, and bone marrow edema lesions. During the second review, FSE-Cube with multiplanar reformations was used to detect these joint abnormalities. With arthroscopic results as the reference standard, the sensitivity and specificity of FSE-Cube and the routine MR imaging protocol in the detection of cartilage lesions, anterior cruciate ligament tears, and meniscal tears were calculated. Permutation tests were used to compare sensitivity and specificity values. RESULTS FSE-Cube had significantly higher sensitivity (P = .039) but significantly lower specificity (P = .003) than the routine MR imaging protocol for detecting cartilage lesions. There were no significant differences (P = .183-.999) in sensitivity and specificity between FSE-Cube and the routine MR imaging protocol in the detection of anterior cruciate ligament tears, medial meniscal tears, or lateral meniscal tears. FSE-Cube depicted 96.2% of medial collateral ligament tears, 100% of lateral collateral ligament tears, and 85.3% of bone marrow edema lesions identified on images obtained with the routine MR imaging protocol. CONCLUSION FSE-Cube has similar diagnostic performance as a routine MR imaging protocol for detecting cartilage lesions, cruciate ligament tears, collateral ligament tears, meniscal tears, and bone marrow edema lesions within the knee joint at 3.0 T.

Development of vocal tract length during early childhood: a magnetic resonance imaging study.

Speech development in children is predicated partly on the growth and anatomic restructuring of the vocal tract. This study examines the growth pattern of the various hard and soft tissue vocal tract structures as visualized by magnetic resonance imaging (MRI), and assesses their relational growth with vocal tract length (VTL). Measurements on lip thickness, hard- and soft-palate length, tongue length, naso-oro-pharyngeal length, mandibular length and depth, and distance of the hyoid bone and larynx from the posterior nasal spine were used from 63 pediatric cases (ages birth to 6 years and 9 months) and 12 adults. Results indicate (a) ongoing growth of all oral and pharyngeal vocal tract structures with no sexual dimorphism, and a period of accelerated growth between birth and 18 months; (b) vocal tract structures region (oral/anterior versus pharyngeal/posterior) and orientation (horizontal versus vertical) determine its growth pattern; and (c) the relational growth of the different structures with VTL changes with development-while the increase in VTL throughout development is predominantly due to growth of pharyngeal/posterior structures, VTL is also substantially affected by the growth of oral/anterior structures during the first 18 months of life. Findings provide normative data that can be used for modeling the development of the vocal tract.

Heterogeneous expression of the lipocalin NGAL in primary breast cancers

We have previously shown that neu oncogene‐initiated rat mammary carcinomas uniquely over‐express neu‐related lipocalin (NRL), a member of the calycin protein superfamily. Here, we characterize the putative human homolog of NRL, neutrophil gelatinase‐associated lipocalin (NGAL). ngal gene expression was found at moderate levels in only 2 of 17 human tissues examined, breast and lung. When breast cancers were examined for NGAL mRNA and protein levels, they were found to exhibit heterogeneous expression. NGAL levels varied in these tumors from undetectable to exceeding those in normal breast parenchyma. Immuno‐histochemical analysis confirmed the presence of NGAL within breast carcinoma cells but detected only low levels of this protein in normal ductal epithelium. In contrast, large amounts of the protein were localized to the lumen of normal breast ducts in the vicinity of NGAL‐expressing tumors. Interestingly, unlike NRL in rat mammary carcinomas, no significant association between NGAL expression and HER‐2/neu activation was found in human breast tumors. In contrast, a significant correlation between NGAL expression in breast cancer was found with several other markers of poor prognosis, including estrogen and progesterone receptor‐negative status and high proliferation (S‐phase fraction). NGAL levels were stratified as high or low in breast cancers from a cohort of node‐positive patients with known outcome. No significant association between NGAL expression and disease‐free or overall survival was observed. Int. J. Cancer (Pred. Oncol.) 79:565–572, 1998.

Resveratrol Inhibits Tumor Growth of Human Neuroblastoma and Mediates Apoptosis by Directly Targeting Mitochondria

Purpose: Neuroblastoma is an aggressive childhood disease of the sympathetic nervous system. Treatments are often ineffective and have serious side effects. Because resveratrol, a natural plant product, has been reported to have limited toxicity at chemotherapeutic levels, we investigated its efficacy in the treatment of neuroblastoma as well as its underlying mechanism of action. Experimental Design: Resveratrol was tested in mouse xenograft models of human neuroblastoma and in vitro using human cell lines. Results: Resveratrol inhibited the outgrowth of tumors by as much as 80%. The bioavailability of the drug in serum was in the low micromolar range (2-10 μmol/L) and no accumulation was observed in tumor tissue. When resveratrol levels were increased by peritumor injection, rapid tumor regression occurred. Resveratrol decreased tumor cell viability in vitro by 75% to 90%, resulting from an inhibition of cell proliferation and an induction of apoptosis. Loss of mitochondrial membrane potential was an early response to resveratrol. In addition, resveratrol treatment of isolated mitochondria also led to depolarization, suggesting that the drug may target mitochondria directly. Following depolarization, resveratrol caused the release of cytochrome c and Smac/Diablo from the mitochondria and subsequently the activation of caspase-9 (4- to 8-fold) and caspase-3 (4- to 6-fold). Conclusions: These studies indicate that, despite low bioavailability, resveratrol is effective at inhibiting tumor growth. Elevated levels of resveratrol enhance its antitumor potency leading to tumor regression, associated with widespread tumor cell death, the underlying mechanism of which involves the direct activation of the mitochondrial intrinsic apoptotic pathway.

Repeatability of magnetic resonance elastography for quantification of hepatic stiffness.

To determine the sources of variability of MRE hepatic stiffness measurements using healthy volunteers and patients and to calculate the minimum change required for statistical significance. Hepatic stiffness measured with magnetic resonance elastography (MRE) has demonstrated tremendous potential as a noninvasive surrogate of hepatic fibrosis, although the underlying repeatability of MRE for longitudinal tracking of liver disease has not been documented.