Host genomics is not the main decision-making factor for bacteria immigrating into human body, but it is an important factor. Two papers recently published in the Proceedings of the National Academy of Sciences help to understand why you are chosen and how the choosers make their decisions.
Benson et al studied microbes of mice C57BL/6J, HR and their offspring. BL6 is a common inbred line prone to diet-induced obesity, type 2 diabetes, and atherosclerosis. They also develop age-related hearing loss, if are not following recommended dietary allowance. High runner (HR) mice is lean and fit and loves to exercise - it's in the genes.
Noninvasive 16S RNA sequencing (Roche 454) showed that the abundance of microbes in "core measurable microbiota" depended on 530 host SNPs, mostly those located in 13 quantitative trait loci and was influenced by 5 more QTLs.
Some of the genetic regions appear to determine what kind of bacteria immigrate and strive in the host, other regions influence the immigration rate, attracting a wide variety pf or specific nationalities. Supplementary material elaborates on sources of variation and genotype frequencies at given SNP locations.
How are bacteria making their decisions to colonize or not to colonize?
In another PNAS article, Ben-Jacob and Schultz explain why microbes could be smarter than humans. We may think that our decisions are well thought and sophisticated, but we are, indeed, influenced by other people and our over-interpretations of other people's reactions. Bacteria can assess the noisy and stressful environment around them more objectively and rationally. They anticipate possible drastic changes in the environment and find the best decisions by providing every bacterium with the freedom to choose its own fate. This may look like throwing dice, but the colony manages the odds and effectively programs the effect of the noise on the gene circuit performance.
Our genes may be shaping microbial communities that could, in their turn, control our physical and mental health. Yet our lifestyle choices could break the patterns and let us decide what types of bacteria we want to live with.
And for those whose fight against unwanted microbes is too hard, there may be light in the end of the tunnel: Personal Genomes project has just announced a new collaboration with Rob Knight and Noah Fierer that will enable to explore the microbial diversity of various habitats of the human body and correlate it to the genotype.
References
Andrew K. Benson,, Scott A. Kelly,, Ryan Legge,, Fangrui Ma,, Soo Jen Low,, Jaehyoung Kim,, Min Zhang,, Phaik Lyn Oh,, Derrick Nehrenberg,, Kunjie Hu,, Stephen D. Kachman,, Etsuko N. Moriyama,, Jens Walter,, Daniel A. Peterson,, & Daniel Pomp10.1073/pnas.1007028107 (2010). Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factorsProceedings of the National Academy of Sciences of the United States of America,Published online before print October 11, 2010
Ben-Jacob E, &; Schultz D (2010). Bacteria determine fate by playing dice with controlled odds. Proceedings of the National Academy of Sciences of the United States of America, 107 (30), 13197-8 PMID: 20660309
"I've just picked up a fault in the AE35 unit. It's going to go 100% failure in 72 hours". These were famous words of the almighty computer HAL in "2001: A Space Odyssey". Few of us believe too much in software forecasts - be it weather, earthquakes or computer hard disk failures. Yet, we all know that sometimes it works. And such systems are very valuable, assuming they continuously improve.
Wellness is always a common theme of the many presentations and experiments of Quantified Self enthusiasts - citizen scientists quantifying everyday life in order to improve it. "Health" was the most frequent word among the two-word introductions of QS #15 attendees, followed by variations of sleep and happiness, and ways to measure and understand it. Are health failures predictable? Nobody argues they are, although most available services - such as genomic testing - provide only long term predictions. Biomarkers that scientists are interested in are obtained through invasive or costly interventions - like blood proteins or intracranial electroencephalograms. Technologies such as Mobile Cardiac Outpatient Telemetry™ (MCOT™) developed by CardioNet are based on real time EKG focused on heart rhythm abnormalities that can't be detected in small 24 or 48 hour windows. These relatively rare events are correlated with symptoms and used for diagnostics.
Your husband just died, … here’s his black box
(from Gordon Bell's presentation)
Perhaps in the future every one of us will leave a black box holding all the truth about our health, helping next generations to better maintain, test and repair their bodies. Many lives have already contributed to the understanding of causes and effects such as the link between cholesterol levels, diet and heart attack. But what about the short term prediction horizon, like the 72-hour window of HAL or 30 seconds to 15-to-45 minutes warning by seizure dogs?
Could computer luminary Gordon Bell predict his heart attack if he wore his heart monitor strap while bicycling? A cardiologist would say "no way", but maybe sometimes it's better to keep quantifying and experiment despite of what medical establishment has to say?
Data from the Women’s Health Initiative study (129,135 postmenopausal women observed over a period of nearly eight years) show thata woman’s resting heart rate may be a good indicator of her risk for a heart attack. Hsia and others (2009) found that women whose resting heart rate is more than 76 beats per minute are significantly more likely to have a heart attack than women with resting heart rate less than 62 beats a minute. This risk factor is particularly strong for women between the ages of 50 and 64, less so for women over the age of 65. (Trial NCT00000611)
Of course, women have different kinds of heart attacks than men do. They are more likely to die from a spasms of heart and the blood vessels leading to the heart, and are more likely to complain of fatigue and sleep disturbances in the weeks and months leading up to a heart attack. Sleep disturbances and decreased physiological differences between day and night are increasing heart attack and stroke risks for males too, at least for shift workers. Exercise tests - known for their false positive results - have better cardiovascular prognostic value for smokers with high cholesterol than healthy men.
Finger arterial pulsatile volume changes or finger blood flow - related to blood pressure - is another medium-to-long term predictor of pending cardiac events. A simple, noninvasive finger sensor test called EndoPAT can predict major cardiac events such as a heart attack or stroke for people who are considered at low or moderate risk.
AngelMed Guardian System (inventor: Dr. Tim Fischell) is an early warning system - telling 24 hrs to a week before if heart attack is coming. Average time between the cardiac event and hospital arrival is 3 hrs, and about 5 hrs before the surgery starts. By that time 90% of muscles could be dead, so 5 or 10 minute warnings could save lives. Unfortunately, Guardian is highly invasive - sized as an iPod, it is implanted directly into the patient's chest, monitoring electrogramwaveforms and other crucial heart-signal data 24-7.
Many portable oximeters and ECG are already in the market - and even though consumers are complaining about noise and difficulties in getting readings of diagnostic intervals, the technologies will continue to improve and self-quantifiers will be finding solutions for better health.
REFERENCES Hsia, J., Larson, J., Ockene, J., Sarto, G., Allison, M., Hendrix, S., Robinson, J., LaCroix, A., Manson, J., & , . (2009). Resting heart rate as a low tech predictor of coronary events in women: prospective cohort study BMJ, 338 (feb03 2) DOI: 10.1136/bmj.b219
Mayo Clinic (2009). High resting heart rate could predict heart attack in women. Mayo Clinic women's healthsource, 13 (7) PMID: 19498326
I am typing this standing in front of my computer. My tall chair is aside.
About a year ago, I realized that I felt better when I stood while working. It turned out I was not alone in this discovery; more and more people are opting for a vertical approach to work, and the benefits are becoming increasingly evident.
We're all familiar with the age-old advice to "eat less and exercise". But this may not be enough. As shown in a recent study, exercise does not counteract the ill effects of sedentary lives, we should keep moving (or at least squatting) throughout the day too. New York Times article about the study (The men who stare at screens) immediately got up-votes from over 100 hackers - those who spend hours staring at screens to code, along with 100+ comments from those staring at screens to read and comment on the news. Stand up while you read this, asked NYT earlier this year. Prolonged sedentarity affects not only cardiovascular and metabolic health, blood clotting, diabetes and cancer. Countless hours of sitting could cause many other ailments reducing the quality of life such as skewed microbial ecology accompanied by strong body odor, diminishing overall quality of life.
Health promotion efforts targeting physical inactivity should emphasize both reducing sedentary activity and increasing regular physical activity for optimal health.
The lead author of the 2010 study says: "Stand up. Pace around your office. Get off the couch and grab a mop or change a light bulb the next time you watch ‘‘Dancing With the Stars.’’ A five-minute stroll is recommended every half hour.
Warren TY, Barry V, Hooker SP, Sui X, Church TS, & Blair SN (2010). Sedentary behaviors increase risk of cardiovascular disease mortality in men. Medicine and science in sports and exercise, 42 (5), 879-85 PMID: 19996993 DOI: 10.1249/MSS.0b013e3181c3aa7e
Dunstan DW, Barr EL, Healy GN, Salmon J, Shaw JE, Balkau B, Magliano DJ, Cameron AJ, Zimmet PZ, & Owen N (2010). Television viewing time and mortality: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). Circulation, 121 (3), 384-91 PMID: 20065160 DOI: 10.1161/CIRCULATIONAHA.109.894824
Katzmarzyk PT, Church TS, Craig CL, & Bouchard C (2009). Sitting time and mortality from all causes, cardiovascular disease, and cancer. Medicine and science in sports and exercise, 41 (5), 998-1005 PMID: 19346988 DOI: 10.1249/MSS.0b013e3181930355
Healy GN, Dunstan DW, Salmon J, Shaw JE, Zimmet PZ, Owen N. (2008). Television time and continuous metabolic risk in physically active adults. Medicine and Science in Sports and Exercise 40, 639-645.(PMID: 18317383)
Khaw K-T, Wareham N, Bingham S, Welch A, Luben R, et al. (2008) Combined Impact of Health Behaviours and Mortality in Men and Women: The EPIC-Norfolk Prospective Population Study. PLoS Med 5(1): e12. doi:10.1371/journal.pmed.0050012 (PMID: 18184033)
Beasley R, Raymond N, Hill S, Nowitz M, Hughes R. (2003) eThrombosis: the 21st century variant of venous thromboembolism associated with immobility. Eur Respir J. 21(2), 374-6. (PMID: 12608454)
Aurametrix is developing next-generation systems for Personal Health Management. Better solutions for a healthier world
Known as microbiota, the trillions of bacteria and other microorganisms could be our little friends. Some of them, dubbed probiotics, help to metabolize calories , provide nutrients, even shape immune responses during health and disease. A common gut bacteria called Bacteroides fragilis alleviates inflammation by restoring a balance of immune cells. It was shown to prevent inflammatory bowel disease in mice. Other bacteria shown to be protective in inflammatory bowel disease includes Lactobacillus casei, Lactobacillus plantarum, Lactobacillus salivarius, Lactobacillus acidophilus, Lactobacillus delbrueckii subspecies bulgaricus, Lactobacillus rhamnosus GG, Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium infantis, Escherichia coli Nissle 1917, Streptococcus salivarius subspecies thermophilus, Bacteriodes thetaiotaomicron, Faecalibacterium prausnitzii, etc.
Humans are much more similar to one another at the level of the genome than the microbiome. Microbial ratios change with an individual's weight, travels, medications, stress, diet. For early men, changes in bacterial ratios favoring increased fat/energy storage was beneficial - as the periods when food was plentiful would be always followed by times when food is scarce. For a modern man, this is a potential health hazard rather than an advantage.
The most abundant bacterial groups detected by molecular screening are Bacteroides (relatively stable population profile) and the bacteria belonging to the Clostridium coccoides group and the Clostridium leptum group (see this article on the Normal Bacterial Flora of Humans).
A lower proportion of gram-positive anaerobes related to Faecalibacterium prausnitzii, Ruminococcus flavefaciens-Ruminococcus bromii, Eubacterium rectale-Clostridium coccoides, and Eubacterium cylindroides. The most widely promoted prebiotics inulin and fructooligosaccharides (neither is absorbed in the upper gastrointestinal tract) have been suggested to increase the number of bifidobacteria. Dahlia inulin was shown to cause a pronounced increase in the number of bacteria related to R. flavefaciens-R. bromii and E. cylindroides.
Other findings suggest that heavier individuals may have a different makeup of gut bugs than thin ones. The gut microbiota of obese mice has been shown to have significantly more of one main type of bacteria called Firmicutes and fewer of another kind called Bacteroidetes (both types populate human guts as well); in normal mice, the distribution is the opposite. Whether you call them thongs, flip-flops or jandals, the simple rubber sandals could be a breeding ground for bacteria too. They allow easy access to oxygen, skin cells and oils, dirt and moisture. Eighty per cent of the population already have Staphylococcus aureus - found on sandals after being work for 4 days - on their skin, in their nose and armpits, yet this microbe aureus could make you pretty sick if it gets into a cut and into your blood, and if your immune system is not robust. Some of bad bacteria can be even found in bottled wateror in Fast Food Soda Fountains (see this article published in International Journal of Food Microbiology). 48% of soda fountains at fast food restaurants contain coliform bacteria. More than 11% of the beverages analyzed contained Escherichia coli and over 17% contained Chryseobacterium meningosepticum. Other opportunistic pathogenic microorganisms isolated from the beverages included species of Klebsiella, Staphylococcus, Stenotrophomonas, Candida, and Serratia.
Bacterial phylotypes Clostridium cocleatum, Clostridium thermosuccinogenes, Coprobacillus catenaformis, Ruminococcus bromii-like, Ruminococcus torques and R. torques were detected in similar amounts in IBS-C and IBS-D patients. C. thermosuccinogenes, however, was quantified in significantly different quantities depending on constipation or diarrhea-predominant cases. Bacteria similar to R. torques was more prevalent in IBS-D patients' intestinal microbiota than in that of control subjects. a R. bromii-like phylotype was associated with IBS-C patients. These findings further emphasized the possible contribution of the gastrointestinal microbiota in IBS. For IBD, novel invasive species of Escherichia colipossibly replacing some Clostridiales were found in inflamed mucosa. The number of E.coli correlated with the severity of Crohn's disease involving the ileum.
Differences in microbiota may depend on genetics, metabolism, environmental exposures during childhood, state of health. Selective increase in novel invasive species of E.coli seems to be involved in the etiopathogenesis to Crohn's disease involving the ileum (different species are implicated in UC). Other bacterial species specific to Crohn's areB. ovatus and B. vulgatus.
Myalgic Encephalomyelitis/Encephalopathy/Chronic Fatique Syndrome may be another condition caused by microbes. People with Cystic Fibrosis, for example, have more microbes enriched in aromatic amino acid metabolism in their airways. Note that this disease causes a distinct acidic breath - the more severe the condition is in an individual, the more acidic his breath becomes. The microbes were especially sensitive to amino-acid starvation indicating that therapeutic measures may be more effective if used to change the respiratory environment, as opposed to shifting the taxonomic composition of resident microbiota.
So, even seemingly innocent gut bacteria may be affecting many aspects of health and behavior. One day we may be even allowed to say: I’m sorry, sir, my microbes made me do it.
Even though the vast majority of our microbes are good for us or can be even used for diagnostics of the processes in our bodies, some are there to get us, contributing to skin diseases, body odor, malabsorption, gastrointestinal problems, ear infections and more.
Almost anything we touch or wear could be a breeding ground for bacteria. Remember the heavily reblogged and retwitted statement: "Wearing headphones for just an hour will increase the bacteria in your ear by 700 times"? Well, not exactly 700 times, 11 times and these are mostly our own bacteria that liked heat and humidity created in the ears and started to multiply more actively, but pretty much anything you stick in your ears - stethoscopes, hearing aids, audiological gear - comes out covered in microbes.
Parade beads could be be contaminated with bacteria too. Gasparilla beads, were shown to be covered with several types of bacteriaincludinf E. coli and salmonella.
Even cigarettes - besides their harmful toxic chemicals - host a bacterial bonanza —hundreds of different germs, including those responsible for many human illnesses, according to a new study. For example, Campylobacter, which can cause food poisoning and Guillain-Barre Syndrome; Clostridium, which causes food poisoning and pneumonias; Corynebacterium, also associated with pneumonias and other diseases; E. coli; Klebsiella, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, all of which are associated not only with pneumonia but also with urinary tract infections; and a number of Staphylococcus species that underlie the most common and serious hospital-associated infections.
Anoter source of pathogens is undercooked and spoiled food. Take pork, for example. Five out of 90 samples of retail pork in Lousiana tested positive for MRSA — an antibiotic-resistant staph infection — thanks to antibiotics piglet's ears. MRSA (pronounced “mersa”) stands for methicillin-resistant Staphylococcus aureus whose new strain ST398 is on the rise.
And of course, people could also pass microbes to each other: Epstein-Barr virus (EBV) (causing mononucleosis - infamously known as the kissing disease), Herpes Simplex Virus-1 (causing cold sores) bacterium Streptococcus (causing various infections such as gum disease and strep throat), H.pylori, Candida or other yeast species, Hepatitis B Virus and cytomegalovirus (CMV) are spread via oral transmission from microbe-containing saliva.
How can we control populations of microbes colonizing us? Besides drugs wiping out entire populations - assuming they are not resistant to these drugs, food could help in cultivation efforts too. Example: vinegar. It was shown to reduce counts of not-so-benefitial bacteria. Diluted solutions of various household sanitizers (apple cider vinegar, white vinegar, bleach, and a reconstituted lemon juice product) were tested for their effectiveness in reducing counts of inoculated Escherichia coli and naturally present aerobic, mesophilic bacteria on lettuce. Of the sanitizers tested, 35% white vinegar (1.9% acetic acid) was the most effective in reducing E. coli and other aerobic microbes.
Aurametrix is developing decision support systems to help you evaluate health risks, decide on preventative measures, estimate cost/benefits of performing diagnostic tests, determine your nutrition needs and life style adjustments. Better solutions for a healthier world.
Study leader Dr. Maya Rao of Columbia University in New York says primary care doctors typically order a blood test called creatinine to measure kidney function, but this alone is not a particularly accurate measure of kidney function.
The distribution of creatinine test results in 6434 people is shown on the right (NHANES 2006 study, weighted for USA demographics, graph by WolframAlpha)
The typical reference ranges in adult males are 0.7 to 1.2 mg/dL according to Wikipedia and 0.6 to 1.2 milligrams (mg) per deciliter (dl) according to medicinenet. In adult females, it's 0.5 to 1.1 milligrams per deciliter (wikipedia) or 0.5 to 1.1 mg/dl (medicinenet). LabCorps lists normal values between 0.57 and 1.00 mg/dL. (see also reference values for other medical tests and Aurametrix blog on liver tests). Men tend to have higher levels of creatinine because they generally have more skeletal muscle mass than women. Muscular young or middle-aged adults may have more creatinine in their blood than the norm for the general population. Vegetarians have been shown to have lower creatinine levels. Creatinine tends to be slightly lower in pregnancy. It increases with height and body weight. While a baseline serum creatinine of 2.0 mg/dL (150 μmol/l) may indicate normal kidney function in a male body builder, a serum creatinine of 0.7 mg/dL (60 μmol/l) can indicate significant renal disease in a frail old woman.
Infants have normal levels of about 0.2 or more, depending on their muscle development. In people with malnutrition, severe weight loss, and long standing illnesses the muscle mass tends to diminish over time and, therefore, their creatinine level may be lower than expected for their age.
A person with only one kidney may have a normal level of about 1.8 or 1.9. Creatinine levels that reach 2.0 or more in babies and 10.0 or more in adults may indicate severe kidney impairment and the need for a dialysis machine to remove wastes from the blood.
In the United States, creatinine is typically reported in mg/dL, while in Canada and Europe μmol/litre may be used. 1 mg/dL of creatinine is 88.4 μmol/l.
Creatinine is a waste product in your blood that comes from muscle activity. It is normally removed from your blood by your kidneys, but when kidney function slows down, the creatinine level rises.
Teenagers love to spend, Health care consumers love to test.
Recent mammogram debate shows why reform will fail - most women don't like to get mammograms later in life and less frequently. Of course, this furious reaction is fueled by those who would face payment cuts if the new guidelines are implemented - radiologists, for example.
How many medical tests do you need to sleep sound at night knowing that you are healthy enough? Billions, trillions, googols? How many out of a few thousand existing medical tests are redundant or irrelevant to individual consumers?
Dr. Kevin Pho, an internist in Nashua, N.H., thinks the rebellion indicates a larger problem with ObamaCare. "The fact that [the administration] is distancing itself from what I consider to be very robust guidelines portends a very poor future for comparative effectiveness," he says. "If they back down now, what's going to happen when a comparative effectiveness body says there's no difference between angioplasty and medical management of heart disease?"
The American College of Obstetrics and Gynecology (ACOG) has just revised their guidelines for Pap smears under some pressure. This resulted from an Annals of Internal Medicine article which documented that only 16.4% of gynecologists followed the College’s prior guidelines. Most did more screenings than indicated, the worst record of the specialties tested. But the ACOG still recommends that nearly all women obtain regular screening at intervals of 1-3 years.
Cervical cancer is a rare disease in the US: just over 11,000 cases are predicted in 2009. There will be nearly as many cases of testicular cancer, 8,400. In comparison both breast and prostate cancer are just under 200,000. Most women have been led to believe that cervical cancer is rampant and they need yearly screening to prevent it. Testicular cancer however, is rarely mentioned. Most physicians don’t even bother to recommend that young men self-examine.
Medicine is as much art as science – there are many cases where there are no “right” answers. Health care providers can prescribe as many procedures as they want and charge whatever they like. It's time for this to be changed.
Personal risk of cervical cancer, for example, can be easily estimated by every woman as it depends on whether she had multiple sexual partners, prior negative Paps, long term mutually monogamous relationship. HIV (that has a five times greater incidence than cervical cancer) tests are not administered to people without risks, right? Well, not quite right, but that's another story.
Dr. Joel Sherman (Medical Privacy, A Patient Oriented Discussion) has seen many women who are angry that the facts on cervical cancer have been hidden from them. They are pushed into getting Paps, but never told the pros and cons of screening. Never mentioned are the high incidence of abnormalities that resolve spontaneously, like negative biopsies and colposcopies.
If the law says insurers have to treat every person the same, without taking into account whether they’re sick or healthy, young or old, a rational insurer will do some rational things. For example, it will assume disproportionate numbers of people who buy a policy from them will be sick and old. Of course, when they do this, the product becomes expensive, and young, healthy people start to wonder if they should even buy it in the first place. After all, they don’t really need insurance, right? Coupled with the overall rise in the cost of health care, insurers now push through new rounds of price increases, which, in turn, create more uninsured people. It is a very nasty cycle.
Workflow, procedures and organization of diagnostic laboratories have changed little since the end of the 19th century. Technology improved quality and safety, lead to higher throughput and allowed private electronic access to patients' lab test results - at least partially, but other than that not much has changed.
The introduction of first generation transcriptome technologies in the mid 1990s (Schenaet al., 1995; DeRisi et al., 1996) has led to a phenomenal abilityto simultaneously measure thousands of genes, create molecular profiles of cancers, all other diseases and conditions.
Proteomics - coined a couple of years later (James, 1997) - was accepted as an even more promising technique for effective diagnostics of diseases. Figure on the left, however, demonstrates that it too faces many challenges from discovery of biomarkers to their verification and approval. After more than a decade (Oliver et al., 1998), metabolomics has been accepted as - at least - an equally promising technique, but it still lagging behin genomics and proteomics.
All these techniques will have significant impact on the business model of diagnostics. Multiplexing (measuring multiple biomarkers at once) is obviously much more cost-effective. Diagnostics industry is historically very resistant to disruptive technological change, but potential cost advantages should outweigh this, leading to novel business models in health management.
A change will also come from the growing near patient testing (NPT) sector. NPT is already finding a role in wellness monitoring. Existing self tests - such as cholesterol kits - may not be very accurate, but with the advent of inexpensive multiplexing assays this will be overcome. Even when blood testing is done by trained professionals in a lab, there can be significant variability in test results. Same applies to blood pressure measurements - you may need to do three measurements per day for five days in order to get a decent baseline. This only justifies the need to have inexpensive tests that can be done more often.
But lets go back to metabolomics and its potential to provide noninvasive inexpensive diagnostics. Are there any clinical trials attempting to translate it into clinical practice? Here are our favorite ones:
OTHER NCT00330603: Metabolomic breath analysis to predict treatment for chronic cough (University of Virginia) NCT00632307: Breath analysis to diagnose COPD; lung cancer; airway infection; interstitial lung disease, sleep apnea; pulmonary disorders with pleural infusions; sarcoidosis (Lung Clinic Hemer, Germany) NCT00294489: Breath analysis to diagnose Hepatitis C (Hadassah Medical Organization, Jerusalem, Israel)
References Schena M, Shalon D, Davis RW, Brown PO 1995 Quantitative monitoring of gene expression patterns with complementary DNA microarray. Science 270 : 467 –470[Abstract/Free Full Text] DeRisi J, Penland L, Brown PO, Bittner ML, Meltzer PS, Ray M, Chen Y, Su YA 1996 Use of a cDNA microarray to analyze gene expression patterns in human cancer. Nat Genet 14 : 457 –460[CrossRef][Medline]
James P 1997 Protein identification in the post-genome era: the rapid rise of proteomics.". Quarterly reviews of biophysics30 (4): 279–331. doi:10.1017/S0033583597003399. PMID9634650.
Oliver SG, Winson MK, Kell DB, Baganz F. 1998. Systematic functional analysis of the yeast genome. Trends in Biotechnology 16: 373-378.
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