The age of personalization really began with the precision cancer movement. A diagnosis of cancer is traditionally defined by the anatomical site of origin, but in 2017 we witnessed regulatory approval of the first cancer drug focused on disturbed cellular function, with the identification of the cancer type linked to a specific mutation of the cancer cell rather than to an organ.¹⁸ As recently as the 1990s, treatment for many cancer patients came in the form of relatively ineffective toxic chemotherapy because 'evidence” -as it was defined in that era- supported the use of these medications. Today, the field of oncology has significantly evolved as a result of the advancement in understanding of the molecular genetic etiology of cancer, which in turn has made it possible to personalize therapeutic interventions in a manner that is more efficient for both physicians and patients.¹⁹ New clinical trial designs were instrumental in forging this new era of cancer treatment. One- an adaptive study design that features 'umbrellas' and 'baskets'-allows for the stratification of patients into various cohorts that are assigned treatments based on personalized genetic information. This type of protocol assists researchers in collecting evidence of a drug's effectiveness in terms of unique patient sensitivity and response to an intervention.²⁰  Stratifying a study population according to specific biomarkers and then using combined cellular and biochemical profiling to identify predictive responses to specific therapies is a pioneering approach.²¹ The increased use of genomic sequencing and profiling has fundamentally changed the nature of diagnosis from that of the population to that of the individual. It is a logical and needed next step for clinical trial design to change in a responsive manner, and for the parameters that guide how evidence in support of therapy is defined to be reexamined as well.²²

個(gè)性化時(shí)代真正開始于精準(zhǔn)化的癌癥治療運(yùn)動(dòng)。癌癥的診斷傳統(tǒng)上是由解剖部位來定義的，但在2017年，我們見證了第一種監(jiān)管機(jī)構(gòu)批準(zhǔn)的以細(xì)胞功能紊亂為切入點(diǎn)的癌癥治療藥物，確定了與癌細(xì)胞的特定基因突變相關(guān)的癌癥類型，而不是與器官相關(guān)的癌癥類型。18-20世紀(jì)90年代，對(duì)于許多癌癥患者來說，治療癌癥的方法實(shí)際上是相對(duì)無效的毒性的化學(xué)療法，但是因?yàn)榇嬖凇白C據(jù)”（依據(jù)那個(gè)時(shí)代的定義）而支持使用這些藥物。如今，隨著對(duì)癌癥分子遺傳學(xué)病因?qū)W理解的進(jìn)步，腫瘤學(xué)領(lǐng)域取得了長足的進(jìn)步，從而使個(gè)性化治療干預(yù)成為可能，使醫(yī)生和患者都能更有效地進(jìn)行治療干預(yù)¹⁹。新的臨床試驗(yàn)設(shè)計(jì)有助于構(gòu)建一個(gè)癌癥治療的新時(shí)代。借助于一種以“雨傘”和“籃子”為特征的適應(yīng)性研究設(shè)計(jì)，可以允許根據(jù)個(gè)性化的遺傳信息將患者分成不同的隊(duì)列，并相應(yīng)分配治療。這種類型的研究方案有助于研究人員收集有關(guān)藥物有效性的證據(jù)，包括患者對(duì)治療干預(yù)的獨(dú)特敏感性和反應(yīng)²⁰。開拓性的方法是，根據(jù)特定的生物標(biāo)志物對(duì)研究人群進(jìn)行分層，然后使用細(xì)胞和生物化學(xué)特征相結(jié)合的方式，來確定可以對(duì)特定療法的反應(yīng)進(jìn)行預(yù)測(cè)的方法²¹?；蚪M測(cè)序分析方法使用的增加，從根本上改變了診斷的性質(zhì)，即從人群轉(zhuǎn)變到個(gè)體的方法。臨床試驗(yàn)設(shè)計(jì)轉(zhuǎn)變?yōu)獒槍?duì)治療反應(yīng)，針對(duì)可以指導(dǎo)證據(jù)如何支持治療的研究參數(shù)，是邏輯和必要的下一步驟，并定義以進(jìn)行重復(fù)檢測(cè)²²。

Diet studies related to cancer therapy have proven to be difficult in terms of demonstrating evidence of effectiveness. There are various reasons for this, including the significant heterogeneity of responses to nutrient signals, as well as the low signal strength of nutritionally derived, biological, response modifying substances.²³  Siddhartha Mukheriee, MD. PhD, and Lewis C Cantley, PhD, both highly respected researchers, have recently announced a collaboration among Weill Cornell Medical College, Columbia University Medical Center, and New York-Presbyterian to evaluate specific dietary interventions in cancer. Previous work done in tumor models in mice revealed key findings about the role of glucose and fructose in enhancing the tumor-promoting effects of insulin through the PI3 kinase signaling network.^24,25 Earlier this year- -in 2019- -a group led by Dr Cantley reported that high-fructose corn syrup enhances intestinal tumor growth in mice.²⁶ This animal work, in combination with clinical observations that low-sugar diets appear to be helpful in reducing the progression of a number of types of cancer, has culminated in a crowdsourcing initiative to fund a human clinical trial.²⁷ Engaging the public in the support and execution of research has been described as 'leveraging the citizen scientist' It is a novel model- one that highlights a new kind of transparency and openness- and it is being now being applied not only to cancer research,but also to the study of diseases such as rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis.^28,29,30,31

與癌癥治療相關(guān)的飲食干預(yù)研究在證明其有效性方面是很困難的。這有多種原因，包括個(gè)體對(duì)營養(yǎng)信號(hào)反應(yīng)的顯著異質(zhì)性，以及營養(yǎng)來源的、生物的、反應(yīng)修飾物質(zhì)信號(hào)的低強(qiáng)度性質(zhì)相關(guān)²³。Siddhartha Mukheriee和Lewis C Cantley博士，這兩位備受尊敬的研究人員最近宣布了一項(xiàng)合作研究項(xiàng)目，即在韋爾康奈爾醫(yī)學(xué)院、哥倫比亞大學(xué)醫(yī)學(xué)中心和紐約長老會(huì)醫(yī)院合作評(píng)估癌癥的具體飲食干預(yù)措施。先前在小鼠腫瘤模型中所做的工作揭示了葡萄糖和果糖通過PI3激酶信號(hào)網(wǎng)絡(luò)系統(tǒng)增強(qiáng)胰島素促腫瘤作用的關(guān)鍵性發(fā)現(xiàn)^24,25。今年早些時(shí)候，由Cantley博士領(lǐng)導(dǎo)的一個(gè)小組報(bào)告說，高果糖玉米糖漿可增強(qiáng)小鼠腸道腫瘤的生長²⁶。這些動(dòng)物研究結(jié)論，結(jié)合臨床觀察表明低糖飲食似乎有助于減少多種癌癥的進(jìn)展，最終促成了多家機(jī)構(gòu)的合作倡議，以為在人類的臨床試驗(yàn)提供資金²⁷。引導(dǎo)公眾參與支持和執(zhí)行研究被稱為“利用公民科學(xué)家”的模式。這是一種強(qiáng)調(diào)透明和開放的新的模式 - 現(xiàn)在不僅應(yīng)用于癌癥研究，也可被應(yīng)用于類風(fēng)濕性關(guān)節(jié)炎、肌萎縮側(cè)索硬化和多發(fā)性硬化等的研究^28,29,30,31。

Stratified trial designs using new biometric and genomic tools are now being applied to the evaluation of epigenetic effects related to a range of interventions, including physical exercise, Ayurvedic practices, and meditation.^32,33,34  Progress has been made in the documentation of individualized responses, which has resulted in the codification of specific procedures for N-of-1 study designs.³⁵ Factors that have been linked to the usefulness of this type of study include the following: the mechanism of action of the treatment is pleomorphic; the study population is heterogeneous; and the clinical endpoints variable in type, duration, frequency, and intensity. Multi-person N-of-1 trials can be designed and effectively executed if the objectives, functional variables, reasons for stratifying the cohorts, and specific intervention rationale are clearly defined. ³⁶

使用新的生物學(xué)特征和基因組工具進(jìn)行分層的試驗(yàn)設(shè)計(jì)，現(xiàn)在被應(yīng)用于與一系列干預(yù)措施相關(guān)的表觀遺傳學(xué)效應(yīng)的評(píng)估，包括體育鍛煉、印度吠陀修習(xí)和冥想^32,33,34。在文獻(xiàn)中有報(bào)告?zhèn)€體化反應(yīng)的進(jìn)展，這導(dǎo)致對(duì)N-of-1研究設(shè)計(jì)的特定程序的編碼³⁵。與這類研究有用性相關(guān)的因素包括：治療的作用機(jī)制是多樣性的；研究人群是異質(zhì)的；臨床終點(diǎn)在類型、持續(xù)時(shí)間、頻率和強(qiáng)度上是可變的。如果明確了研究目標(biāo)、功能變量、隊(duì)列分層因素和具體的干預(yù)理由，就可以設(shè)計(jì)并有效執(zhí)行多人的N-of-1試驗(yàn)³⁶。

There is evidence that single -subject N-of-1 studies can be useful in establishing evidence of effectiveness in translational nutrition research.³⁷ Optimally, these N-of-1 designs should employ integrated use of multiple functional assessments, in combination with biometric assays and omics tools, to identify individual metabolic phenotypes. Using this array of assessment tools to identify the functional status of the individual before and after nutritional intervention allows for the development of valid evidence. Multiple individual N-of-1 studies using the same assessment tools and outcome measures can provide additional evidentiary support for use of the intervention in patients who share similar metabolic phenotypes.

有證據(jù)表明，單受試者N-of-1研究可有助于證明營養(yǎng)干預(yù)轉(zhuǎn)化研究的有效性³⁷。最理想的情況是，這些N-of-1設(shè)計(jì)應(yīng)綜合使用多種功能性評(píng)估，結(jié)合生物學(xué)測(cè)定和組學(xué)工具，以確定個(gè)體的代謝表型。利用這一系列的評(píng)估工具來識(shí)別營養(yǎng)干預(yù)前后個(gè)體的功能狀態(tài)，從而形成有效性的證據(jù)。使用相同評(píng)估工具和結(jié)果測(cè)量方法的多個(gè)體N-of-1研究可為具有相似代謝表型的患者使用干預(yù)提供額外的證據(jù)支持。 

Obesity is a condition marked by complex physiology and psychology. As such, the application of gene –based personalization of dietary advice for nutritional weight management in patients with this condition has historically resulted in only limited success.³⁸ This field of studying the relationship between genes and weight, which is now commonly referred to as nutrigenomics, recently took a major step forward. Amit Khera, MD, and Sekar Kathiresan, MD, who are both affiliated with the Center for Genomic Medicine at Massachusetts General Hospital, the Broad Institute at MIT, and Harvard Medical School, have worked with a team of collaborators to create a polygenic prediction algorithm to track weight and obesity trajectories from birth to adulthood based on the analysis of 2.1 million common genetic variants.³⁹ This work is truly groundbreaking because it relates to establishing specific genetically determined risk categories for complex health issues such as obesity. Interestingly, when the number of genetic variants in the computational algorithm only included those that had been identified by GWAS studies on obesity , no significant predictive ability was noted. However, when the larger set of 2.1 million common variants was used, the predictive ability of the algorithm became significant, even though most of the gens had not been identified a being associated with obesity. This fact demonstrates the high level of biological heterogeneity that exists in an individual’s response to diet . AIi Torkamani, PhD. and Eric Topol, MD, of the Scripps Research Translational Institute, jointly authored a commentary about the work of Khera et al and suggest it is an important illustration of why nutritional intervention trials often fail to produce clear evidence of improved outcome.⁴⁰ In the future, use of the polygenic risk score in combination with biometric information, functional data related to the impact of the gut microbiome on metabolism, and lifestyle and dietary factors may frame the design of N-of-1 approaches that will provide us with evidence about the relationship between a personalized diet and health outcomes.

肥胖是一種以復(fù)雜的生理和心理為特征的疾病。因此，基于基因的個(gè)性化飲食建議在這種疾患的營養(yǎng)學(xué)體重管理中的應(yīng)用，在歷史上獲得的成功是有限的³⁸。這一研究基因與體重之間關(guān)系的領(lǐng)域，現(xiàn)在通常被稱為基因營養(yǎng)學(xué)，最近取得了重大進(jìn)展。Amit Khera和Sekar Kathiresan醫(yī)學(xué)博士都隸屬于馬薩諸塞州總醫(yī)院基因組醫(yī)學(xué)中心、麻省理工學(xué)院布羅德研究所和哈佛醫(yī)學(xué)院，他們與一組研究者合作，創(chuàng)建了一個(gè)多基因預(yù)測(cè)算法來跟蹤從出生到成年的體重和肥胖軌跡。在對(duì)210萬種常見基因變異的分析中，這項(xiàng)工作確實(shí)是開創(chuàng)性的，因?yàn)樗婕暗綖橹T如肥胖等復(fù)雜的健康問題建立特定的以基因確定風(fēng)險(xiǎn)類別的方法。有趣的是，當(dāng)計(jì)算算法中的遺傳變異數(shù)僅包括那些通過GWAS肥胖研究確定的變異數(shù)時(shí)，沒有發(fā)現(xiàn)顯著的預(yù)測(cè)能力。然而，當(dāng)使用210萬個(gè)常見突變的較大集合時(shí)，算法的預(yù)測(cè)能力變得顯著，即使大多數(shù)基因沒有被確定為與肥胖有關(guān)。這一事實(shí)表明，個(gè)體對(duì)飲食的反應(yīng)存在高度的生物異質(zhì)性。Scripps研究轉(zhuǎn)化研究所的Ai Torkamani博士和Eric Topol醫(yī)學(xué)博士，聯(lián)合撰寫了一篇關(guān)于Khera等人研究工作的評(píng)論，并建議這是一個(gè)重要的例證，說明為什么營養(yǎng)干預(yù)試驗(yàn)往往不能產(chǎn)生明顯的改善結(jié)果的證據(jù)⁴⁰。未來，多基因風(fēng)險(xiǎn)評(píng)分結(jié)合生物特征學(xué)、腸道微生物群對(duì)新陳代謝、生活方式和飲食因素影響相關(guān)的功能性數(shù)據(jù)，可能構(gòu)成N-of-1方法的設(shè)計(jì)，這將為我們提供個(gè)性化飲食與健康結(jié)果之間關(guān)系的證據(jù)。

N-of-1 studies provide information from which a nested series of case reports can be developed to serve as additional supporting evidence for defining outcome. There is now an established format for publishing case reports under consensus-based guidelines called the Case REport (CARE) Statement and Checklist.⁴¹ The CARE approach includes the following: development of an appropriate abstract; an introduction; patient information; assessment criteria; therapeutic intervention; outcomes; discussion of strengths and weaknesses of the report; patient perspectives on their experience with the intervention; and informed consent.⁴²

N-of-1研究提供了一系列嵌套式病例報(bào)告的信息，這些報(bào)告可作為確認(rèn)結(jié)果的額外支持證據(jù)。現(xiàn)在已經(jīng)有一種基于共識(shí)的指南發(fā)布的病例報(bào)告的既定格式，稱為Case REport (CARE)聲明和列表⁴¹。CARE方法包括以下內(nèi)容：制定合適的摘要；前言；患者信息；評(píng)估標(biāo)準(zhǔn)；治療干預(yù)；結(jié)果；報(bào)告強(qiáng)項(xiàng)和弱點(diǎn)的討論；患者對(duì)干預(yù)體驗(yàn)性的看法和知情同意⁴²。 

Empirical evaluations have indicated that important treatment effects are often revealed through well-designed small studies that are properly stratified for participants within specific functional categories.⁴³ It is well understood that population-based RCTs have value in identifying specific, single-agent effects in acute disease states, but have limited application to personalized interventions in complex chronic disease. There are now a number of study designs available to assess the impact of personalized interventions and provide the evidence necessary to support the use of systems biology precepts and the application of Functional Medicine approaches to chronic disease management.⁴⁴

經(jīng)驗(yàn)性評(píng)估表明，重要的治療效果往往通過精心設(shè)計(jì)的小規(guī)模研究來揭示，這些小規(guī)模研究對(duì)特定功能類別的參與者進(jìn)行了適當(dāng)?shù)姆謱?span>⁴³。眾所周知，基于人群的RCT在識(shí)別急性疾病狀態(tài)下的特定單效應(yīng)因素方面具有價(jià)值，但在應(yīng)用于復(fù)雜慢性疾病的個(gè)性化干預(yù)時(shí)，RCT的意義有限?，F(xiàn)在有許多研究設(shè)計(jì)可用于評(píng)估個(gè)性化干預(yù)的影響，并提供支持使用系統(tǒng)生物學(xué)規(guī)則和將功能醫(yī)學(xué)方法應(yīng)用于慢性病管理的必要證據(jù)⁴⁴。

The April 9, 2019 issue of the Journal of the American Medical Association features an editorial titled 'The Evolving Uses of ‘Real-World’ Data.' As the article outlines, real-world data (RWD) and real world evidence (RWE) constitutes information that is not derived from RCTs or similar experiments. And yet- the authors point out- such information is now considered to have value in establishing the landscape related to the effectiveness of specific clinical interventions They write: The frenzy of interest in RWD has also been fueled by the Food and Drug Administration (FDA) signaling receptiveness to consider these data sources in regulatory review, and recent publication of a framework for doing so.45

在美國醫(yī)學(xué)會(huì)雜志（JAMA） 2019年4月9日一期上刊載了一篇社論，題為：不斷發(fā)展的“ 真實(shí)世界 ”數(shù)據(jù)的使用。正如文章所述， 真實(shí)世界數(shù)據(jù)（RWD）和真實(shí)世界證據(jù)（RWE） 構(gòu)成了非RCT或類似試驗(yàn)的信息。然而，作者指出，這些信息現(xiàn)在被認(rèn)為在建立與特定臨床干預(yù)有效性相關(guān)的更為全面的視角方面具有價(jià)值。他們寫道：對(duì)RWD的狂熱也受到食品藥品管理局（FDA）的推動(dòng)，F(xiàn)DA發(fā)出了在監(jiān)管方面考慮接受該類數(shù)據(jù)的信號(hào)，并在最近出版一個(gè)框架性的指導(dǎo)意見⁴⁵。  

In addition to this new interest in real-world data, patient-experience information has also become an increasingly important contributor to the evaluation of treatment effectiveness.⁴⁶ In a recently published editorial about evidence supporting cardiovascular clinical guidelines, authors Robert O. Bonow, MD, MS, and Eugene Braunwald, MD, state: “There will never be enough time, effort, or funding to implement RCTs to address all clinical scenarios that confront physicians. Moreover, RCTS are usually confined to patients of specific ages with single conditions. .... Individual patients are unique and many differ from those enrolled in RCTs on which the guidelines are based.' They continue:“This results in the common need to extrapolate guideline recommendations built upon ideal patients to the real patients seen in practice...”⁴⁷ The 21st century has already demonstrated itself to be an era of change for medicine and science. There is a new openness -to ideas, to a shift in perspectives, to a redefinition of evidence and the many ways it can be gathered. It is a fertile time on many fronts, including an expanded reach for a systems biology formalism and the Functional Medicine movement.

除了對(duì)真實(shí)世界數(shù)據(jù)的這種新的興趣外，患者體驗(yàn)信息也日益成為評(píng)價(jià)治療效果的重要因素⁴⁶。作者Robert O.Bonow和Eugene Braunwald醫(yī)學(xué)博士在最近出版的一篇關(guān)于支持心血管臨床指南證據(jù)的社論中指出：“永遠(yuǎn)不會(huì)有足夠的時(shí)間、努力或資金來實(shí)施RCT，以解決醫(yī)生面臨的所有臨床情況。此外，RCT通常僅限于特定年齡、有單一疾病的患者…個(gè)體患者是獨(dú)一無二的，許多患者與RCT中的患者不同”。他們繼續(xù)說：“這導(dǎo)致人們需要普遍將建立在理想患者基礎(chǔ)上的指南建議，外推到實(shí)踐中所見到的真正患者身上…”⁴⁷。21世紀(jì)已經(jīng)證明了自己在醫(yī)學(xué)和科學(xué)方面是一個(gè)變革的時(shí)代?，F(xiàn)在有了新的開放性的視角 - 思想的開放，觀點(diǎn)的轉(zhuǎn)變，對(duì)證據(jù)的重新定義以及收集證據(jù)的多種方式。這是一個(gè)產(chǎn)出頗豐的時(shí)期，包括了系統(tǒng)生物學(xué)的廣泛運(yùn)用和功能醫(yī)學(xué)的興起。