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What is the Best Combat Flight Simulator for PC? | LevelSkip
LevelSkip». Simulation Games». What is the Best Combat Flight Simulator for PC? With so many options these days, it can be hard to decide what flight simulator, combat sim, or flying games to buy. You certainly can't always rely on advertisements.
Combat flight simulator – Wikipedia
Combat flight simulators are video games (similar to flight simulator or amateur flight simulation software) used to simulate military aircraft and their operations. These video games are distinct from dedicated flight simulators used for military flight training which consist of realistic physical…
The Best Combat Flight Simulator Games of All Time
added by quarantinetimer Digital Combat Simulator: A-10C Warthog 2011. Tagged: games, video games, Simulation, best video games, video game genres, aviation, action games, simulation games, Combat flight simulator.
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Best Combat Flight Sim 2011 Though taking it up can … Top Picks – Military Combat Flight Simulator Computer … Jim Kallinen/Flickr Rise of Flight is a state-of-the-art PC flight simulation title that sets a new …
Microsoft Combat Flight Simulator 2 | Evans Flight
May 13, 2011. Combat flight simulators, although derived from standard aircraft flight simulators, are not simply aimed at leisure flying in a nicely simulated environment.
Best flight simulators and aircraft combat games for Mac | iMore
Falcon 4.0: Allied Force is the latest iteration of its classic F-16 Falcon flight simulator, taking you to the Balkans and the Korean peninsula for realistic combat missions. Arm your aircraft with realistic weapons and ordnance…
10 Realistic PC Combat Flight Simulator Games [HD] – YouTube
Combat Flight Simulator 3: Battle for Europe – 2002 (YouTube Гейминг). Top 10 Best Most REALISTIC PC Combat Jet/Warplane Fighter Simulators 2015 – Продолжительность: 6:20 Top10Eagle 127 273 просмотра.
Best Simulations of 2011 | SimHQ | Land & Armor Combat
Best Simulations of 2011. By SimHQ on January 4, 2012 in _commentary. Interactive calendars Cloud Imperium Games DayZ DCS DCS World Digital Combat Simulator Eagle Dynamics Elite: Dangerous Elite Dangerous: Horizons flight simulation Frontier Developments Gaming PC Ground…
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Simulation Games In a brilliant but flawed sequel to their original Combat Flight Simulator, Microsoft have given us a good sim that, like "Falcon 4", has the capacity to become a great one.
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6 Shares. Share. Tweet. Share. Share. Email. Comments. Some add-ons bolt new features onto games, and others make good games better, but the rarest mod is one that transforms a decent title into something truly outstanding.
Combat flight simulator | Academic Dictionaries and Encyclopedias
Combat flight simulators are video games (similar to flight simulator or amateur flight simulation software) used to simulate military aircraft and their operations. As of 2011, the community development is still highly active.
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Review : Microsoft Combat Flight Simulator 3, The Battle for Europe By Hugh Shoults. How to make FS2002 Aircraft mdl work in CFS2 By Sergio Dolcemascolo (download file – 185K). The original Combat Flight Simulator: A Retrospective.
Flight Gear Flight Simulator
The FlightGear flight simulator project is an open-source, multi-platform, cooperative flight simulator development project. Source code for the entire project is available. (OpenGL)[OS Independent]…
Is there a good combat flight simulator for windows 7? – Page 3
It is by far the best combat flight simulator you can get, especially with all the mods you can get. I have over 300 flyable airplanes in my modded installation and I couldn't be happier. Joined: Feb 2011. Location: Memphis, TN.
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The Real Flight Simulation Game With Combat Flight Simulator Game Download Bonus. Some details are simplified, in particular the engine handling and some over-stresses are not simulated or are without any consequence.
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American Truck Simulator. America's Army. Apache: Air Assault. ArmA: Combat Operations (Armed Assault). Colin McRae Rally 2004. Combat Air Patrol 2. Combat Flight Simulator 3.
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What is the Best Combat Flight Simulator for PC? A round-up of some of the best new flight simulators available right now. This article covers everything from World War I right up to the present day, and just about every theatre of conflict.
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Other Simulator Lists: * As Real As They Get: BEST SIMULATORS * Evolution of Racing Simulators * Fly the Friendly Skies: History of Flight Sims * WWI Air Combat Flight Simulators * Dive!
10 Best Android Flight Simulator Games
Note: The best flight simulator games for Android were tested on a Samsung Galaxy Note III smartphone. The apps performed well and no problems were faced during the testing. 1. Infinite Flight Simulator – $4.99 with In-app Purchases.
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Key points. The official online multiplayer service is no longer available. General information. Official game site (archived). The game has no save feature. In-game general settings. In-game advanced video settings. In-game general control settings. In-game general control settings.
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WarBirds : flight simulator game. World war II fast action aerial warfare! "The WarBirds series has been around for some time, and continues to be one of the best combat flight simulations around." -Gamespy.
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Search for and download any torrent from the pirate bay using search query combat flight simulator. Direct download via magnet link. Combat Flight Simulator 2. Uploaded 11-15 2011, Size 848.11 MiB, ULed by esharoth.


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After Saturday's storms, and then the blustery cold front, Houston will see a lot of sunshine. Then we'll see another front Thursday, which should hopefully set us up for a mostly sunny holiday weekend. We can be pretty confident in this point in a rain-free Easter, at least as confident as one can be six days out.
Today should be a rather pleasant day for the region, with sunny skies, and highs around 80 degrees. South winds will pick up a bit today, so the drier air we saw this weekend will give way to rising humidity. Lows tonight will be down around 60 degrees—warmer along the coast and a bit cooler inland. One concern: Today is an ozone action day for Houston, when high levels of ozone pollution are possible.
As southerly winds return, we'll see an increase in clouds on Tuesday, although the sunshine won't go away entirely. Southerly winds will be noticeable, likely picking up to 15 to 20mph, and this increasing moisture will set the stage for some rain showers later in the week. Highs Tuesday will depend upon the extent of sunshine over your location, but probably will be in the vicinity of 80 degrees. Lows Tuesday night, as clouds build and with the influx of warmer air, are unlikely to fall much below 70.
Wednesday and Thursday
The region's next cold front will approach the region on Wednesday, and bring with it the potential for severe weather. At this point, it looks like the best dynamics for stronger storms will occur to the north and northwest of Houston, particularly along the I-35 corridor from the Dallas-Fort Worth area south to Austin. We'll continue to monitor the potential for more local storms, however.
For Houston, our best guess at this point is lower rain totals of about 0.5 inch along the coast, rising to 1.0 or 1.5 inches for inland areas such as The Woodlands and points north. In terms of timing, the best chance for showers will likely come from Wednesday afternoon through Thursday morning, with highs in the low 80s Wednesday, and mid-70s on Thursday.
Easter weekend
Thursday's front should set up a fine weekend for the region. Sunny skies will reign on Friday and Saturday, and we should see at least partly sunny skies on Sunday. Look for highs in the 70s Friday, low 80s on Saturday, and then perhaps low-to-mid 80s on Sunday. The key for Easter will be the timing of moisture return—the later it occurs after Thursday's front, the more sunnier and less humid Sunday will be. At this point, I think, we can be reasonably confident that it will not rain on the holiday.


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Peru Elementary School District 124 Board of Education met March 13.
Here is the minutes as provided by the board:
Present: Mark Lamboley, Jim Renk and C.G. Pillai
Others Present: Mark Cross
The meeting was called to order by Chairperson Mark Lamboley at 5:04 p.m.
• Mr. Cross presented the Finance Committee with FY20 salary proposals for employees who are not already under a contract or collective bargaining agreement. Proposals were reviewed for teacher aides and secretaries, as well as the district secretary, bookkeeper, nurse, IT director, bilingual tutor, summer workers, and similar positions.
• After some discussion, it was agreed that compensation for most hourly rate and salaried positions would be recommended to the full Board in a range from 2.25 to 2.50 percent, depending on the position. Mr. Cross stated that positions on a table with five year pay increase increments do not require the same wage increase as positions with no built-in increase in compensation.
• The Finance Committee also discussed the potential impact of the new minimum wage bill for Illinois. Mr. Cross stated that while it does not have any impact in the short term, it will have longer term implications for the district in coming years. The committee agreed that this should be monitored after the law is implemented and more long-term projections are made.
• Mr. Lamboley also brought up when the current collective bargaining agreements expire. Mr. Cross reminded the committee that the teacher contract will be up in June of 2020, and the custodian and food service agreements will be up in June of 2021.
The committee adjourned at 5:32 p.m.


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HG Angie 0627 Change Orders
A change order might be only a piece of paper, but it could prove the only thing that stands between you and hundreds or thousands of dollars worth of misunderstanding — or worse, unauthorized work that inflates the price of a project.
This addendum to a contract ensures the service provider and customer are in agreement before making changes to a job in progress.
"You need to have a written record of the project," says Robert Criner, founder of Criner Remodeling , in Newport News, Virginia. "It keeps the job running smooth, and there aren't any surprises for anybody." Criner serves as vice chairman of the National Association of Home Builders Remodelers.
For a construction or remodeling job — a common place for the change order — it details that switch in tile styles you asked for in the bathroom or outlines additional work a contractor needs to do after finding rot under the floor.
The agreement should communicate changes to job scope, cost, when you're expected to pay (if it adds to the price tag) and any changes to the completion datem Criner said.
Contractors say most change orders occur as a result of customers' suggested tweaks once the project has started. Unforeseen issues can result in change orders on the contractor's side, too, but experts caution consumers to be wary of an endless stream of paperwork.
"Unfortunately, there are contractors out there that rely on change orders to make their margins," said Charlie Griffey, owner of Griffey Remodeling n Columbus, Ohio. "When you hear about people low-balling their estimates, it comes down to how detailed is their proposal and scale of work?"
In advance of signing off on any project, you should expect a thorough proposal that not only outlines what you'll physically see in the space — the new divider wall and paint color — but also what you don't, such as that pre-formed base put in before a shower install to prevent leaks.
"It's not unusual for us to have a six-page proposal on even a bathroom remodel," said Griffey, adding that this helps keep change orders to a minimum. "If it's not a detailed proposal or scope of work, there's always going to be change orders."
But a lack of change orders to account for modifications made to a project in progress is also a red flag.
Contractors and customers should work closely to determine early on if changes in project scope might be needed, whether the contractor suspects damage from water seeping into a wall or the project involves lead paint. "The proposal should at least note that some form of remediation could be included in the project and that could affect cost," Griffey said.


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madhya pradesh high court news
MP Honey-Trap Scandal: PIL Filed in HC for CBI Probe, Denial of Bail to Female Accused
Five women and a man were arrested in Indore and Bhopal on Wednesday and Thursday for allegedly running the racket, and police had seized electronic gadgets including spy cameras as well as mobile phones and cashVivek Trivedi, September 23, 2019, 6:05 pm explore: India
Govt Returns File to Collegium on Justice Kureshi's Elevation as MP Chief Justice, Say Sources
Sources indicated that the government was not averse to elevating Justice Kureshi as the chief justice of some other high court. However, it did not give reasons behind the government's decision to send back the file.August 28, 2019, 11:03 pm explore: India
Pragya Thakur Gets Court Notice Over Plea Challenging Her Election on Grounds of 'Corrupt Practices'
The petition filed in Madhya Pradesh High Court seeks to set aside her election on grounds that she allegedly adopted 'corrupt practices' and whipped up communal passions during the campaign.Vivek Trivedi, August 1, 2019, 9:43 pm explore: Politics
Madhya Pradesh HC Asks Govt official to Plant Saplings for Contempt of Court
The court was hearing a contempt petition against chief engineer S K Andhwan for not implementing a direction to appoint a person on compassionate grounds, said petitioner's lawyer Vipin YadavJuly 31, 2019, 9:32 pm explore: India
Congress Accuses BJP of 'Politicisation' of Judiciary, Ignoring Collegium Recommendation
BJP government's collusive laxity in ignoring repeated requests of SC to impeach J Shukla & overzealousness to ignore J.A.A.Kureshi from being appointed CJ stinks of politicisation of judiciary with the intent to remote control the temple of justice," Congress' chief spokesperson Randeep Surjewala tweetedJune 23, 2019, 10:04 pm explore: India
Madhya Pradesh HC Declines to Stay Release of PM Narendra Modi's Biopic
High courts in Delhi and Bombay had on Monday also turned down petitions seeking interference in the release of the movie, slated to hit theaters on Friday.April 3, 2019, 10:09 pm explore: India
MP High Court Stays Kamal Nath Govt's Decision to Hike OBC Quota From 14% to 27%
A two-judge bench of Justices RS Jha and Sanjay Dwivedi ordered that the counselling for MBBS seats, which gets underway from March 25, would be undertaken as per the 14 per cent reservation granted to OBCs.Vivek Trivedi, March 19, 2019, 6:57 pm explore: India
Can't Give Job Back to Woman Judge Who Accused HC Judge of Sexual Harassment, SC Told
The affidavit by the High Court said the woman cannot be permitted to withdraw the resignation or to seek reinstatement since resignation once tendered and accepted by the employer cannot be withdrawn under the service jurisprudence.Utkarsh Anand, January 11, 2019, 11:06 am explore: India
Supreme Court to Hear Plea for Reinstatement of Woman Trial Court Judge in MP
On October 12, the court had issued notices to registrar general of the Madhya Pradesh High Court and state government seeking their response within six weeks.November 26, 2018, 7:18 pm explore: India
SC Gets Four New Judges Within 48 Hours of Collegium Recommendation; Working Strength Rises to 28
On Tuesday, the SC collegium, headed by Chief Justice Ranjan Gogoi, had recommended the names of Justices Hemant Gupta, Ajay Rastogi, MR Shah and R Subhash Reddy for their elevation as apex court judges.November 1, 2018, 11:06 pm explore: India
MP High Court Recruitment 2018 Begins for 140 Civil Judge Posts, Apply before 4th September 2018
Interested candidates must apply for the post on or before 4th September 2018 at mphc.gov.in.August 7, 2018, 12:50 pm explore: India
MP High Court Directs Junior Doctors to Resume Work as Strike Paralyses Health Services
Patients were inconvenienced as 1,200 junior doctors struck work to seek higher stipend and protection on duty among other demands.Vivek Trivedi, July 25, 2018, 10:54 pm explore: India
Mandsaur Farmer Deaths Probe Panel Gives Clean Chit to Police; Says Firing 'Justified'
The report, a copy of which is with News18, has clearly given a clean chit to the police. The report mentions that it was 'required and justified' to open fire on the mob to bring things under control.Manoj Sharma, June 20, 2018, 7:13 am explore: India
Madhya Pradesh High Court Recruitment 2018: 27 English Stenographer Posts, Apply before 11th June 2018
Madhya Pradesh High Court Recruitment 2018 application process to fill 27 vacancies for the post of English Stenographer under Jabalpur bench has begun on the official website of the Hon'able High Court of Madhya Pradesh - mphc.gov.in. Interested and eligible candidates must apply for the post on or before 11th June 2018.May 15, 2018, 11:39 am explore: India
Reprieve for Country's Sole Happiness Minister in Murder Trial
On Monday, a bench of Justices Adarsh K Goel and Uday U Lalit refused to interfere with an order by the Madhya Pradesh High Court whereby the trial in this case has been stayed. "Since the special leave petition has been filed against the interim order, we do not find any ground to interfere with the impugned order," stated the Court order.Utkarsh Anand, March 6, 2018, 9:42 am explore: India
No Toilets For Women Cops, Madhya Pradesh Govt Fails to Give Answers in Court
The Madhya Pradesh government, which was required to submit its reply before the HC could not file its response on Friday and the court, has now posted the matter for hearing to January 16.Vivek Trivedi, December 16, 2017, 7:40 am explore: India
Bhopal Gangrape: HC Notices to Chief Secretary, DGP Over Medical Report
The woman was allegedly raped by four men for almost three hours near the railway tracks in Bhopal when she was returning home after attending a coaching class on October 31 night.November 11, 2017, 8:08 pm explore: India
MP High Court Quashes Warrant Against Abu Salem in Bhopal Double Murder Case
The verdict came on Salem's petition challenging the production warrant issued against him on January 15, 2014 in the double murder case. The HC also quashed the production warrant issued by the ADJ Bhopal.Vivek Trivedi, November 10, 2017, 10:33 pm explore: India
CBI Closes 9 Special Vyapam Courts, to Shift Cases for Better Monitoring
The HC had set up 22 special courts for hearing Vyapam scam-related cases. It had closed four of them earlier.September 17, 2017, 12:49 pm explore: India
Sardar Sarovar Oustees Protest: Medha Patkar Granted Bail by HC
Patkar's lawyer said the abduction charge against her was baseless as public servants who alleged abduction had consultation with Patkar and her aides at a public place.Vivek Trivedi, August 23, 2017, 9:11 pm explore: India
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hi dear,**I hope you are doing fine,**my car number is *******,**I parked the car which is Tiguan Eager (CFYM***) at **Bastion Street (On Street) at *** Fort York Blvd,*so I park the car at *** Fort York Blvd, I hope you can let the next customer know the car was changed place to park,**I was so sorry about that,**but when I went to pick up my zip car today, I can not find the car and the weather was so cold and windy,**the important point is no one tell me the pickup palace was changed!**I made a call to your staff and she helped me to change the car, but took half hour and near the lake which is so freezing to find that new zip car,**when I came back I fond my phone was no power and I can not find * Bastion Street,**which more is the I booked the car from *pm-*pm,**I made a call to customer service and no one answer me,**so I park the car at *** Fort York Blvd which at least I have known how to find it without the GPS ,**and I want to file the complaint about today's situation because after I was taking half an hour to find the car I was so upset and frustrated, a car accident almost happens to me.
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text: Clinical Research Methodology 1 Study Designs and Methodologic Sources of ErrorSessler, Daniel I. MD*; Imrey, Peter B. PhD†Anesthesia & Analgesia: October 2015 - Volume 121 - Issue 4 - p 1034–1042 doi: 10.1213/ANE.0000000000000815 General Articles: Review Article Free Abstract Author InformationAuthors Article OutlineOutline Article MetricsMetrics Clinical research can be categorized by the timing of data collection: retrospective or prospective. Clinical research also can be categorized by study design. In case-control studies, investigators compare previous exposures (including genetic and other personal factors, environmental influences, and medical treatments) among groups distinguished by later disease status (broadly defined to include the development of disease or response to treatment). In cohort studies, investigators compare subsequent incidences of disease among groups distinguished by one or more exposures. Comparative clinical trials are prospective cohort studies that compare treatments assigned to patients by the researchers. Most errors in clinical research findings arise from 5 largely distinguishable classes of methodologic problems: selection bias, confounding, measurement bias, reverse causation, and excessive chance variation. From the Departments of *Outcomes Research and †Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio. Accepted for publication April 7, 2015. Funding: Internal departmental funds. The authors declare no conflicts of interest. Address correspondence to Daniel I. Sessler, MD, Department of Outcomes Research, Cleveland Clinic, 9500 Euclid Ave./P77, Cleveland, OH 44195. Address e-mail to email@example.com. Abstract RESEARCH APPROACHES SOURCES OF ERROR Chance Selection Bias Measurement Bias Confounding Reverse Causation CONCLUSIONS DISCLOSURES REFERENCES For most of medical history, practice has been largely ad hoc, based on suboptimal evidence from personal experience and anecdotes shared among physicians. Although individual cases and experiences often yield invaluable insights to perceptive physicians, multiple anecdotes do not replace systematically collected data and organized comparisons, and practice mostly based on personal experience often has subsequently been shown to be suboptimal. (The pleural of anecdote is not data!) Voltaire nicely summarized early medical practice in 1760, writing that physicians "poured drugs of which they knew little, for diseases of which they knew less, into humans of which they knew nothing." One hundred years after Voltaire's comment but considerably before the microbial origin of disease was accepted, the British anesthesiologist John Snow, informed by work of John Graunt and formal vital statistics systems established in mid-16th century London,1 used systematic, dispassionate data collection to infer that a contaminated water supply was the proximal cause of mid-18th century London cholera outbreaks.2 During the next century, frameworks for systematic collection and evaluation of data, such as Koch's postulates for assessing microbial causation3 and Hill's guidelines for inferring causality more generally,4 fostered greater scientific rigor in conjunction with clinical observation. Clinical research methods have since matured immensely. The meticulous work of Feinstein,5–7 Sackett,8 and others on the intellectual foundations of clinical epidemiology; the fostering of randomized clinical trials (RCTs) particularly by Hill,9,10 Chalmers,11,12 and Cochrane13; and the emergence of evidence-based medicine, midwifed by Sackett et al.,14 have contributed greatly to revolutionary advances in clinical understanding and practice. The application of formal meta-analytic techniques from education and social science to medicine and epidemiology, through evidence-based medicine centers and the Cochrane Collaboration,15,16 has systematized aggregation of research evidence for the medical community. We thus now know much about how humans work and how they respond to disease and drugs. And we know even more about how cells and rodents respond. Physicians are thus encouraged to practice evidence-based medicine, which means that clinical decisions should be based on good evidence, preferably from relevant, high-quality, and reproducible studies in humans rather than on the physician's personal clinical experience alone. However, any physician who tries restricting practice to methods established on the basis of strong evidence in humans quickly discovers that there is distressingly little basis for current medical care, although cardiology and oncology, with histories of strong National Institutes of Health funding and methodologic innovation, seem ahead of most specialties in this regard.17,18 The purpose of clinical research is to bridge the remaining wide gap from the understanding of basic and animal science to the care of patients in an effort to improve medical outcomes. Systematic clinical research is necessary because humans have proven to be a poor model for rodents! Even the best clinical studies have potential limitations, and it is helpful to understand the strengths and weaknesses of various approaches. By this, we do not mean that clinical research is generally problematic. However, it helps to understand how study design can influence results, and which types of studies are most reliable and thus the best basis for clinical decisions. In this and 2 subsequent articles, we will discuss aspects of clinical research methodology as a guide to understanding and interpreting reported results. Even a series of articles can only have limited scope. Our focus will be on design choices in clinical research and the advantages and disadvantages of various approaches to address clinical research questions. We focus on design because, although error can occur in design, data collection, and/or analysis and reporting of a study, poor study design generally cannot be remedied by subsequent steps. A consequence of our focus on design is that we will not discuss operational issues, including ways to maintain blinding, electronic data acquisition, how to minimize and deal with missing data, or strategies for the prevention of fraud.19 Nor will we discuss result reporting, which also is subject to various types of error and potential influence of competing interests. Furthermore, the 3 articles in this series will include only the most basic statistical approaches. Back to Top | Article Outline RESEARCH APPROACHES Clinical research studies can be broadly categorized as retrospective or prospective. Retrospective studies use existing data on current and past patients to answer questions. These studies are conducted by assembling and organizing contemporaneously recorded information on past events, analyzing previously stored biosamples, and/or by returning to patients and physicians for further information about the past. Prospective studies answer questions by collecting new data on current and future patients over a future period during which medically relevant events occur, generally using methods specific to the intended research. Prospective studies can be either observational (noninterventional) or experimental (interventional), in the sense of manipulating study-related treatments. For example, an observational study might involve determining the concentration of a blood biomarker and evaluating relevant outcomes. Conversely, experimental interventions might include the use of a novel anesthesia regimen, intraoperative monitoring device, or temperature management protocol. Clinical studies also can be characterized by timing. In cross-sectional studies, for example, exposure and outcome are evaluated simultaneously. Cross-sectional studies thus essentially survey the state of affairs at a particular time without looking forward or backward. For example, is hypertension more common among current cigarette smokers than among nonsmokers? Or, is reflux less common among patients who take antacids? Cross-sectional studies, although useful for certain questions such as evaluating the prevalence of disease, are poor at capturing changes over time and hence provide little useful information for distinguishing causal from other relationships. Furthermore, cross-sectional studies may exclude important groups, such as people who die quickly, and thus are no longer represented in the population when the study is conducted. Consequently, cross-sectional studies are used only rarely in anesthesia research or in studies of treatment more generally, and we will not consider them further in this series. In case-control studies, investigators ask whether people with a particular disease, or whose disease has progressed, had different previous exposures than people who remained free of the disease or whose disease remained stable or improved. For example, are surgical patients who develop anaphylactic reactions more likely to have been exposed to latex, or are patients who experience intraoperative malignant hyperthermia crises more likely to have a history of heat stroke? In cohort studies, investigators look forward in time from exposure to outcome, by comparing frequencies and severities of outcomes in groups defined by different exposures. For example, do people with low vitamin D serum concentrations more often develop serious postoperative complications? The distinction can be nonobvious. For example, consider a study in which investigators compared anesthetic requirement in patients with and without fibromyalgia. The design might appear to be case-control because patients with and without disease are being selected. But, in fact, fibromyalgia is the exposure in this study and anesthetic requirement is the outcome. It is thus a cohort design. An advantage of prospective studies is that they allow researchers to plan and manage data collection, which usually improves data quality. Prospective studies also allow investigators to answer specific research questions more directly than is usually possible in retrospective research. The trade-off for these benefits is higher research costs and longer waiting times for answers. Comparative studies on treatments can be observational, when the researcher simply observes and describes current clinical practice. However, experimental studies generally are less prone to spurious findings than observational studies, and prospective cohort studies become experiments when researchers manage, rather than simply observe, the choice and use of treatments. When treatments are allocated randomly (i.e., "randomized") to patients, the result is a special type of cohort study called a randomized clinical trial (RCT). Randomization commonly is used, often in conjunction with concealment of treatment assignments from study participants and some investigators, a process known as "masking" or "blinding" allocation. RCTs that are blinded to the extent practical provide the clearest evidence of a therapy's effects but are not always practical, and there are other legitimate approaches to error mitigation, including alternating intervention designs.20 Two subsequent articles will discuss observational and randomized blinded studies in more detail. Back to Top | Article Outline SOURCES OF ERROR There is no perfect study. All are limited by practical and ethical considerations, and it is impossible to control all sources of error—even in fully randomized and meticulously blinded trials. Multiple studies are thus usually required to convincingly confirm (or disprove) a hypothesis. Most errors in clinical research arise from 5 major sources of methodologic problems: selection bias, measurement bias, reverse causation, excessive random (chance) variation, and confounding (Fig. 1). Within each of these general classes are many specific types of error such as recall bias, attrition bias, confounding by indication, and so on.21 Imperfect execution also hinders clinical research, as it does all human activities, but does not constitute methodologic error, and is hence beyond our scope here. Figure 1 Selection bias, measurement bias, and reverse causation are systematic sources of error. They stem from intrinsic aspects of a study's design and would be expected to occur similarly in multiple repetitions of similarly designed studies. In contrast, chance or random error describes the net effect of idiosyncratic influences, human variation, and trend-free time-to-time fluctuations in measurements and measurement processes. Random errors because of such chance variation would not, therefore, be expected to similarly recur were the study to be repeated. Confounding is a phenomenon—essentially, mistakenly attributing the influence of one exposure to another—that can be inherent in the medical situation being addressed or can arise as a consequence of selection bias, measurement bias, or chance. For example, pretzel consumption is associated with hepatic cirrhosis. However, pretzels do not cause cirrhosis; instead, it is beer consumed with pretzels that damages the liver. Statistical planning and analysis can be effective in controlling and assessing the effects of chance and in removing distortions because of anticipatable confounding. The other sources of error—selection bias, measurement bias, reverse causation, and possible confounding by unanticipated or even unknown factors—are most effectively addressed by strong study design. Back to Top | Article Outline Chance Chance error refers to the fact that the results of any given study will differ somewhat from the true biological situation because of random variation. Such variability is known to occur at multiple levels in medical research: from one patient to another, from measurements of the same patient from one time to another, and from one measurement to another of the same patient at the same time. For example, results may differ when portions of the same serum sample are analyzed by multiple autoanalyzers in the same or different laboratories. Similarly, interpretations of images and biopsy samples by multiple radiologists and pathologists may differ, as might results from the same radiologists and pathologists at different times. Such errors are more common and of greater magnitude than generally assumed.22–24 Undetected data recording error, from misplaced decimals, reversed digits, and transcriptions from incorrect fields on clinical report forms and spreadsheets are an omnipresent contributor to random variation in study results. Another source of random error can be artifact from inaccurate or missing information because of random malfunctions or inappropriate settings of an automated data collection instrument: for example, when a blood pressure cuff is disconnected or is positioned incorrectly during surgery. Similarly, artifact can occur in nonautomated data collection because of random misunderstanding of definitions by database coders. A type of measurement error, artifacts are more common than generally appreciated and have considerable potential to degrade analyses. We will discuss them later in this review in connection with measurement bias. In large, well-designed studies, the net effects of chance on estimated treatment effects and other primary study conclusions usually are limited. Sometimes, however, just by bad luck, and especially in studies with few patients and/or imprecise measurement methods, the influence of chance can be substantial and lead to an incorrect conclusion (i.e., no benefit or even harm, rather than benefit). The trouble is that without replication of a study or another form of confirmation, no one can know if its results faithfully represent the "true" biological situation or if chance (bad luck) led to a seriously mistaken inference. Before starting a study, investigators develop a scientific hypothesis: a specific statement of the biological mechanism or clinical theory for which evidence will be collected. For example: "delirium is reduced by propofol vs. postoperative sevoflurane anesthesia." From this base, 2 "statistical hypotheses" are generated against which evidence collected by the study will be weighed. The first, conventionally called the "null hypothesis H0," is that only chance governs variation in patient responses and thus that some systematic relationship implied by the scientific hypothesis does not exist: for example, "H0: Delirium is equally likely after propofol and sevoflurane anesthesia." The second is a statement about the sort of relationship anticipated if the scientific hypothesis were true, proffered as a logical alternative to chance variation alone as reflected in H0, and hence called the "alternative hypothesis" HA. Here, for instance, the alternative hypothesis would be "HA: Delirium is less common after propofol than sevoflurane anesthesia." This is a predicted consequence of the initial scientific conjecture in large populations of similar patients receiving the 2 types of anesthesia for similar surgeries, and can be reasonably assessed by observing samples of patients. A more general alternative hypothesis, appropriate to a less specific theory, would be H′A: the delirium incidences after propofol and sevoflurane anesthesia differ. This is a "2-sided" alternative because it counts departures from the null hypothesis H0 favoring either anesthetic as supportive, in contrast to the "1-sided" alternative specifying which best reduces delirium. (In general, investigators should a priori designate the most specific hypothesis consistent with their biological understanding, including expected directionality.) Researchers attempt to support alternative statistical hypotheses HA, and consequently the scientific hypotheses generating them, by obtaining enough data consistent with HA to falsify the corresponding null hypotheses Ho. This is effectively done if the data are shown to be of a very unusual sort if only chance were involved. Let us say that in the resulting study sample, delirium is actually less common after propofol than after sevoflurane anesthesia. The question then is whether the observed reduction is real (a true reflection of the biology) or whether it resulted from chance and/or from bias or confounding. The influence of bias and confounding is hard to evaluate and can be substantial; however, random error (chance) can be managed by the use of statistical tools, the 2 most common of which are P values and confidence intervals. The P value is an index between 0 and 1 of how easily the data can be accounted for by pure chance variation. Specifically, P values reflect whether the observed data are compatible with what might be expected within the range of chance variation for a study of similar size when the null hypothesis is true. In the most common circumstances, when the null hypothesis represents lack of difference or equality of treatment effects, the P value is an index of compatibility of the data with biological inactivity or with identical average effects of competing treatments. Thus, small P values are interpreted as representing data essentially incompatible with random chance, and hence "statistically significant" in supporting the hypothesized treatment effect by falsifying H0. A P value <0.05 is conventionally considered statistically significant, with smaller values reflecting collections of data less and less compatible with chance, and hence for which chance is less and less plausible as a sole explanation. The conventional P value threshold of 0.05 is essentially arbitrary, and there are certainly situations (i.e., biologically implausible associations) in which it is reasonable to require smaller P values. Similarly, differences that are not statistically significant may well be clinically important. We note though that a P value neither describes the actual magnitude of the clinical effect nor precludes the true effect differing considerably from that observed in a given study. The reason is that observed results are a combination of chance error superimposed on treatment benefit. Confidence intervals are thus used to describe the range of plausible treatment effects. For instance, a 95% confidence interval of 5% to 15% for the difference in the fractions of surgical patients who develop postoperative delirium after propofol or sevoflurane anesthesia is interpreted as meaning that the study data are compatible with a reduction in delirium risk anywhere between 5% and 15%. Formally, a confidence interval is a range of estimates of an unknown numerical characteristic of a population from which the study sample is obtained, such as delirium incidences in patients given propofol or sevoflurane in the population of interest rather than the study sample. This range is determined from the study data using a method that provides a specified chance, called the "confidence coefficient," that the range will include the parameter's true value. Other things being equal, high confidence requires wide intervals; narrow intervals can be obtained by accepting a greater chance of missing the target and thus lower confidence. Assuming technical assumptions are correct, approximately 95% of 95% confidence intervals can be expected to include the corresponding true targeted values. Investigators who state, based on their data, that the true reduction in delirium risk with propofol is between 5% and 15% can thus be 95% confident that the statement is true, assuming chance is the only source of error. The use of 95% in defining confidence intervals is arbitrary but has become a widely accepted medical research convention, largely because of a useful connection between confidence intervals and hypothesis tests. It is possible to test statistical effects, such as a difference in mean responses or a ratio of the fractions responding, by rejecting the hypothesized value if the confidence interval for the statistical effect excludes that value. For instance, we might hypothesize that the fraction of patients experiencing delirium after propofol anesthesia is half of the fraction experiencing it after sevoflurane anesthesia. That hypothesis would be rejected if the 95% confidence interval for the ratio of propofol to sevoflurane delirium risks generated by the data in our study excludes the value 0.5. Hypothesis testing defined this way will have false-positive probability (i.e., type 1 error, symbolically α) equal to the amount by which the interval's confidence coefficient falls short of certainty, that is, short of 100%. Thus, a 95% confidence interval extends the result of a conventional α = 5% level test of a statistical null hypothesis, by summarizing the results of similar tests of every possible other hypothesis: those with hypothesized values outside the interval are rejected, whereas those with hypothesized values in the interval are retained; this is the sense in which the latter are termed compatible with data (Fig. 2). Figure 2 An additional, and sometimes serious, source of chance error results when investigators either informally or formally test various hypotheses, thereafter choosing one that is "significant" or consistent with their biases. This process, colloquially known as "data mining," is much more prone to false-positive error than is conveyed by the conventional α = 5% associated with each individual test. This underlying "multiple testing" issue occurs in various guises. For example, the relationships of a disease to many possible risk factors (e.g., foods, occupational exposures, gene markers) may be simultaneously evaluated. Similarly, many different outcomes may be evaluated or a single outcome may be assessed at multiple time points. And finally, accumulating results of a study may be assessed periodically. The problem is that if each of a number of tests has chance α of producing a false-positive result when no effect is present, then the chance of at least some false positives when no effect is present increases with the number of tests performed to the point where false positives become virtually certain. The trouble is that false positives cannot readily be distinguished from true positives. Several strategies are available to address this problem. Perhaps the most important is a priori designation of a single primary outcome or of multiple outcomes with appropriate statistical compensation to preserve total false-positive error at a specified level α. Similarly, the specific statistical approach should be designated a priori. To assure a priori designation of these important design elements, most journals will only consider manuscripts describing clinical trials if the trials were publically registered before trial enrollment starts. Various study registries are available, but perhaps the most commonly used is Clinical Trials, which can be accessed at ClinicalTrials.gov. Despite its name, the registry is not restricted to trials and will accept cohort, case-control, and other types of clinical research. Trial registries contain important but limited information. Increasingly, investigators are separately publishing detailed methods of proposed studies, and some major journals are requiring submission and/or posting of study protocols, thus publically documenting a priori design and analysis choices. Unfortunately, neither P values nor confidence intervals preclude or incorporate effects of systematic errors, which are often far more important than chance errors. In other words, the chance of meaningful random error can be very low, but the results still completely wrong because of bias and/or confounding. Back to Top | Article Outline Selection Bias Selection bias occurs when otherwise-eligible participants are chosen nonrandomly for study inclusion and/or assigned to one treatment or another for nonrandom reasons, including reasons that might influence their response to treatment. This can result from subtle forms of the disease being missed or treatment being directed to patients thought most likely to benefit. For example, patients with better education or stronger support systems may seek treatment earlier or be given more aggressive treatment. Similarly, patients may comply poorly with or even stop particular treatments, either for perceived lack of efficacy or because of side effects, essentially selecting themselves out of a study. For example, in a study of postoperative cognitive deficits, those with compromised executive function may simply be unable to organize a return visit for testing, with the consequence that attrition bias makes the tested cohort appear to have better cognitive function than the full study population. The extent to which any of these events occur nonrandomly usually is difficult to assess. Directing a treatment to patients subjectively thought most likely to benefit is a perfectly natural and appropriate tendency in clinical care; however, the selection bias that results leads to what is known as "confounding by indication" in observational treatment comparisons, and the consequence is that one cannot be sure whether differences in treatment outcomes are because of differences in the effects of the treatments or initial constitutional differences in selected patients. In experimental studies, selection bias can largely be prevented by proper randomization followed by encouragement of patients, caregivers, and investigators to maintain the designated treatment allocation. Back to Top | Article Outline Measurement Bias In studies that use retrospective data collection, the quality of records is often poor because most recording systems were designed for clinical or administrative purposes rather than research. The difficulty is that existing record quality may vary nonrandomly. In contrast, the quality of prospectively collected data can be excellent in well-conducted studies in which data collection methods can be tailored to the research rather than to administrative objectives external to it. Measurement bias can result in any type of study, when any aspects of data quality, availability, or measurement method vary for reasons other than chance. For example, patients given new treatments may be watched more closely than those receiving conventional therapy, and enthusiastic clinicians may overestimate the benefits of new treatments or underestimate associated complications. Data artifacts also can easily produce measurement bias when data are distorted or missing nonrandomly. However, vulnerability to bias depends on precisely what is meant by "nonrandom." Errors or missingness occur "completely at random" if there are no correlates of their occurrence and magnitude, "at random" if their occurrence and magnitude have correlates but are independent of the data missed or distorted, and "not at random" if occurrence or magnitude depends on the unobserved true values of the distorted or missing data. Problems that occur completely at random increase chance variability but do not necessarily produce measurement bias, depending on the specific nature of the problem. In contrast, "at random" problems can easily generate bias, but such bias can be corrected by careful analysis if the correlates of the problem are known and have been measured, for example, if data are more frequently missing in the elderly but age is recorded. Measurement bias because of nonrandom artifact or missingness cannot be corrected in data analysis, and hence presents the greatest threat to research conclusions. The sensitivity of results to such problems, however, can be explored by "sensitivity analyses," that is, multiple analyses under different assumptions about the error-generating mechanism. Many papers presenting registry analyses do not adequately describe how artifact, and data accuracy more generally, were evaluated and handled, and how much artifact was found. It is likely that detailed descriptions of artifact definition, quantity, and handling will soon be required in registry reports, along with sensitivity analyses when artifact has the potential to substantively influence conclusions. Measurement bias in clinical data collection can be subtle and hard to detect. Consider, for example, a classic study by Schull and Cobb (Schull and Cobb 1969). The investigators asked an important question: Is arthritis hereditary? The experiment consisted of asking otherwise-similar people, with and without arthritis, whether their parents had arthritis. Their results are shown in Table 1. The results were clear: people with arthritis were far more likely to report that one or both parents also had arthritis. The difference was highly statistically significant, with a P value of 0.003. Table 1 There was just one problem. The subjects with arthritis and the subjects without arthritis were siblings; they had exactly the same parents! So what happened here? Were some of the subjects lying? Unlikely. Most likely, people with rheumatoid arthritis thought much more about arthritis than those who did not. And they were far more likely to have discussed the issue with their parents and thus know (and remember) whether their parents had arthritis. This is "family information bias," a specific example of what is more generally called "recall bias." There are many other types of measurement bias, some of which are equally subtle. An analog is that people with cancer are preoccupied with cancer and spend lots of time asking "why me?" Various environmental exposures, such as pesticides and workplace chemicals, are known to cause cancer in animal models and are thought or known to cause certain specific cancers in humans. Now let us say investigators are interested in whether environmental exposure contributes to the development of cancer. The most obvious approach would be to find a group of patients with cancer and a similar group without cancer, and then ask about their environmental exposures. The results are predictable: those with cancer will come up with long lists of exposures because the question was already on their minds. But when the investigators ask noncancer subjects if they have had major environmental exposures, the answers will usually be something like "Uh, no; not that I remember." The point is that such a difference in reported exposure would almost surely be statistically significant in a large study and almost certainly exaggerate the difference between cases and controls, if any, in real exposure. This is another example of recall bias. Measurement bias also results from the placebo effect, which should never be underestimated. This is especially the case for subjective responses such as pain and quality-of-life, but placebo effects also have repeatedly been shown to influence supposedly objective outcomes25–27 and, amazingly, patients report benefit from placebo administration even when they know that their "treatment" is a placebo (Fig. 3).27 Taking a placebo—even one they know is a placebo—makes people feel better or at least believe and say they feel better! Figure 3 Measurement bias in clinical trials can be largely controlled by blinding, sometimes called double blinding or triple blinding, to the extent that patients, clinicians who make treatment decisions and investigators who assess outcomes are unaware of which patients receive which treatments. Blinding does not remove placebo effects, which no one knows how to do, but distributes their benefits equally across patients in all treatment groups. Back to Top | Article Outline Confounding Confounding is distortion of an apparent association between 2 factors that results from failure to account for a third factor associated with both. Confounding most often is contemplated and recognized when it produces a statistically significant relationship that is not clinically or biologically real; however, confounding can also hide a true association. Confounding is an important and sometimes subtle source of error because such alternative influences may not even be suspected. In retrospective studies, potential confounding factors may be well known but unavailable for analysis by virtue of not being included in clinical records. To take a trivial example, the rate of mortality is much greater in Florida than Alaska. Is this because Florida is a more dangerous place to live? Should Florida retirees move to Alaska to enjoy a longer retirement? No. To do so would be to mistakenly attribute effects of biology to effects of geography. Mortality is greater in Florida because the median age of Floridians is 7 years greater than that in Alaska. In other words, the relationship of mortality to the state in which one resides is confounded by age, the factor that links exposure (the state of residence) with outcome (mortality). Of course, if investigators know that age is important, and know the ages of people in each state, then it is easy to compensate. For example, you might compare mortality of subgroups of people of similar ages in each state; you might also use statistical adjustments to compensate for differing ages. The trouble is that potential confounding factors often are unknown. Alternatively, factors may be suspected confounders, but the data needed for adequate statistical compensation may not be available. To the extent that these factors influence the results, conclusions can be quite wrong, with the extent of the error being essentially unknown. As an example of confounding by indication, blood transfusions are strongly associated with adverse outcomes, including mortality. However, blood transfusions are far more likely to be required by patients who are sickest in the first place. When one compares the mortality of groups differing in how many blood transfusions have been administered, one is implicitly comparing groups with very different levels of underlying illnesses. It is quite possible that underlying illness contributes more to subsequent mortality than the blood transfusions themselves. Consider, for example, patients who have anemia, which often accompanies chronic diseases, including cancer, or patients having especially long and/or large operations. These patients are more likely than others to need a blood transfusion, and they are more likely to have bad outcomes. But the 2 are not necessarily directly linked; instead, they are indirectly linked (i.e., confounded) by the fact that sicker patients having larger operations are more likely to both need blood and have bad outcomes. The important point is that a statistical association (i.e., P < 0.05) of transfusions with bad outcomes would not necessarily imply that restricting transfusions will improve outcomes because an entirely beneficial causal effect of transfusions may be concealed by the competing causal effect of the poorer initial conditions of patients who require them. Even an exceptionally statistically significant excess of adverse outcomes in transfused patients might be completely spurious, because of the separate associations of the need for transfusion and adverse outcomes with initially poor prognosis for unrelated reasons. The extent to which these subtle and hard-to-quantify confounding factors contribute to research conclusions can be difficult to determine retrospectively. In other words, blood transfusions may actually worsen outcomes, but it is equally possible that outcomes are worse in patients given transfusions by virtue of factors that led to their being transfused. The distinction is critical because restricting transfusions will only improve outcomes if the first mechanism is accurate. Or, to make a stronger statement, basing transfusion policy on a spurious relationship would likely harm patients by denying them needed transfusions. It is easy to confuse confounding, a statistical problem that can arise without a biologically or clinically meaningful basis, solely because of composition of a research sample, with "effect modification," which is a manifestation of nature's complexity that may be of critical clinical importance. Consider 2 examples. First, suppose therapy A outperforms therapy B to a similar degree whether men or women are treated, but women generally do better than men. Suppose 10% of men but only 1% of women experience the least desirable outcome, regardless of which therapy they receive. If therapy A has an unpleasant side effect occurring mostly in men, so men receive B more than women, then the relative benefit of A will be exaggerated by comparing the more frequently female recipients of A with the more frequently male recipients of B. For instance, if 70% of those receiving therapy A are female, and 70% of those receiving therapy B are male, then the least desirable outcome will be experienced by only 0.3 × 10% + 0.7 × 1% = 3.7% of those on therapy A but by 0.7 × 10% + 0.3 × 1% = 7.3% of those on therapy B. To the naive who compare these proportions without regard to the different gender compositions of the patient groups, therapy A will appear to have halved the event rate relative to therapy B, although the performances of the 2 therapies are actually identical. This is confounding, (specifically, confounding by indication), a failure to compare appropriately similar groups, in a manner fully analogous to the earlier geographical example, with therapies A and B playing the respective roles of Alaska and Florida, and men and women playing the respective roles of seniors and younger folks. Second, consider a situation in which, because of underlying biological mechanisms, therapy A is more effective and less toxic in men whereas therapy B is more effective and less toxic in women. Or, to take an extreme example, for a disease with case fatality of 50% in untreated patients, suppose for those receiving therapy A the case fatality decreases to 25% in men but increases to 75% in women, with these numbers reversed, case fatalities of 75% in men but 25% in women, among recipients of therapy B. This is effect modification, in which the relative effect of an exposure or treatment differs from group to group, in this case as a function of sex. In this example, the effect of therapy A relative to therapy B is to triple (75% vs 25%) the case fatality among women, but to reduce it by two-thirds (25% vs 75%) among men. Unlike confounding, which is essentially a research error, effect modification describes biological situations with distinct clinical implications and needs to be understood if treatments are to be optimally applied. Aspects of the patient's condition or circumstances are candidates for effect modifiers. A well-known example is that the benefit of streptokinase and other thrombolytic agents for improving stroke outcomes depends on the time elapsed after stroke onset. Specifically, the substantial benefit achievable with early administration is modified (in this case largely lost) when a thrombolytic is given too late. Back to Top | Article Outline Reverse Causation Reverse causation is a special and rare type of error in which the roles of cause and effect are misconstrued, so an effect is mistaken for a cause and a cause mistaken for an effect. For example, certain organisms are more commonly isolated from the esophagus in patients with esophageal cancer or precancerous conditions than from healthy controls. However, a conclusion that such organisms cause the cancer would be incorrect because the cancerous condition may produce tissue changes altering the microenvironment and consequently the esophageal microflora. Reverse causation errors occur when investigators have difficulty identifying the timing, and particularly the ordering, of when a patient is exposed to a risk factor of interest and when the relevant disease outcome first occurred. Such errors are of most concern in studies with retrospective data collection. However, reverse causation error also can occur in prospective studies of long-term exposures and/or chronic disease, where data collected prospectively may reflect long-standing lifestyle and environmental factors and disease signs or symptoms that may have originated much earlier with sequence unknown. For instance, prospective cohort studies of cancer etiology typically exclude cases diagnosed early during the follow-up period because they may have been latent at the study's start and been initiated before the study's assessment of the exposure. The problem this causes is evident in studies on smoking and lung cancer. In such studies, lung cancer is found more often among smokers who recently quit than among current smokers because some people with early symptoms of cancer stop smoking before accruing a formal diagnosis. Reverse causation thus makes it appear as if quitting smoking promotes cancer, which is not actually the case. Back to Top | Article Outline CONCLUSIONS Clinical research can be categorized by the timing of data collection: retrospective or prospective. Clinical research also can be categorized by study design. In cross-sectional studies, exposure and outcome are evaluated simultaneously. In case-control studies, investigators compare previous exposures (including genetic and other personal factors, environmental influences, and medical treatments) between groups distinguished by later disease status (broadly defined to include the development of disease or response to treatment). In cohort studies, investigators compare the subsequent incidence of disease between groups distinguished by one or more exposures. The major sources of error in clinical research are selection bias, confounding, measurement bias, reverse causation, and chance. Selection bias results from nonrandom allocation of patients to exposures in a way that influences outcomes. Confounding results when an apparent association between a particular exposure and disease actually results from their separate relationships with something else, termed a "confounder." Measurement bias results from nonrandom errors in assessing exposure and/or disease. Reverse causation errors occur when the timing of exposure and disease development are unclear, allowing a consequence of a disease process to be mistaken for a contributing cause. Chance error refers to the fact that the results of any given study will not perfectly reflect the true biological situation because of random variation from one patient to another, of the same patient from one time to another, and from one measurement to another. Clinical research errors in general, and biases in particular, are best avoided by a strong study design coupled with thoughtful statistical analysis. Although the latter can compensate for confounding to the extent that factors are known and measured, formal statistical methods are most effective in coping with evaluating random variation. Hence, although design and analysis are both important, prevention by design is usually much preferable to correction by analysis. Our next article will discuss observational study designs and the nature of statistical corrections for confounding in observational studies in more detail. The third article will focus on experimentation, specifically on the design features of RCTs that attempt, and may reasonably be expected to succeed, in protecting against the 5 major sources of clinical research errors. Back to Top | Article Outline DISCLOSURES Name: Daniel I. Sessler, MD. Contribution: This author helped write the manuscript. Attestation: Daniel I. Sessler approved the final manuscript. Name: Peter B. Imrey, PhD. Contribution: This author helped write the manuscript. Attestation: Peter B. Imrey approved the final manuscript. This manuscript was handled by: Steven L. Shafer, MD.Back to Top | Article Outline REFERENCES 1. Graunt J Natural and political observations mentioned in a following index, and made upon the bills of morality. London: Thomas Roycroft, 1667. Available at: http://www.edstephan.org/Graunt/o.html. Accessed June 26, 2015 Cited Here... 2. Snow J On the mode of communication of cholera. London, England: John Churchill, 1855. Available at: http://www.ph.ucla.edu/epi/snow/snowbook.html. Accessed June 26, 2015 Cited Here... 3. Koch R Investigations into the Etiology of Traumatic Infective Diseases. 1880 London The New Sydenham Society Cited Here... 4. Hill AB. The environment and disease: association or causation? J R Soc Med. 1965;108:32–7 Cited Here... 5. Feinstein AR Clinical Judgement. 1967 Baltimore, MD Williams & Wilkins Cited Here... 6. Feinstein AR The Architecture of Clinical Research. 1985 Philadelphia, PA W.B. Saunders Company Cited Here... 7. Feinstein AR Clinimetrics. 1987 New Haven, CT Yale University Press Cited Here... 8. Sackett DL, Haynes RB, Tugwell P, Guyatt G Clinical Epidemiology: A Basic Science for Clinical Medicine. 19912nd edition Philadelphia, PA Lippincott, Williams and Wilkins Cited Here... 9. Medical Research Council Investigation, Streptomycin in Tuberculosis Trials Committee. . Streptomycin treatment of pulmonary tuberculosis. Br Med J. 1948;2:769–82 Cited Here... 10. Medical Research Council Investigation. . The prevention of whooping-cough by vaccination. Br Med J. 1951;1:1463–71 Cited Here... 11. Chalmers TC. Randomization and coronary artery surgery. Ann Thorac Surg. 1972;14:323–7 Cited Here... | PubMed | CrossRef 12. Chalmers TC, Eckhardt RD, Reynolds WE, Cigarroa JG Jr, Deane N, Reifenstein RW, Smith CW, Davidson CS. The treatment of acute infectious hepatitis. Controlled studies of the effects of diet, rest, and physical reconditioning on the acute course of the disease and on the incidence of relapses and residual abnormalities. J Clin Invest. 1955;34:1163–235 Cited Here... | PubMed | CrossRef 13. Cochrane AL Effectiveness and Efficiency: Random Reflections on Health Services. 1973 London Nuffield Provincial Hospitals Trust Cited Here... 14. Sackett DL, Richardson SW, Rosenberg W, Haynes RB Evidence-Based Medicine: How to Practice and Teach. 1996 Edinburgh Churchill Livingstone Cited Here... 15. Antman EM, Lau J, Kupelnick B, Mosteller F, Chalmers TC. A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts. Treatments for myocardial infarction. JAMA. 1992;268:240–8 Cited Here... | PubMed | CrossRef 16. Chalmers I, Haynes B. Reporting, updating, and correcting systematic reviews of the effects of health care. BMJ. 1994;309:862–5 Cited Here... | View Full Text | PubMed | CrossRef 17. Ware JH. Statistical practice and statistical education in cardiology. Circulation. 1987;75:307–10 Cited Here... | View Full Text | PubMed | CrossRef 18. Ivanova A, Rosner GL, Marchenko O, Parke T, Perevozskaya I, Wang Y. Advances in statistical approaches oncology drug development. Ther Innov Regul Sci. 2014;48:81–9 Cited Here... 19. Sessler DI, Kurz A. Departmental and institutional strategies for reducing fraud in clinical research. Anesth Analg. 2012;115:474–6 Cited Here... | View Full Text | PubMed | CrossRef 20. Kopyeva T, Sessler DI, Weiss S, Dalton JE, Mascha EJ, Lee JH, Kiran RP, Udeh B, Kurz A. Effects of volatile anesthetic choice on hospital length-of-stay: a retrospective study and a prospective trial. Anesthesiology. 2013;119:61–70 Cited Here... | View Full Text | PubMed | CrossRef 21. Chavalarias D, Ioannidis JP. Science mapping analysis characterizes 235 biases in biomedical research. J Clin Epidemiol. 2010;63:1205–15 Cited Here... | PubMed | CrossRef 22. Freedman M, Osicka T. Reader variability: what we can learn from computer-aided detection experiments. J Am Coll Radiol. 2006;3:446–55 Cited Here... | PubMed 23. Whiteside JL, Hijaz A, Imrey PB, Barber MD, Paraiso MF, Rackley RR, Vasavada SP, Walters MD, Daneshgari F. Reliability and agreement of urodynamics interpretations in a female pelvic medicine center. Obstet Gynecol. 2006;108:315–23 Cited Here... | View Full Text | PubMed | CrossRef 24. Quinn TJ, Dawson J, Walters MR, Lees KR. Reliability of the modified Rankin Scale: a systematic review. Stroke. 2009;40:3393–5 Cited Here... | View Full Text | PubMed | CrossRef 25. Price DD, Finniss DG, Benedetti F. A comprehensive review of the placebo effect: recent advances and current thought. Annu Rev Psychol. 2008;59:565–90 Cited Here... | View Full Text | PubMed | CrossRef 26. Benedetti F. Placebo and the new physiology of the doctor-patient relationship. Physiol Rev. 2013;93:1207–46 Cited Here... | PubMed | CrossRef 27. 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Today marks six weeks. Six weeks since Killian died. As of tomorrow, he will have been gone longer than he was here. It's surreal. It's raw. It opens up some of those deep wounds that had begun to start to heal. I have missed my baby longer than I didn't. I've look at his pictures … Continue reading Six weeks since my baby died
Tag: illness
Infant and child loss…I am 1 in 4.
When people look at me they see a lot. Some may thing I look nice. Some may think I look unapproachable and cold. Some may think I look like I have all my shit together. Some may think I look like a hot mess. Funny, crazy, confident, strange, friendly, cold. When you look at anyone, … Continue reading Infant and child loss…I am 1 in 4.


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Alice Fredenham was a highly unusual contestant. Instead of bringing her adoring fan club of friends and family members, Alice decided against having anyone coming in with her. She was so terrified of anyone knowing she signed up, let alone sang, that she didn't tell a soul. A pre-stage interview revealed that she suffered from intense stage fright. She was tearing up just talking about the immense anxiety that she felt at the thought of going out on stage and hearing the judges reject her.
The shy 28-year-old reasoned that if she wasn't successful she "wouldn't have to admit that to anyone" if no one came along to watch her. Already balling up in an awkward stance, Alice stepped up to the microphone with her hands folded in front of her.
For anyone who doesn't suffer under the plight of social anxiety or stage fright in general, it's hard to understand why this was such an act of courage for this young woman. Your heart beats its way up into your throat, and a flood of thoughts batter the insides of your head. It's like your mind and body don't want to cooperate anymore. For her to get on that stage and speak to the judges was brave enough but singing the way she did, feeling the way she did, was incredible.
Simon Cowell, the king of mean, manages to utter a shocked "Oh My God" as the other judges subsequently profess their love for the brilliant singer before them. My heart really goes out to this inspiring lady for overcoming her fears. Watch her wonderful performance in the video below.
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- Number of Stones: 1
- Shape: Round
- Stone Color: White
- Stone Type: Pearl
Product Details
Sterling Silver Freshwater Button Pearl and Cubic Zirconia Heart Necklace
Beautiful and elegant this necklace from PearlGirl features a round 10-11 mm freshwater white pearl with round cubic zirconia set in sterling silver. This heart pendant is hung on a cable chain and is secured with a spring ring clasp.
Freshwater Pearl:
Pearl type: Freshwater
Grade: AA
Color: White
Pearl size: 8-8.5 mm
Cultured pearls
Cubic Zirconia:
Gemstone: One
Color: White
Cut: Round
Metal information and dimensions:
Style: Necklace
Shape: Drop
Metal: Sterling silver
Finish: High polish
Chain: Ball
Chain length: 18 inches
Clasp: Spring ring
Metal weight: 0.6 grams
Pendant dimensions: 9 mm wide by 1 inch long
Necklace dimensions: 3-4 mm wide x 18 inches long
- PearlGirl Sterling Silver Freshwater Button Pearl and Cubic Zirconia Heart Necklace (10 - 11mm)
- Perfect for Gift Giving!
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Sterling Silver Freshwater Button Pearl and Cubic Zirconia Heart Necklace Sterling Silver Pearl White Round Under 1/10 ct June Birthstones Freshwater Cultured
- Pendant and Necklace Total Number of Stones (Genuine and Lab-Created Gemstones): 1
- Necklace Length: 18 to 19.75 Inches
- Necklace Type: Pendants
- Metal Stamp: 925 Sterling
- Dimensions: 1.0 inches (H) x 2.0 inches (W) x 2.0 inches (L)
- Weight: 3.0 ounces
- Included in the box: 1 STG Chain 1 STG Pendant
- Made in Canada
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