Coherent modeling of longitudinal causal effects on binary outcomes

Analyses of biomedical studies often necessitate modeling longitudinal causal effects. The current focus on personalized medicine and effect heterogeneity makes this task even more challenging. Toward this end, structural nested mean models (SNMMs) are fundamental tools for studying heterogeneous treatment effects in longitudinal studies. However, when outcomes are binary, current methods for estimating multiplicative and additive SNMM parameters suffer from variation dependence between the causal parameters and the noncausal nuisance parameters. This leads to a series of difficulties in interpretation, estimation, and computation. These difficulties have hindered the uptake of SNMMs in biomedical practice, where binary outcomes are very common. We solve the variation dependence problem for the binary multiplicative SNMM via a reparameterization of the noncausal nuisance parameters. Our novel nuisance parameters are variation independent of the causal parameters, and hence allow for coherent modeling of heterogeneous effects from longitudinal studies with binary outcomes. Our parameterization also provides a key building block for flexible doubly robust estimation of the causal parameters. Along the way, we prove that an additive SNMM with binary outcomes does not admit a variation independent parameterization, thereby justifying the restriction to multiplicative SNMMs.     

Effect of Ethnicity and Geographical Location on Body Weight,Dietary Restraint,and Abnormal Eating Attitudes

Previous studies have examined the effect of ethnicity on obesity, concerns about shape and weight, and attitudes about eating. We hypothesized that geographical location would also influence these variables, and that students growing up in the northern part of the United States and attending northern colleges would differ from students from the South. To examine this, we studied a random sample of 275 African-Americans (AA) and 224 white college students in the entering class of two northern colleges (University of Pittsburgh or University of Massachusetts) or two southern colleges (Augusta or Paine College). All subjects were weighed and completed the Revised Restraint Scale and the EAT-26. AA women were heavier than white women, with no differences due to geographical location. Despite being thinner, white women reported more dietary restraint than AA women. This difference between AA and white women was apparent in both northern and southern college students. In contrast, geographical location was the strongest determinant of bulimic attitudes; both men and women at northern colleges reported higher bulimia scores than those at southern schools. Thus ethnicity appears to be a major determinant of body weight and attitudes about shape and dieting, whereas geographical location appears to exert greater influence on bulimic attitudes.     

BLUE-GREEN ALGAL MATS IN A SMALL STREAM1

Bedrock erosional features in a small stream (Little Schultz Creek, Bibb County, Alabama) created a variety of habitats for epilithic growth. One suck habitat was illustrated by the occurrence of small falls (<0.3 m) in the main channel of the stream and blue-green algal mats associated with them. The cohesive, laminar algal mats were found at 15 such sites along a 250-m reach of the stream. The primary mat matrix consisted of the blue-green alga Oscillatoria submembranacea Ardissone and Strafforella. The uppermost portion of each mat consisted of a thin (<1 mm thick) green layer of biologically active filaments. The lower layers were thicker (up to 2 cm thick) and consisted of brown laminae of Oscillatoria filaments, and associated sediments. In addition, numerous diatoms mere associated with the mat surface. Some were loosely attached (e.g. Achnanthes); others (Cymbella tumida (Bréb.) V. H.) were stalked. These mats were present throughout the year and showed a bimodal annual distribution with maxima hi February and July. In February, total mat coverage was higher than in July. This winter maximum may have been related to a mode of growth dependent upon sedimentation from storm events and subsequent upward growth of the alga. Mat primary productivity on an areal basis (432 mg C · m^?2· d^?1 in March and 907 mg C · M^?2· d^?1 in April) was 2–12 times the maxima measured on epizoic and cobbles surfaces and other bedrock surfaces in the same stream. The limited areal coverage of the mats, when compared to other surfaces available for algal colonization, made them less important than other epilithic and epizoic surfaces in terms of total primary production in this stream reach. However, we propose that the combination of their unique structure and high primary productivity may make these algal mats sites of high algal and bacterial metabolic activity, which may include anaerobic processes in midchannel, where such activity would not be expected to occur.     

Steroid hormone responsiveness of a family of closely related mouse proviral elements

Regulation of the mouse sex-limited protein (Slp) gene is unusual in that hormone response is conferred by the 5′ LTR of an upstream inserted provirus, dubbed the imposon (imp1). In a search for additional genes whose regulation has been affected by retrotransposition events, we isolated two partial proviral elements by stringent screening of a mouse genomic library. One clone (imp2) contained a portion of the envelope gene and a 3′ LTR that was nearly identical to the 3′ LTR of imp1; this similarity extended to insertion into a B1 repetitive element. The second proviral clone (imp3) contained a 5′ LTR and associated coding sequences, but lacked its 3′ LTR; the LTR of imp3 differed by 12% from the imp1 sequence. To assess potential hormone response, proviral enhancer regions cloned into reporter vectors were tested in transfection. The imp2 enhancer was similar in behavior to imp1, conferring both androgen and glucocorticoid induction in one fragment context and an androgen-specific response in another. In contrast, the imp3 enhancer allowed high expression in the absence of hormone and was less responsive to steroids in general and androgen in particular. These three proviral elements define a small family of steroid responsive proviruses in the mouse genome, and at least one member has had a lasting impact on an endogenous gene's regulation. Received: 29 April 1997 / Accepted: 14 July 1997     

Assessing the consultation: method for measuring changes in patient stress and arousal.

A method has been developed to assess anxiety levels in terms of stress and arousal in patients before and after a consultation with a general practitioner. The MACL self report mood scale has been used in hospital outpatient studies. An adaptation of the scale using 26 items of low vocabulary was applied to general practice patients in a novel way to show appreciable reductions in stress and increases in arousal after consultations. Since arousal is related to efficiency of performance and stress has been inversely related to recall of information given in the consultation factors that affect stress and arousal in patients could usefully be identified.     

Biosynthesis and localization of lactate dehydrogenase X in pachytene spermatocytes and spermatids of mouse testes

The presence and biosynthesis of the testis-specific isozyme of lactate dehydrogenase (LDH-X) in cells at various stages of spermatogenesis have been examined. Enrichment of testicular cells in various stages of spermatogenesis has been achieved by two methods: (1) cell separation by velocity sedimentation in the Elutriator rotor and (2) γ irradiation of testes to eliminate specific classes of testicular cells. Separation of cells from immature mice indicated that cells prior to the midpachytene stage contain no LDH-X. Measurement of LDH-X levels in cells separated from adult mice and in testicular homogenates prepared at various times after irradiation indicated that the highest level of LDH-X per cell (normalized for DNA content) was in spermatids. Synthesis of LDH-X was determined, after in vivo injection of [³H]valine, by measurement of the radioactivity in LDH-X precipitated with specific antiserum. After irradiation, the rate of LDH-X synthesis remained constant, despite the loss of early primary spermatocytes. In separated cells, the rate of LDH-X synthesis was highest in late pachytene spermatocytes, lower in round spermatids, and even lower, but still significant, in elongated spermatids. Therefore, the synthesis of LDH-X begins at a specific point during spermatogenesis, the midpachytene stage of spermatocyte development, and continues throughout spermatid differentiation.     

Analysis of the reducible components of the muscle protein, connectin: absence of lysine-derived cross-links

After exhaustive salt extractions of rabbit and human skeletal muscle, the amino acid compositions of the residual proteins were similar to those reported for connectin. Complete removal of collagen contamination was achieved only after treatment of the connectin preparations with bacterial collagenase. On reduction with KB³H₄, the small amounts of lysine-derived reducible cross-links that were present in the initial connectin preparations were completely absent after treatment with collagenase. In adult human connectin some hexitol-lysine derivatives were present after reduction. These results indicate that, in contrast to previous reports, connectin does not participate in the same lysyl oxidase-mediated cross-linking system that occurs in collagen and elastin.     

Measurement of the rates of protein synthesis in rabbits. A method for the estimation of rates of change in the specific radioactivities of free amino acids during continuous infusions.

1. A method is described by which, from analysis of terminal samples, the rate constants that define the changes in specific radioactivity of free amino acids during continuous infusions can be estimated. The method involves the infusion of 3H-labelled and 14C-labelled forms of an amino acid for different, but overlapping, periods. 2. The procedure was developed for infusions of proline and tyrosine into New Zealand White rabbits and the rate constants were determined for blood and muscle. 3. The rate constant for equilibrium of radioactive free proline was much lower in muscle than in blood, and indicated that a plateau condition may not be attained in muscle by the end of a 6 h infusion. 4. Comparison of the ratio of areas under the curves of estimated specific radioactivity plotted versus time with the 3H/14C ratio of bound amino acid in muscle protein suggested that radioactive proline and tyrosine may be incorporated preferentially from an extracellular rather than an intracellular source.     

The role of glutathione in amino-acid absorption. Lack of correlation between glutathione turnover and amino-acid absorption by the yeast Candida utilis.

The rate of degradation of glutathione has been determined in the yeast Candida utilis by using a method that minimizes the effect of amino-acid recycling. When yeast are grown in amino-acid-free medium, the half-life of glutathione was found to be 230 min. C. utilis was also found to absorb various L-amino acids rapidly without producing any significant decrease in the half-life of glutathione. While the gamma-glutamyl cycle is thus operating in C. utilis, the rate of degradation of glutathione is found to be 100 times too slow for the cycle to be mediating the transport of these amino acids.