High-density data acquisition system and signal preprocessor for interfacing with microelectromechanical system-based biosensor arrays.

Microelectromechanical system (MEMS) development has become an active area for research in over the last decade. This area has advanced rapidly in recent years due to the potential ability of MEMS devices to perform complex functions in a smaller area. There is also the prospect to develop devices that can (1) be easily manufactured, (2) offer low power consumption, and (3) reduce waste. Especially in the BioMEMS area these advantages are important in terms of applied devices for biosensing, clinical diagnostics, physiological sensing, flow cytometry, and other lab-on-a-chip applications. However, one major obstacle that has been overlooked is the interface of these microdevices with the macroworld. This is critical to enable applications and development of the technology, as currently testing and analysis of data from these devices is mostly limited to generic microprobe stations. New advancements in BioMEMS have to occur in concert with the development of data acquisition systems and signal preprocessors to fully appreciate and test these developing technologies. In this work, we present the development of a cost effective, high throughput data acquisition system (Bio-HD DAQ) and a signal preprocessor for a MEMS-based cell electrophysiology lab-on-a-Chip (CEL-C) device. The signal preprocessor consists of a printed circuit board mounted with the CEL-C device and a 64-channel filter/amplifier circuit array. The data acquisition system includes a high-density crosspoint switching matrix that connects the signal preprocessor to a 16-channel, 18 bit, and 625 kSs DAQ card. Multimodule custom software designed on LABVIEW 7.0 is used to control the DAQ system. While this version of the Bio-HD DAQ system and accompanying software are designed keeping in view the specific requirements of the CEL-C device, it is highly adaptable and, with minor modifications, can become a generic data acquisition system for MEMS development, testing, and application.

Meta-analysis of sib pair linkage studies of asthma and the interleukin-9 gene (IL9).

Asthma is a complex disease, with an etiology that includes both genetic and environmental influences that may interact. The moderate heritability of asthma has led researchers to investigate its molecular genetic basis using both exploratory investigations of linkage via genome scans, as well as targeted studies of specific candidate genes. Promising candidate genes include the cytokine genes on chromosome 5q23-31. Both genome scans and association studies of these candidate genes/genomic regions have yielded mixed findings, which raise the possibilities of a true relation that emerges more strongly in certain samples simply due to sampling variability, as well as of genetic heterogeneity. Meta-analytic approaches that combine data across samples and examine how findings may vary as a function of effect modifiers can address both of these possibilities. In this study, we used a meta-analytic approach to examine linkage between the interleukin-9 gene (IL9), one of the cytokine genes located on chromosome 5q31, and asthma diagnoses and serum IgE levels in four samples. We analyzed IBD allele sharing for affected, unaffected, and discordant sib pairs, and as a function of sibling differences in IgE levels. We used a recently developed logistic regression-based method that allows for the inclusion of covariates and/or effect modifiers in the analysis of allele sharing in sib-pairs [Rice et al., Genet Epidemiol 17(Suppl. 1):S691-5, 1999]. Sex of the siblings and transmitting parent were considered both as covariates and effect modifiers in analyses. The results provided little evidence for linkage, or for heterogeneity therein due to sex or transmitting parent, either within or across samples.

The Williams syndrome cognitive profile.

Williams syndrome is a rare neurodevelopmental disorder caused by a hemizygous deletion of approximately 1.5 megabases on chromosome 7q11.23. In this article, we outline a Williams Syndrome Cognitive Profile (WSCP) that operationalizes the cognitive characteristics of the syndrome using measures of absolute and relative performance on subtests of the Differential Abilities Scales (Elliot, 1990a). Testing confirmed excellent sensitivity and specificity scores for the WSCP. Seventy-four of 84 individuals with Williams syndrome fit the WSCP while only 4 participants in a contrast group met all of the WSCP criteria. It was also found that the WSCP does not vary greatly with chronological age or overall level of cognitive ability for individuals with Williams syndrome. Possible applications for the WSCP include psychoeducational evaluation and empirical research such as the search for genotype/phenotype relations in this genetically based syndrome.

Expressive vocabulary ability of toddlers with Williams syndrome or Down syndrome: a comparison.

School-aged children and adults with Williams syndrome have repeatedly been found to evidence an expressive vocabulary advantage relative to same-aged individuals with Down syndrome. However, Singer Harris, Bellugi, Bates, Jones, and Rossen (1997) argued that this advantage is reversed during the initial period of language acquisition; during this time, children with Down syndrome have larger expressive vocabularies than children with Williams syndrome. This result may have been due to methodological problems, however. This study uses a different design to reconsider the question of whether toddlers with Williams syndrome show an expressive vocabulary advantage over same-aged toddlers with Down syndrome. Parents of twenty-four 2-year-olds with Williams syndrome and twenty-eight 2-year-olds with Down syndrome completed the vocabulary checklist from the MacArthur Communicative Development Inventory: Words and Sentences. The 2 groups were carefully matched for chronological age (CA). Results indicated that the toddlers with Williams syndrome had substantially and significantly larger expressive vocabulary sizes than did the CA-matched children with Down syndrome. Additional analyses of children for whom data were available between the ages of 2 years 0 months and 2 years 3 months indicated that the expressive vocabulary advantage for children with Williams syndrome was present even at this very young age when none of the children had begun to produce word combinations. The Discussion section that follows addresses the discrepancy between these findings and those of Singer Harris et al. and considers the variability present within both the Williams syndrome and Down syndrome samples. Also discussed is the continuity across the lifespan in both the expressive vocabulary advantage shown by individuals with Williams syndrome relative to same-aged individuals with Down syndrome and the expressive vocabulary variability within each syndrome.

A logistic regression extension of the transmission disequilibrium test for continuous traits: application to linkage disequilibrium between alcoholism and the candidate genes DRD2 and ADH3.

The transmission disequilibrium test (TDT) recently has become a popular method of testing for linkage in the presence of association due to its simplicity and advantages over other within-family analytic methods. In this paper, we describe a logistic regression extension to the TDT that can be used to test for differences in linkage disequilibrium as a function of one or more continuous and/or categorical explanatory variables. We highlight important features of this method and demonstrate some of its possible uses. We applied these analyses to test for linkage disequilibrium between the dopamine receptor D2 (DRD2) and alcohol dehydrogenase 3 (ADH3) genes and both diagnostic and quantitative indices of alcoholism. Using data from the Collaborative Study on the Genetics of Alcoholism data set, we found evidence suggesting linkage disequilibrium between DRD2 and ADH3 and quantitative indices of alcoholism and correlated phenotypes corresponding to smoking and personality. None of the evidence for linkage disequilibrium varied by sex or age.

Methodological issues in cross-syndrome comparisons: matching procedures, sensitivity (Se), and specificity (Sp).

We are impressed with the magnitude and potential importance of the studies presented by Sigman and Ruskin in this monograph. The within-syndrome findings for the children with autism concerning relations between early joint attention and a range of cognitive abilities a full 9 years later provide the strongest evidence so far that early nonverbal communication skills play an important role in the later development of language, intelligence, and social relations with peers. The purpose of the monograph was not limited to within-syndrome research questions, however. Sigman and Ruskin state that a major goal of the research reported in the monograph was to identify specific, unique, and universal deficits for autism and Down syndrome. They base their method of identifying such syndrome characteristics on the group-matching procedure. Given that this procedure is fraught with difficulties, we are concerned that many of Sigman and Ruskin's cross-syndrome comparisons may be incorrect. We do not mean to single out Sigman and Ruskin. The group-matching method is frequently used in special populations research, with the null hypothesis of no differences on the control variable being accepted at dangerously low p values. Our concerns with the group-matching problem extend to much of the extant research that attempts to identify characteristics of individuals based on the performance of their syndrome group relative to a control group. The profiling procedure we outlined seems more fruitful and conceptually satisfying than the traditional matching method. When profiling is not possible, however, it is important to consider the impact of CA confounds and statistical decision procedures used to ensure matching on the control variable, when interpreting syndrome differences on variables of interest.

Comparing productive vocabulary measures from the CDI and a systematic diary study.

Expressive vocabulary data gathered during a systematic diary study of one male child's early language development are compared to data that would have resulted from longitudinal administration of the MacArthur Communicative Development Inventories spoken vocabulary checklist (CDI). Comparisons are made for (1) the number of words at monthly intervals (9; 10.15 to 2; 0.15), (2) proportion of words by lexical class (i.e. noun, predicate, closed class, 'other'), (3) growth curves. The CDI underestimates the number of words in the diary study, with the underestimation increasing as vocabulary size increases. The proportion of diary study words appearing on the CDI differed as a function of lexical class. Finally, despite the differences in vocabulary size, logistic curves proved to be the best fitting model to characterize vocabulary development as measured by both the diary study and the CDI. Implications for the longitudinal use of the CDI are discussed.

A logistic regression based extension of the TDT for continuous and categorical traits.

The transmission disequilibrium test (TDT), designed as a test of linkage in the presence of association (i.e. linkage disequilibrium), has received considerable attention in the recent statistical genetics literature due to its advantages over other within-family analytic methods. One limitation of the conventional TDT is its application solely to linkage disequilibrium between a genetic marker and a single categorical trait (e.g. presence or absence of a disease). In this paper, we present an extension of the TDT using logistic regression to examine the relation between a candidate gene or genetic marker and one or more continuous or categorical explanatory variables. This logistic regression extension of the TDT possesses all of the desirable features of the conventional TDT, as well as many advantages associated with traditional regression analysis. We describe the model and its properties, as well as a number of its possible applications, and apply it to examine linkage disequilibrium between the dopamine receptor D2 gene (DRD2) and symptoms of childhood attention deficit hyperactivity disorder (ADHD). We also briefly compare the logistic regression TDT to other quantitative TDTs that have been proposed in the literature, and highlight the advantages of a regression-based approach for examining the relation between a candidate gene and one or more continuous or categorical traits. Given its features, we regard the logistic regression extension of the TDT as a flexible new data analytic method with extensive potential applications to problems in medical, psychiatric, and behavioral genetics.

Disentangling early language development: modeling lexical and grammatical acquisition using an extension of case-study methodology.

The early lexical and grammatical development of 1 male child is examined with growth curves and dynamic-systems modeling procedures. Lexical-development described a pattern of logistic growth (R2 = .98). Lexical and plural development shared the following characteristics: Plural growth began only after a threshold was reached in vocabulary size; lexical growth slowed as plural growth increased. As plural use reached full mastery, lexical growth began again to increase. It was hypothesized that a precursor model (P. van Geert, 1991) would fit these data. Subsequent testing indicated that the precursor model, modified to incorporate brief yet intensive plural growth, provided a suitable fit. The value of the modified precursor model for the explication of processes implicated in language development is discussed.

Linkage disequilibrium between the dopamine transporter gene (DAT1) and bipolar disorder: extending the transmission disequilibrium test (TDT) to examine genetic heterogeneity.

Since its introduction into the statistical genetics literature, the transmission disequilibrium test (TDT) has seen widespread use in analyses of linkage and association due not only to its simplicity but also to its desirable properties relative to other within-family analytic methods. In this paper, we describe an extension to the TDT useful for examining genetic heterogeneity. This extension uses contingency table analyses such as log-linear analysis to test for differences in linkage disequilibrium across levels of one or more moderator variables. We applied these analyses to test for linkage disequilibrium between the dopamine transporter gene (DAT1) and bipolar disorder, as well as for genetic heterogeneity due to sex, diagnostic breadth, and study site. Using data from two studies (the UCSD/UBC and Cardiff data sets), we found evidence suggesting linkage disequilibrium between DAT1 and bipolar disorder, as well as heterogeneity due to diagnostic breadth and study site.

LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition.

To identify genes important for human cognitive development, we studied Williams syndrome (WS), a developmental disorder that includes poor visuospatial constructive cognition. Here we describe two families with a partial WS phenotype; affected members have the specific WS cognitive profile and vascular disease, but lack other WS features. Submicroscopic chromosome 7q11.23 deletions cosegregate with this phenotype in both families. DNA sequence analyses of the region affected by the smallest deletion (83.6 kb) revealed two genes, elastin (ELN) and LIM-kinase1 (LIMK1). The latter encodes a novel protein kinase with LIM domains and is strongly expressed in the brain. Because ELN mutations cause vascular disease but not cognitive abnormalities, these data implicate LIMK1 hemizygosity in imparied visuospatial constructive cognition.

Mapping the meanings of novel visual symbols by youth with moderate or severe mental retardation.

The word-learning ability of 12 school-age subjects with moderate or severe mental retardation was assessed. Subjects had little or no functional speech and used the System for Augmenting Language with visual-graphic symbols for communication. Their ability to fast map novel symbols revealed whether they possessed the novel name-nameless category (N3C) lexical operating principle. On first exposure, 7 subjects were able to map symbol meanings for novel objects. Follow-up assessments indicated that mappers retained comprehension of some of the novel words for up to delays of 15 days and generalized their knowledge to production. Ability to fast map reliably was related to symbol achievement status. Implications for understanding vocabulary acquisition by youth with mental retardation were discussed.

Cholesterol:phospholipid ratio is elevated in platelet plasma membrane in patients with hypertension.

The cholesterol:phospholipid ratio was measured in platelet plasma membrane, red blood cell (RBC) membranes, low density lipoprotein (LDL) and whole plasma in patients with primary hypertension and in matched normal controls. The cholesterol:phospholipid ratio was raised in the platelet membrane from hypertensive patients compared with that from normal controls (0.65 +/- 0.03 vs 0.53 +/- 0.02: mean +/- SEM; P less than 0.01). The ratio observed in RBC membranes, LDL and whole blood was similar in the two groups. If this abnormality in the lipid composition of platelet plasma membrane is present in other cells it could account for some of the changes in cell membrane function that have been described in hypertension.

Autoregulation in the human forearm: differences between normal subjects and patients with hypertension.

Autoregulation was assessed in the forearm vascular bed of 16 men with normal arterial pressure and 19 patients with hypertension. The perfusion pressure was varied by changing the height of the forearm above the heart and blood flow was measured by venous occlusion plethysmography. In normal subjects, autoregulation was weak and flow usually increased more than pressure. In the hypertensive patients autoregulation was, on average, better than in the normal subjects, but the responses varied widely; in some patients, blood flow fell as pressure increased. The pattern of responses observed in the patients could be the result of a functional change in the smooth muscle, but it could also be the result of an increased wall: lumen ratio in the resistance vessels.

Differences in response to dilator agents in blood vessels of different types: physiological bases for selectivity.

Differences in the activation systems by which contraction is maintained in blood vessels of different types are an important cause of selectivity in the action of dilator agents. The sympathetic nervous system is the main stimulus for contraction in the limb veins whereas intrinsic (or myogenic) tone makes an important contribution to the contraction of resistance vessels. Drugs that inhibit the effect of the sympathetic nervous system are therefore selective dilators of the veins and drugs that prevent membrane depolarization or block calcium channels are strongly selective for resistance vessels. Substances such as the nitrovasodilators that increase intracellular concentrations of cyclic (c)GMP act preferentially on the veins. Those that act by increasing the concentrations of cyclic (c)AMP show little selectivity unless, as with the beta-adrenoceptor agonists, they act through receptors whose distribution varies between vessels. Differences in the distribution of receptors may also be important in the action of some other vasoactive substances such as the prostaglandins.

Is the increased responsiveness to verapamil in the forearm resistance vessels of patients with hypertension a consequence of structural change?

A mathematical model has been developed that relates wall tension in resistance vessels to changes in both distending pressure and flow; the effect of alterations in wall: lumen ratio is taken into account. The model indicates that increased autoregulatory activity in the forearm circulation of patients with primary hypertension could result from an increased response of the vascular smooth muscle to increased intraluminal pressure, but it could be accounted for by an increase in wall:lumen ratio from about 0.2 to 0.3. When the effect of the same increase in wall:lumen ratio on response to dilator agents is examined, it appears that the enhanced response to verapamil could be accounted for by structural change and there is no need to postulate a functional change. If this view is correct, however, it becomes necessary to assume a reduced response of the vascular smooth muscle to sodium nitroprusside in patients with hypertension if the unchanged dilator effect of this drug is to be explained.

Verapamil and bendrofluazide in the treatment of hypertension: a controlled study of effectiveness alone and in combination.

The effects of verapamil and bendrofluazide used singly and in combination were examined in patients with primary hypertension in a patient blind, partly observer blind placebo controlled study of parallel group design; there were ten subjects in each arm of the trial. Verapamil 160 mg twice daily caused supine mean arterial pressure to fall by 21 mmHg; this reduction was significantly greater (p less than 0.05) than that induced by bendrofluazide 5 mg daily which caused a fall of only 10 mmHg. The addition of verapamil 160 mg twice daily to bendrofluazide 5 mg daily caused a further fall in pressure of 18 mmHg (p less than 0.005), but the reduction in pressure when bendrofluazide was added to verapamil was only 1 mmHg and not significant. Bendrofluazide therapy caused a fall in plasma potassium concentration and an increase in plasma urate concentration; urinary calcium excretion was reduced. Verapamil caused no detectable biochemical alterations in plasma or urine.