Personal Dense Dynamic Data Clouds Connect Systems Biomedicine to Scientific Wellness.

The dramatic convergence of molecular biology, genomics, proteomics, metabolomics, bioinformatics, and artificial intelligence has provided a substrate for deep understanding of the biological basis of health and disease. Systems biology is a holistic, dynamic, integrative, cross-disciplinary approach to biological complexity that embraces experimentation, technology, computation, and clinical translation. Systems Medicine integrates genome analyses and longitudinal deep phenotyping with biological pathways and networks to understand mechanisms of disease, identify relevant blood biomarkers, define druggable molecular targets, and enhance the maintenance or restoration of wellness. Two programs initiated our understanding of data-driven population-based wellness. The Pioneer 100 Study of Scientific Wellness and the much larger Arivale commercial program that followed had two spectacular results: demonstrating the feasibility and utility of collecting longitudinal multiomic data, and then generating dense, dynamic data clouds for each individual to utilize actionable metrics for promoting health and preventing disease when combined with personalized coaching. Future developments in these domains will enable better population health and personal, preventive, predictive, participatory (P4) health care.

The NIH National Center for Integrative Biomedical Informatics (NCIBI).

The National Center for Integrative and Biomedical Informatics (NCIBI) is one of the eight NCBCs. NCIBI supports information access and data analysis for biomedical researchers, enabling them to build computational and knowledge models of biological systems to address the Driving Biological Problems (DBPs). The NCIBI DBPs have included prostate cancer progression, organ-specific complications of type 1 and 2 diabetes, bipolar disorder, and metabolic analysis of obesity syndrome. Collaborating with these and other partners, NCIBI has developed a series of software tools for exploratory analysis, concept visualization, and literature searches, as well as core database and web services resources. Many of our training and outreach initiatives have been in collaboration with the Research Centers at Minority Institutions (RCMI), integrating NCIBI and RCMI faculty and students, culminating each year in an annual workshop. Our future directions include focusing on the TranSMART data sharing and analysis initiative.

Considering the case for vitamin B12 fortification of flour.

Reasons to fortify flour with vitamin B12 are considered, including the high prevalence of depletion and deficiency of this vitamin that occurs in persons of all ages in resource-poor countries and in the elderly in wealthier countries, and the adverse functional consequences of poor vitamin B12 status. From a global perspective, the main cause of inadequate intake and status is a low intake of animal-source foods; even lacto-ovo vegetarians have lower serum vitamin B12 concentrations than omnivores, and for various reasons many populations have limited consumption of animal-source foods. Infants are vitamin B12-depleted from early infancy if their mothers' vitamin B12 status and intake are poor during pregnancy and lactation. Even in the United States, more than 20% of the elderly have serum vitamin B12 concentrations that indicate depletion, and an additional 6% have deficiency, primarily due to gastric atrophy, which impairs the absorption of the vitamin from food but usually not from supplements or fortified foods. Although the evidence is limited, it shows that fortified flour, consumed as bread, can improve vitamin B12 status. Where vitamin B12 fortification is implemented, the recommendation is to add 20 microg/kg flour, assuming consumption of 75 to 100 g flour per day, to provide 75% to 100% of the Estimated Average Requirement; the amount of the vitamin that can be added is limited by its cost. The effectiveness of this level of addition for improving vitamin B12 status in programs needs to be determined and monitored. In addition, further research should evaluate the bioavailability of the vitamin from fortified flour by elderly people with food cobalamin malabsorption and gastric atrophy.

Overview of the HUPO Plasma Proteome Project: results from the pilot phase with 35 collaborating laboratories and multiple analytical groups, generating a core dataset of 3020 proteins and a publicly-available database.

HUPO initiated the Plasma Proteome Project (PPP) in 2002. Its pilot phase has (1) evaluated advantages and limitations of many depletion, fractionation, and MS technology platforms; (2) compared PPP reference specimens of human serum and EDTA, heparin, and citrate-anti-coagulated plasma; and (3) created a publicly-available knowledge base (www.bioinformatics.med.umich.edu/hupo/ppp; www.ebi.ac.uk/pride). Thirty-five participating laboratories in 13 countries submitted datasets. Working groups addressed (a) specimen stability and protein concentrations; (b) protein identifications from 18 MS/MS datasets; (c) independent analyses from raw MS-MS spectra; (d) search engine performance, subproteome analyses, and biological insights; (e) antibody arrays; and (f) direct MS/SELDI analyses. MS-MS datasets had 15 710 different International Protein Index (IPI) protein IDs; our integration algorithm applied to multiple matches of peptide sequences yielded 9504 IPI proteins identified with one or more peptides and 3020 proteins identified with two or more peptides (the Core Dataset). These proteins have been characterized with Gene Ontology, InterPro, Novartis Atlas, OMIM, and immunoassay-based concentration determinations. The database permits examination of many other subsets, such as 1274 proteins identified with three or more peptides. Reverse protein to DNA matching identified proteins for 118 previously unidentified ORFs. We recommend use of plasma instead of serum, with EDTA (or citrate) for anticoagulation. To improve resolution, sensitivity and reproducibility of peptide identifications and protein matches, we recommend combinations of depletion, fractionation, and MS/MS technologies, with explicit criteria for evaluation of spectra, use of search algorithms, and integration of homologous protein matches. This Special Issue of PROTEOMICS presents papers integral to the collaborative analysis plus many reports of supplementary work on various aspects of the PPP workplan. These PPP results on complexity, dynamic range, incomplete sampling, false-positive matches, and integration of diverse datasets for plasma and serum proteins lay a foundation for development and validation of circulating protein biomarkers in health and disease.

Predictors of lung cancer among asbestos-exposed men in the {beta}-carotene and retinol efficacy trial.

Despite numerous published studies, debate continues regarding the risk of developing lung cancer among men exposed occupationally to asbestos, particularly those without radiographic or functional evidence of asbestosis. The beta-Carotene and Retinol Efficacy Trial (CARET), a study of vitamin supplementation for chemoprevention of lung cancer, has followed 4,060 heavily exposed US men for 9-17 years. Lung cancer incidence for 1989-2002 was analyzed using a stratified proportional hazards model. The study confirmed excessive rates of lung cancer among men with radiographic asbestosis. Comparison of study arms revealed a strong, unanticipated synergy between radiographic profusion category and the active intervention. In the large subgroup of men with normal lung parenchyma on chest radiograph at baseline, there was evidence of exposure-related lung cancer risk: Men with more than 40 years' exposure in high-risk trades had a risk approximately fivefold higher than men with 5-10 years, after adjustment for covariates. The effect in these men was independent of study intervention arm, but pleural plaques on the baseline radiograph and abnormal baseline flow rate were strong independent predictors of subsequent lung cancer. Residual confounding by subclinical asbestosis, exposure to unmeasured lung carcinogens, or differences in smoking are unlikely to explain these observations better than a carcinogenic effect of asbestos per se.

The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements.

BACKGROUND: The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the effect of daily beta-carotene (30 mg) and retinyl palmitate (25,000 IU) on the incidence of lung cancer, other cancers, and death in 18,314 participants who were at high risk for lung cancer because of a history of smoking or asbestos exposure. CARET was stopped ahead of schedule in January 1996 because participants who were randomly assigned to receive the active intervention were found to have a 28% increase in incidence of lung cancer, a 17% increase in incidence of death and a higher rate of cardiovascular disease mortality compared with participants in the placebo group. METHODS: After the intervention ended, CARET participants returned the study vitamins to their study center and provided a final blood sample. They continue to be followed annually by telephone and mail self-report. Self-reported cancer endpoints were confirmed by review of pathology reports, and death endpoints were confirmed by review of death certificates. All statistical tests were two-sided. RESULTS: With follow-up through December 31, 2001, the post-intervention relative risks of lung cancer and all-cause mortality for the active intervention group compared with the placebo group were 1.12 (95% confidence interval [CI] = 0.97 to 1.31) and 1.08 (95% CI = 0.99 to 1.17), respectively. Smoothed relative risk curves for lung cancer incidence and all-cause mortality indicated that relative risks remained above 1.0 throughout the post-intervention follow-up. By contrast, the relative risk of cardiovascular disease mortality decreased rapidly to 1.0 after the intervention was stopped. During the post-intervention phase, females had larger relative risks of lung cancer mortality (1.33 versus 1.14; P = .36), cardiovascular disease mortality (1.44 versus 0.93; P = .03), and all-cause mortality (1.37 versus 0.98; P = .001) than males. CONCLUSIONS: The previously reported adverse effects of beta-carotene and retinyl palmitate on lung cancer incidence and all-cause mortality in cigarette smokers and individuals with occupational exposure to asbestos persisted after drug administration was stopped although they are no longer statistically significant. Planned subgroup analyses suggest that the excess risks of lung cancer were restricted primarily to females, and cardiovascular disease mortality primarily to females and to former smokers.

Human lung cancer chemoprevention strategies: Parker B. Francis lecture.

Pharmacologic or nutritional prevention of lung cancers is needed, especially for 60 million Americans who are former smokers. A portfolio of large-scale trials of beta-carotene, beta-carotene with and without vitamin E, and beta-carotene plus vitamin A demonstrated no benefit whatsoever from beta-carotene. The alpha-Tocopherol/beta-Carotene Trial and the beta-Carotene and Retinol Efficacy Trial found significant increases in lung cancer risk and total mortality. Laboratory research soon identified multiple adverse molecular effects. Nevertheless, chemoprevention remains an active, promising strategy, with new hypotheses and new candidate agents, including many already approved as therapies. The most active area currently is focused on selective inhibition of arachidonic metabolism, both Cox-2 and Lox pathways.

The association between lung and prostate cancer risk, and serum micronutrients: results and lessons learned from beta-carotene and retinol efficacy trial.

beta-Carotene and Retinol Efficacy Trial is a nationwide chemoprevention trial that recruited 18,314 high-risk individuals to test the effect of supplemental beta-carotene and retinol on lung cancer incidence. In this report, we conducted a prospective nested case-control study of the association between serum carotenoids, retinoids, and tocopherols on both lung and prostate cancer incidence. Prerandomization serum samples were selected from 278 lung cancer cases and 205 prostate cancer cases, and 483 controls matched by high-risk population, study center location, age, sex (lung cancer only), smoking status, and year of randomization. Carotenoids, retinoids, and tocopherols were analyzed by high-performance liquid chromatography. Endpoints were confirmed by pathology review (lung cancer) or review of the pathology report (prostate cancer). In the control-only population, there was a significant association between tobacco use and serum micronutrient concentration. Current smokers compared with former smokers had lower mean levels of all of the micronutrients tested with zeaxanthin, beta-cryptoxanthin, alpha-carotene, alpha-tocopherol, retinol, and retinyl palmitate reaching statistical significance at P = 0.05. In the overall population, the mean serum concentrations of all of the micronutrients except gamma-tocopherol were lower for lung cancer cases than controls. Statistically significant trends across quartiles were observed in lutein (P = 0.02), zeaxanthin (P = 0.02), and alpha-tocopherol (P = 0.03). The carotenoid findings in the overall population were because of the strong inverse association between serum micronutrients and lung cancer in females. Statistically significant odds ratios (ORs) comparing 4(th) to 1st quartiles in the female population were seen in lutein [OR, 0.31; confidence interval (CI), 0.13-0.75], zeaxanthin (OR, 0.31; CI, 0.12-0.77), and beta-cryptoxanthin (OR, 0.34; CI, 0.14-0.81). For prostate cancer, mean serum concentrations were lower in cases for all of the nutrients except alpha-carotene. Only for alpha-tocopherol (P(trend) = 0.04) were the findings statistically significant. There was no statistically significant association between serum carotenoids and prostate cancer. Our findings provide additional support for the association between physiological levels of dietary micronutrients and cancer incidence.

Fruits and vegetables are associated with lower lung cancer risk only in the placebo arm of the beta-carotene and retinol efficacy trial (CARET).

Despite the unexpected results from the beta-Carotene and Retinol Efficacy Trial (CARET) and similar supplementation trials showing that supplementation with beta-carotene increased, rather than decreased, lung cancer incidence, considerable interest remains in investigating how other compounds in fruits and vegetables may affect lung cancer risk. We used data from 14,120 CARET participants who completed food frequency questionnaires to examine associations of diet with lung cancer risk. After 12 years of follow-up (1989-2001), 742 participants developed lung cancer. We used Cox proportional hazards models to estimate multivariate relative risks (RRs) and 95% confidence intervals (CIs). Analyses were controlled for smoking, asbestos exposure, and other covariates. Analyses of specific botanical groups were also controlled for total fruit and vegetable intake. All models were stratified by CARET treatment arm, and all statistical tests were two-sided. Statistically significant associations of fruit and vegetable intake with lower lung cancer risk were restricted to the CARET placebo arm. The RR for highest versus lowest quintile of total fruit consumption in the placebo arm was 0.56 (95% CI, 0.39-0.81) with a two-sided P for trend = 0.003. Two specific botanical groups were associated with reduced risk of lung cancer. Compared with the lowest quintile of rosaceae fruit consumption, placebo participants in the top quintile had a RR of 0.63 (95% CI, 0.42-0.94; P for trend = 0.02); for cruciferae vegetables, the RR was 0.68 (95% CI, 0.45-1.04; P for trend = 0.01). We did not observe any statistically significant associations of fruit and vegetable intake with lung cancer risk among participants randomized to receive the CARET supplements (30 mg of beta-carotene and 25,000 IU of retinyl palmitate). This report provides evidence that plant foods have an important preventive influence in a population at high risk for lung cancer. However, persons who use beta-carotene supplements do not benefit from the protective compounds in plant foods.

Homocyst(e)ine and coronary heart disease: pharmacoeconomic support for interventions to lower hyperhomocyst(e)inaemia.

Homocyst(e)ine, a sulphur-containing amino acid, is an intermediate formed during the metabolism of the essential amino acid methionine. Biological and epidemiological evidence suggest that elevated plasma levels of homocyst(e)ine are a risk factor for atherosclerosis and coronary heart disease (CHD). In the general US population, hyperhomocyst(e)inaemia is common and most often due to mild nutritional deficiencies in the B vitamins (folic acid, vitamin B(12) and vitamin B(6)). While high homocyst(e)ine levels can be effectively lowered using folic acid and other B vitamins, it is unknown whether such vitamin therapy will lead to clinical benefits. Given that strategies for homocyst(e)ine-lowering are safe and inexpensive, however, even small reductions in CHD risk will be highly cost effective. Thus, it may be prudent for patients to ensure an adequate daily intake of dietary folic acid and other B vitamins and for physicians to screen high-risk adults such as those with established CHD as we await definitive results from ongoing clinical trials.