Understanding and avoiding the "weights of regression": Heterogeneous effects, misspecification, and longstanding solutions

Researchers in many fields endeavor to estimate treatment effects by regressing outcome data (Y) on a treatment (D) and observed confounders (X). Even absent unobserved confounding, the regression coefficient on the treatment reports a weighted average of strata-specific treatment effects (Angrist, 1998). Where heterogeneous treatment effects cannot be ruled out, the resulting coefficient is thus not generally equal to the average treatment effect (ATE), and is unlikely to be the quantity of direct scientific or policy interest. The difference between the coefficient and the ATE has led researchers to propose various interpretational, bounding, and diagnostic aids (Humphreys, 2009; Aronow and Samii, 2016; Sloczynski, 2022; Chattopadhyay and Zubizarreta, 2023). We note that the linear regression of Y on D and X can be misspecified when the treatment effect is heterogeneous in X. The "weights of regression", for which we provide a new (more general) expression, simply characterize how the OLS coefficient will depart from the ATE under the misspecification resulting from unmodeled treatment effect heterogeneity. Consequently, a natural alternative to suffering these weights is to address the misspecification that gives rise to them. For investigators committed to linear approaches, we propose relying on the slightly weaker assumption that the potential outcomes are linear in X. Numerous well-known estimators are unbiased for the ATE under this assumption, namely regression-imputation/g-computation/T-learner, regression with an interaction of the treatment and covariates (Lin, 2013), and balancing weights. Any of these approaches avoid the apparent weighting problem of the misspecified linear regression, at an efficiency cost that will be small when there are few covariates relative to sample size. We demonstrate these lessons using simulations in observational and experimental settings

Cavernous Hemangioma of the Conjunctiva

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Under-nutrition among adolescents: a survey in five secondary schools in rural Goa.

BACKGROUND: This study was done in 2008-09 to assess the nutritional status among adolescents (10-19 years of age, Classes V-XII) in 5 schools in rural Goa to inform the content of a health promotion intervention in these schools. METHODS: Three methods were used. First, nutritional status was measured by assessing body mass index among 1015 students during a health camp in each school. Second, a diet analysis was done to measure energy and protein Intake of 76 randomly selected underweight students. Third, a self-report questionnaire survey measured the prevalence of hunger among 684 students. RESULTS: One-third of students (338; 37.8% boys and 27.5% girls) who attended the health camps were underweight and 59.2% of the 684 students who completed the survey reported experiencing hunger due to inadequate food consumption. More boys were underweight than girls (p<0.001) and under-nutrition was uniform across all the years of schooling. Energy intake of underweight students was significantly lower than the recommended daily allowance. The results were shared with the School Health Promotion Advisory Boards to generate information on the stakeholders' perception about the issue and ways to address it. CONCLUSION: There is an immediate need to address the high burden of hunger and under-nutrition in adolescents of both sexes in schools by instituting routine annual monitoring of nutritional status, extending the mid-day meal programme to all school-going adolescents, providing nutritional counselling for underweight adolescents and expanding research on the causes and impact of under-nutrition and evaluation of the impact of the enhanced mid-day meal programme

The ERAD Inhibitor Eeyarestatin I Is a Bifunctional Compound with a Membrane-Binding Domain and a p97/VCP Inhibitory Group

Protein homeostasis in the endoplasmic reticulum (ER) has recently emerged as a therapeutic target for cancer treatment. Disruption of ER homeostasis results in ER stress, which is a major cause of cell death in cells exposed to the proteasome inhibitor Bortezomib, an anti-cancer drug approved for treatment of multiple myeloma and Mantle cell lymphoma. We recently reported that the ERAD inhibitor Eeyarestatin I (EerI) also disturbs ER homeostasis and has anti-cancer activities resembling that of Bortezomib.Here we developed in vitro binding and cell-based functional assays to demonstrate that a nitrofuran-containing (NFC) group in EerI is the functional domain responsible for the cytotoxicity. Using both SPR and pull down assays, we show that EerI directly binds the p97 ATPase, an essential component of the ERAD machinery, via the NFC domain. An aromatic domain in EerI, although not required for p97 interaction, can localize EerI to the ER membrane, which improves its target specificity. Substitution of the aromatic module with another benzene-containing domain that maintains membrane localization generates a structurally distinct compound that nonetheless has similar biologic activities as EerI.Our findings reveal a class of bifunctional chemical agents that can preferentially inhibit membrane-bound p97 to disrupt ER homeostasis and to induce tumor cell death. These results also suggest that the AAA ATPase p97 may be a potential drug target for cancer therapeutics

Preclinical Pharmacology of BA-TPQ, a Novel Synthetic Iminoquinone Anticancer Agent

Marine natural products and their synthetic derivatives represent a major source of novel candidate anti-cancer compounds. We have recently tested the anti-cancer activity of more than forty novel compounds based on an iminoquinone makaluvamine scaffold, and have found that many of the compounds exert potent cytotoxic activity against human cancer cell lines. One of the most potent compounds, BA-TPQ [(11,12),7-(benzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one], was active against a variety of human cancer cell lines, and inhibited the growth of breast and prostate xenograft tumors in mice. However, there was some toxicity noted in the mice following administration of the compound. In order to further the development of BA-TPQ, and in a search for potential sites of accumulation that might underlie the observed toxicity of the compound, we accomplished preclinical pharmacological studies of the compound. We herein report the in vitro and in vivo pharmacological properties of BA-TPQ, including its stability in plasma, plasma protein binding, metabolism by S9 enzymes, and plasma and tissue distribution. We believe these studies will be useful for further investigations, and may be useful for other investigators examining the use of similar compounds for cancer therapy

Synthesis of the Marine Pyrroloiminoquinone Alkaloids, Discorhabdins

Many natural products with biologically interesting structures have been isolated from marine animals and plants such as sponges, corals, worms, etc. Some of them are discorhabdin alkaloids. The discorhabdin alkaloids (discorhabdin A-X), isolated from marine sponges, have a unique structure with azacarbocyclic spirocyclohexanone and pyrroloiminoquinone units. Due to their prominent potent antitumor activity, discorhabdins have attracted considerable attention. Many studies have been reported toward the synthesis of discorhabdins. We have accomplished the first total synthesis of discorhabdin A (1), having the strongest activity in vitro among discorhabdins in 2003. In 2009, we have also accomplished the first total synthesis of prianosin B (2), having the 16,17-dehydropyrroloiminoquinone moiety, by a novel dehydrogenation reaction with a catalytic amount of NaN3. These synthetic studies, as well as syntheses of the discorhabdins by various chemists to-date, are reviewed here

Cissus extracts in dentistry: A comprehensive review on its untapped potential

Natural products have received a lot of attention in a variety of medical sectors, including dentistry. Cissus, a flowering plant genus, has long been used for its therapeutic benefits. The purpose of this review is to thoroughly investigate the possibilities of Cissus extracts in dentistry. To that end, we used specific selection criteria for the selection of pertinent scientific articles published in the scientific information databases of PubMed, Web of Science, Google Scholar, Scopus, and ProQuest. We found that the diverse array of bioactive compounds found in varied species of Cissus holds promise for applications ranging from oral wound healing to periodontal health. This review summarizes known studies on antibacterial, anti-inflammatory, and tissue-regenerative characteristics of Cissus extracts, shedding light on their potential significance in modernizing modern dental practices. It exerts that Cissus extracts have the potential to supplement established dentistry therapies by providing all-natural remedies for a variety of oral health conditions