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How to Make Hypotheses,顧進裕高醫大腎臟內科,啟川大樓14ES07-3121101 EXT.735312,How to Make Hypotheses,IntroductionResearchLogicCausationHypothesisDiscussion,不知道與好奇心生下了為什麼為什麼與數學生下了科學科學與藝術生下了醫學,Ren Descartes(March 31,1596 February 11,1650),我思故我在(Cogito,ergo sum),1.除了清楚明白的觀念外，絕不接受其他任何東西 2.必須將每個問題分成若干個簡單的部分來處理3.思想必須從簡單到複雜4.我們應該時常進行徹底的檢查，確保沒有遺漏任何東西,懷疑是智慧的源頭:,讀書時，不要急著辯駁，也不要盲目信從，或僅僅想找一個茶餘飯後的話題，而是要去思考和判斷。有些書淺嚐即可，有些書不妨狼吞虎嚥，有些書卻需要細細嚼、慢慢嚥，換句話說，有些書只需要選讀，有些書只需要瀏覽，有些書卻需要從頭到尾，仔細地體悟與省思。Francis Bacon,The difficulty lies,not in the new ideas,but in escaping the old ones.-John Maynard Keynes,English economist,創造力的來源遺傳努力工作(genius is 99%perspiration)知識(Francis Bacon)忘記學校所教的(H.P.);遊戲蘋果;在沙灘撿石頭;站在巨人肩上洗澡犯錯(Penicillin)看星星(PCR)做夢(aromatic)修行(朱銘),頓悟Quantum leap,Paradigm shift,If at first the idea is not absurd,then there is no hope for it.Imagination is more important than knowledge.Education is what remains after one has forgotten everything he learned in school.The important thing is not to stop questioning.Curiosity has its own reason for existing.Anyone who has never made a mistake has never tried anything new.,Sir Arthur Conan Doyle,1859-1930,Inspector Gregory:“Is there any other point to which you would wish to draw my attention?”Holmes:“To the curious incident of the dog in the night-time.”“The dog did nothing in the night time.”“That was the curious incident,”remarked Sherlock Holmes.-The adventure of Silver Blaze,GoogleGoogle scholarPubmedWikimediaLibrary of KMU,Heuristics(啟發式思考)1.If you are having difficulty understanding a problem,try drawing a picture.2.If you cant find a solution,try assuming that you have a solution and seeing what you can derive from that(working backward).3.If the problem is abstract,try examining a concrete example.4.Try solving a more general problem first(the inventors paradox:the more ambitious plan may have more chances of success).-How to Solve,科學理論的標準,清晰及合符邏輯(Logical and Clear)內部一致(Internal Consistency)提供可驗證的假說(Testable Hypotheses Can be Deduced)可被推翻和否定的(Can be Disconfirmed or Falsified)通則性(Generalizability)簡約的(Parsimonious):Occams razor,理論及假說的建構,需要抽象的思維及合理的邏輯推論。合乎科學理論的標準。難有具體的指引及系統的步驟可供跟隨。必須對相關的文獻作一回顧，先了解前人對相關構念及題目的研究。最好是把這些研究用不同的準則來分類，也試看一下有那些問題是尚未為它們所回答的。到一定程度時嘗試用簡單的構念和它們之間的關係來回答那些有趣的問題。,小結,真正的科學研究必由理論出發，而以驗證及改良理論為終如果尚未建構清楚的理論模型及假說，不應以碰運氣的方式從實證的資料中看那些變項呈相關，然後撰寫報告，我們稱這樣的做法為在資料中採礦(data mining)，是不應該的，因為這與科學研究的本意相違背如果我們在驗證理論時，從資料中發現意外的現象，那就作為日後進一步驗證新的假說的基礎,How to Make Hypotheses,IntroductionResearchLogicCausationHypothesisDiscussion,研究的種類,A:Hypothesis-drivenDiscovery-drivenMethodB:基礎研究:分子、細胞、動物臨床研究:診斷或篩檢、治療、預後、病因或副作用C:相關:Observational因果:Experimental,研究問題(Research Problem),重要性:那一個最重要?貢獻性原創性常見性花錢性致病性與致命性相關性影響性知識性與理論性實用性可行性,Goals&Objectives,Goal:Long-term goal to solve the problemObjectives(specific aims):Short-term objectives to solve the specific problems or answer the questions(hypotheses).It should be logical(inevitable from the background)Exploration,description,hypothesis testing,case study,Would you tell me,please,which way I ought to go from here?said Alice.That depends a good deal on where you want to get to,said the Cat.I dont much care where-said Alice.Then it doesnt matter which way you go,said the Cat.-so long as I get SOMEWHERE,Alice added as an explanation.Oh,youre sure to do that,said the Cat,if you only walk long enough.,Goals&Objectives,醫學論文各節的功能,題目與摘要:敘述問題與答案前言:為什麼(Why)問這個問題材料與方法:如何(How)解決這個問題結果與圖表:發現什麼(What)去解決這個問題討論:提出並解釋對於這個問題的答案參考文獻:我站在巨人的肩上,所以(對於這個問題)能看得更遠-牛頓,Hypotheses or Questions(1),The most important statement in“Introduction”A super-topic sentence(in present tense)Sometimes stated as objectives(specific aims)Logical(inevitable)from the background(every question must have a background),Hypotheses or Questions(2),If question has been stated completely in the unknown in“Background”:To answer this question,If question has been stated only partially in the unknown:Therefore(Hence),we tested the hypothesis that we asked(the question)whether we(attempted to)determine were studied to address X questions:First,If question is to be stated as an objective:To determine whether(which),we,How to Make Hypotheses,IntroductionResearchLogicCausationHypothesisDiscussion,表1歸納法與演繹法比較,Logical reasoning Given preconditions,postconditions and the rule R1:(therefore).Deduction:determining.It is using the rule and its preconditions to make a conclusion(R1).Induction:determining R1.It is learning R1 after numerous examples of and.Abduction(溯因):Inference to the best explanation.One chooses hypothesis which would,if true,best explain the evidence(R1).,Inductive ReasoningGeneralization:My cat likes tuna,his cat likes tuna,etc.All or most cats like tunaStatistical syllogism:Most cats like tuna.Sloth is a catSloth likes tunaSimple induction:All of the cats Ive known like tunaThis new cat will like tunaAnalogy:Jim and Bill have similar characteristics.Jim is loved by his classmatesBill is liked by his classmates,Deductive Reasoning(I),Deductive Reasoning(II),已知所有的藥物都有副作用,若某甲宣稱他的新藥沒有副作用此話為真,則邏輯上如何?某奶粉公司添加抗體,宣稱能預防病菌?某酵素能在試管中化痰,請問該酵素口服後是否可能有效?某科學家訓練一隻跳蚤在聽到大聲後便會跳高,當他把該跳蚤的雙腿剪斷後,跳蚤在聽到大聲後卻不會跳高,因此證明了跳蚤是用雙腿聽聲音?,Logic(1),科學論文是由論證(argument)所構成的論證=前提(premise)+推論(inference)+結論(conclusion)有效的(valid)論證:前提蘊含結論,若你接受前提,則你必須接受結論真確的(sound)論證:“前提是真”的有效論證,已知:若 P 則 Q演繹法(deduction,數學上的必然):若 P 則 Q;若 Q 則 P歸納法(induction,統計上的可能):簡單枚舉法、排除歸納法與統計歸納法 假設法(abduction,科學上的創新):若Q 則 P;若 P 則 Q,Logic(2),已知:若p53基因突變(P)則有癌症(Q)演繹法(deduction,數學上的必然):一定對某甲的p53基因有突變,因此有癌症某乙沒有癌症,因此他的p53基因沒有突變歸納法(induction,統計上的可能):可能對我所遇見的每一個癌症病人其p53基因都有突變,因此我歸納:若p53基因突變則有癌症假設法(abduction,科學上的創新):可能對某丙有癌症,因此他的p53基因可能有突變;若p53基因沒有突變,則某丙不會有癌症,Logic(3),How to Make Hypotheses,IntroductionResearchLogicCausationHypothesisDiscussion,Kochs Postulates1.The organism must be found in all animals with the dis.(but not in healthy animals).2.The organism must be isolated from a dis.animal and grown in pure culture.3.The cultured organism should cause dis.when introduced into healthy animals.4.The organism must be reisolated from the experimentally infected animal.,因果相關(Bradford-Hill Criteria),一致性:所有的研究結果都一致強度特異性:沒有其他的原因或解釋能造成這樣的結果 劑量-效應性:因素愈強,效果愈大時間性:原因一定要出現在結果之前生物學的可能性:生理病理學上的可能性凝聚性:與現有的理論不矛盾實驗性:可用實驗來改變原因而改變結果,How to Make Hypotheses,IntroductionResearchLogicCausationHypothesisDiscussion,科學研究的主要內容變項:被研究對象的某一屬性因時地人物不同而在質或量上的變化操作型定義:根據可觀察測量或可操作的特徵來界定某一名詞或概念 假設:變項之間的假設性關係 假說:經過證實的假設 定律:經過重複驗證的假說 理論:有組織、有架構、具有邏輯關係的假說或定律,醫學是不確定的科學也是可能性的藝術Medicine is a science of uncertainty and an art of probability-William Osler,The more precisely the position is determined,the less precisely the momentum is known in this instant,and vice versa.-Heisenberg,uncertainty paper,1927,科學是確定的學問嗎?,Karl Raimund Popper1902-1994,真不能被證明，只有偽可以被證明(真理是到現在為止尚未被否証的假說),科學的假說,事實論點皆須客觀地驗證，而非不證自明。不能完全依賴傳統、主觀信念、或常識來檢驗科學知識。科學思維是要抱持懷疑、批判的態度。,沒有不證自明(self-evidence)的事,知識是來自人們的經驗,所有知識是暫時性的,強調科學知識應基於經驗方面可觀察的假設之上。,科學家目前採用的証據、方法和理論，來提出其暫時性的知識，它有可能隨時被修正。,Hypothesis A suggested explanation for a phenomenon or of a reasoned proposal suggesting a possible correlation between multiple phenomena.The scientific method requires that one can test a scientific hypothesis.Hypotheses are based on previous observations or on extensions of scientific theories.,Types of Hypotheses1.A causes B:If a particular independent variable changes,then a certain dependent variable also changes.This formulation,also known as an If and Then statement.2.A is related to B:Investigators may have more difficulty in verifying causal relationships than other correlations,because quite commonly intervening variables also become involved.,假設(Hypothesis),有時候以問題的方式提出,每一個假設都要有背景目的:解釋舊事實、預測新事實、挑戰舊理論、建構新理論、尋找真理能回答的能被否證(falsifiable)的要素:研究的族群、變數(自變數與應變數)之間的關係(因果相關或純相關),Functions of Hypotheses,To explain old factsTo predict new factsTo challenge an old theoryTo build a new theoryTo search for truth(research=to search again),Hypotheses or Questions,Falsifiable(measurable&testable):虛無假設(否証,若P0.05 則否証失敗)、對立假設Answerable(methods to answer)Species/population studied,relationship(causal or correlational)between in-dependent&dependent variables,Hypothetico-deductive model 1.Gather data(something that is unknown,unexplained,or new)2.Hypothesize an explanation for those observations.3.Deduce a consequence of that explanation.(A prediction)3.Design an experiment to see if the predicted consequence is observed.4.Wait for corroboration.If there is corroboration,go to step 3.If not,the hypothesis is falsified.Go to step 2.,Evaluating HypothesesTestibilitySimplicity(as in the application of Occams Razor,discouraging the postulation of excessive numbers of entities)3.Scope-the apparent application of the hypothesis to multiple cases of phenomena 4.Fruitfulness-the prospect that a hypothesis may explain further phenomena in the future 5.Conservatism-the degree of fit with existing recognised knowledge-systems,Hypothesis A proposition about the solution to a problem,the relationship of variables:1.An expected relationship between variables2.Based on either theory or evidence3.Testable4.Brief with clarity5.Stated in declarative form6.Be operational by eliminating ambiguity in the variables or proposed relationships,HypothesisTestibility(compare falsifiability as discussed above)Simplicity(as in the application of Occams Razor,discouraging the postulation of excessive numbers of entities)Scope-the apparent application of the hypothesis to multiple cases of phenomena Fruitfulness-the prospect that a hypothesis may explain further phenomena in the future Conservatism-the degree of fit with existing recognised knowledge-systems,Testability of HypothesesContingency,defeasibility,or falsifiability:Counterexamples to the hypothesis are logically possible Feasibility of observing a reproducible series of such counterexamples if they do exist.In short,a hypothesis is testable if there is some real hope of deciding whether it is true or false of real experience.Upon this property of its constituent hypotheses rests the ability to decide whether a theory can be confirmed or falsified by the data of actual experience,Four Components of a Hypothesis1.Subject group:Who are you interested in studying?2.Treatment or exposure:What is being done to your subject group?3.Outcome measure:How is the treatment or exposure assessed?(defined precisely and unambiguously)4.Control group:Who are you comparing to.It is important for the control group to be as similar as possible to those who receive a treatment or exposure.Not every research hypotheses will have all four components.For example,a cross-over design involves applying both a new treatment and a standard treatment using the same patients.For this study,the hypothesis would not involve a separate control group.Correlational studies look at relationships within a single group,such as a study of the factors that cause medication errors.This type of study would not have a treatment/exposure.The structure mentioned here,however,is still useful for developing most research hypotheses.,統計的假設,用反駁法來證明建立虛無假設（null hypothesis），以及替代假設(alternative hypothesis)虛無假設自變數與應變數之間沒有關聯替代性假設自變數與應變數之間有關聯以推翻虛無假設來支持實驗的假設,How to Make Hypotheses,IntroductionResearchLogicCausationHypothesisDiscussion,假說型實驗或敘述型實驗,一般而言，假說型實驗較受喜歡。假說型實驗之決定點在於新穎性及可行性。但這兩者常是相互矛盾，所以通常會用混合型。敘述型實驗，不管有些科學家喜不喜歡，是很重要，常是重要科學發現之基礎。敘述型實驗常是用來產生假說，所以在描述敘述型實驗，應再說明可能產生之假說及如何進一步深入探討。或在敘述型實驗中加入重要性及比較性。,非假說型實驗之必要性,The basic study of E.coli system lead to the development of recombinant DNA.Human Genome ProjectKnockout mice experiments lead to important scientific developments.Structural study or structure-function study are mostly non-hypothesis based.Assay of MAPK,JNK,ERK pathways,systematic analysis.,Reductionism Complex things is reduced to the nature of sums of simpler or more fundamental things,e.g.objects,phenomena,explanations,theories,meanings:Chemistry is based on physics,biology and geology are based on chemistry,psychology is based on biology,sociology is based on psychology,and political science,anthropology,and even economics are based on sociology.,Systems thinking The component parts of a system will act differently when isolated from its environment or other parts of the system,and argues against Descartess reductionist view.It views systems in a holistic manner,rather than through purely reductionist techniques,Hypothesis-driven(Reductionism),Discovery-driven(Systems biology),To Beginners,Dont be too ambitious,and try to focus on too many aims.,