Missing data in randomized clinical trials for weight loss: scope of the problem, state of the field, and performance of statistical methods.

BACKGROUND: Dropouts and missing data are nearly-ubiquitous in obesity randomized controlled trails, threatening validity and generalizability of conclusions. Herein, we meta-analytically evaluate the extent of missing data, the frequency with which various analytic methods are employed to accommodate dropouts, and the performance of multiple statistical methods. METHODOLOGY/PRINCIPAL FINDINGS: We searched PubMed and Cochrane databases (2000-2006) for articles published in English and manually searched bibliographic references. Articles of pharmaceutical randomized controlled trials with weight loss or weight gain prevention as major endpoints were included. Two authors independently reviewed each publication for inclusion. 121 articles met the inclusion criteria. Two authors independently extracted treatment, sample size, drop-out rates, study duration, and statistical method used to handle missing data from all articles and resolved disagreements by consensus. In the meta-analysis, drop-out rates were substantial with the survival (non-dropout) rates being approximated by an exponential decay curve (e(-lambdat)) where lambda was estimated to be .0088 (95% bootstrap confidence interval: .0076 to .0100) and t represents time in weeks. The estimated drop-out rate at 1 year was 37%. Most studies used last observation carried forward as the primary analytic method to handle missing data. We also obtained 12 raw obesity randomized controlled trial datasets for empirical analyses. Analyses of raw randomized controlled trial data suggested that both mixed models and multiple imputation performed well, but that multiple imputation may be more robust when missing data are extensive. CONCLUSION/SIGNIFICANCE: Our analysis offers an equation for predictions of dropout rates useful for future study planning. Our raw data analyses suggests that multiple imputation is better than other methods for handling missing data in obesity randomized controlled trials, followed closely by mixed models. We suggest these methods supplant last observation carried forward as the primary method of analysis.

The effect of involuntary job loss on smoking intensity and relapse.

AIMS: To assess the impact of involuntary job loss due to plant closure or layoff on relapse to smoking and smoking intensity among older workers. DESIGN, PARTICIPANTS, SAMPLE: Data come from the Health and Retirement Study, a nationally representative survey of older Americans aged 51-61 in 1991 followed every 2 years beginning in 1992. The 3052 participants who were working at the initial wave and had any history of smoking comprise the main sample. METHODS: Primary outcomes are smoking relapse at wave 2 (1994) among baseline former smokers, and smoking quantity at wave 2 among baseline current smokers. As reported at the wave 2 follow-up, 6.8% of the sample experienced an involuntary job loss between waves 1 and 2. FINDINGS: Older workers have over two times greater odds of relapse subsequent to involuntary job loss than those who did not. Further, those who were current smokers prior to displacement that did not obtain new employment were found to be smoking more cigarettes, on average, post-job loss. CONCLUSIONS: The stress of job loss, along with other significant changes associated with leaving one's job, which would tend to increase cigarette consumption, must outweigh the financial hardship which would tend to reduce consumption. This highlights job loss as an important health risk factor for older smokers.

Conservation, duplication, and loss of the Tor signaling pathway in the fungal kingdom.

BACKGROUND: The nutrient-sensing Tor pathway governs cell growth and is conserved in nearly all eukaryotic organisms from unicellular yeasts to multicellular organisms, including humans. Tor is the target of the immunosuppressive drug rapamycin, which in complex with the prolyl isomerase FKBP12 inhibits Tor functions. Rapamycin is a gold standard drug for organ transplant recipients that was approved by the FDA in 1999 and is finding additional clinical indications as a chemotherapeutic and antiproliferative agent. Capitalizing on the plethora of recently sequenced genomes we have conducted comparative genomic studies to annotate the Tor pathway throughout the fungal kingdom and related unicellular opisthokonts, including Monosiga brevicollis, Salpingoeca rosetta, and Capsaspora owczarzaki. RESULTS: Interestingly, the Tor signaling cascade is absent in three microsporidian species with available genome sequences, the only known instance of a eukaryotic group lacking this conserved pathway. The microsporidia are obligate intracellular pathogens with highly reduced genomes, and we hypothesize that they lost the Tor pathway as they adapted and streamlined their genomes for intracellular growth in a nutrient-rich environment. Two TOR paralogs are present in several fungal species as a result of either a whole genome duplication or independent gene/segmental duplication events. One such event was identified in the amphibian pathogen Batrachochytrium dendrobatidis, a chytrid responsible for worldwide global amphibian declines and extinctions. CONCLUSIONS: The repeated independent duplications of the TOR gene in the fungal kingdom might reflect selective pressure acting upon this kinase that populates two proteinaceous complexes with different cellular roles. These comparative genomic analyses illustrate the evolutionary trajectory of a central nutrient-sensing cascade that enables diverse eukaryotic organisms to respond to their natural environments.

Unprecedented loss of ammonia assimilation capability in a urease-encoding bacterial mutualist.

BACKGROUND: Blochmannia are obligately intracellular bacterial mutualists of ants of the tribe Camponotini. Blochmannia perform key nutritional functions for the host, including synthesis of several essential amino acids. We used Illumina technology to sequence the genome of Blochmannia associated with Camponotus vafer. RESULTS: Although Blochmannia vafer retains many nutritional functions, it is missing glutamine synthetase (glnA), a component of the nitrogen recycling pathway encoded by the previously sequenced B. floridanus and B. pennsylvanicus. With the exception of Ureaplasma, B. vafer is the only sequenced bacterium to date that encodes urease but lacks the ability to assimilate ammonia into glutamine or glutamate. Loss of glnA occurred in a deletion hotspot near the putative replication origin. Overall, compared to the likely gene set of their common ancestor, 31 genes are missing or eroded in B. vafer, compared to 28 in B. floridanus and four in B. pennsylvanicus. Three genes (queA, visC and yggS) show convergent loss or erosion, suggesting relaxed selection for their functions. Eight B. vafer genes contain frameshifts in homopolymeric tracts that may be corrected by transcriptional slippage. Two of these encode DNA replication proteins: dnaX, which we infer is also frameshifted in B. floridanus, and dnaG. CONCLUSIONS: Comparing the B. vafer genome with B. pennsylvanicus and B. floridanus refines the core genes shared within the mutualist group, thereby clarifying functions required across ant host species. This third genome also allows us to track gene loss and erosion in a phylogenetic context to more fully understand processes of genome reduction.

Comparison of a reduced carbohydrate and reduced fat diet for LDL, HDL, and VLDL subclasses during 9-months of weight maintenance subsequent to weight loss.

OBJECTIVES: This study compared LDL, HDL, and VLDL subclasses in overweight or obese adults consuming either a reduced carbohydrate (RC) or reduced fat (RF) weight maintenance diet for 9 months following significant weight loss. METHODS: Thirty-five (21 RC; 14 RF) overweight or obese middle-aged adults completed a 1-year weight management clinic. Participants met weekly for the first six months and bi-weekly thereafter. Meetings included instruction for diet, physical activity, and behavior change related to weight management. Additionally, participants followed a liquid very low-energy diet of approximately 2092 kJ per day for the first three months of the study. Subsequently, participants followed a dietary plan for nine months that targeted a reduced percentage of carbohydrate (approximately 20%) or fat (approximately 30%) intake and an energy intake level calculated to maintain weight loss. Lipid subclasses using NMR spectroscopy were analyzed prior to weight loss and at multiple intervals during weight maintenance. RESULTS: Body weight change was not significantly different within or between groups during weight maintenance (p>0.05). The RC group showed significant increases in mean LDL size, large LDL, total HDL, large and small HDL, mean VLDL size, and large VLDL during weight maintenance while the RF group showed increases in total HDL, large and small HDL, total VLDL, and large, medium, and small VLDL (p<0.05). Group*time interactions were significant for large and medium VLDL (p>0.05). CONCLUSION: Some individual lipid subclasses improved in both dietary groups. Large and medium VLDL subclasses increased to a greater extent across weight maintenance in the RF group.

Eco-evolutionary trophic dynamics: loss of top predators drives trophic evolution and ecology of prey.

Ecosystems are being altered on a global scale by the extirpation of top predators. The ecological effects of predator removal have been investigated widely; however, predator removal can also change natural selection acting on prey, resulting in contemporary evolution. Here we tested the role of predator removal on the contemporary evolution of trophic traits in prey. We utilized a historical introduction experiment where Trinidadian guppies (Poecilia reticulata) were relocated from a site with predatory fishes to a site lacking predators. To assess the trophic consequences of predator release, we linked individual morphology (cranial, jaw, and body) to foraging performance. Our results show that predator release caused an increase in guppy density and a "sharpening" of guppy trophic traits, which enhanced food consumption rates. Predator release appears to have shifted natural selection away from predator escape ability and towards resource acquisition ability. Related diet and mesocosm studies suggest that this shift enhances the impact of guppies on lower trophic levels in a fashion nuanced by the omnivorous feeding ecology of the species. We conclude that extirpation of top predators may commonly select for enhanced feeding performance in prey, with important cascading consequences for communities and ecosystems.

Low-loss directional cloaks without superluminal velocity or magnetic response.

The possibility of making an optically large (many wavelengths in diameter) object appear invisible has been a subject of many recent studies. Exact invisibility scenarios for large (relative to the wavelength) objects involve (meta)materials with superluminal phase velocity [refractive index (RI) less than unity] and/or magnetic response. We introduce a new approximation applicable to certain device geometries in the eikonal limit: piecewise-uniform scaling of the RI. This transformation preserves the ray trajectories but leads to a uniform phase delay. We show how to take advantage of phase delays to achieve a limited (directional and wavelength-dependent) form of invisibility that does not require loss-ridden (meta)materials with superluminal phase velocities.

Measurements of Epidural Space Depth Using Preexisting CT Scans Correlate with Loss of Resistance Depth during Thoracic Epidural Catheter Placement.

Background. Thoracic epidural catheters provide the best quality postoperative pain relief for major abdominal and thoracic surgical procedures, but placement is one of the most challenging procedures in the repertoire of an anesthesiologist. Most patients presenting for a procedure that would benefit from a thoracic epidural catheter have already had high resolution imaging that may be useful to assist placement of a catheter. Methods. This retrospective study used data from 168 patients to examine the association and predictive power of epidural-skin distance (ESD) on computed tomography (CT) to determine loss of resistance depth acquired during epidural placement. Additionally, the ability of anesthesiologists to measure this distance was compared to a radiologist, who specializes in spine imaging. Results. There was a strong association between CT measurement and loss of resistance depth (P < 0.0001); the presence of morbid obesity (BMI > 35) changed this relationship (P = 0.007). The ability of anesthesiologists to make CT measurements was similar to a gold standard radiologist (all individual ICCs > 0.9). Conclusions. Overall, this study supports the examination of a recent CT scan to aid in the placement of a thoracic epidural catheter. Making use of these scans may lead to faster epidural placements, fewer accidental dural punctures, and better epidural blockade.

When the library is located in prime real estate: a case study on the loss of space from the Duke University Medical Center Library and Archives.

The Duke University Medical Center Library and Archives is located in the heart of the Duke Medicine campus, surrounded by Duke Hospital, ambulatory clinics, and numerous research facilities. Its location is considered prime real estate, given its adjacency to patient care, research, and educational activities. In 2005, the Duke University Library Space Planning Committee had recommended creating a learning center in the library that would support a variety of educational activities. However, the health system needed to convert the library's top floor into office space to make way for expansion of the hospital and cancer center. The library had only five months to plan the storage and consolidation of its journal and book collections, while working with the facilities design office and architect on the replacement of key user spaces on the top floor. Library staff worked together to develop plans for storing, weeding, and consolidating the collections and provided input into renovation plans for users spaces on its mezzanine level. The library lost 15,238 square feet (29%) of its net assignable square footage and a total of 16,897 (30%) gross square feet. This included 50% of the total space allotted to collections and over 15% of user spaces. The top-floor space now houses offices for Duke Medicine oncology faculty and staff. By storing a large portion of its collection off-site, the library was able to remove more stacks on the remaining stack level and convert them to user spaces, a long-term goal for the library. Additional space on the mezzanine level had to be converted to replace lost study and conference room spaces. While this project did not match the recommended space plans for the library, it underscored the need for the library to think creatively about the future of its facility and to work toward a more cohesive master plan.