薬理と治療

小児領域で汎用されている医薬品の60～70％は，「適応外使用」といわれているが漫然と投与されているのが現実である。この「適応外使用」の要因はさまざまであるが，適応が取得されている薬剤のみで薬物療法を実施するのは事実上不可能である。この小児での適応外使用を解決していくためには，薬事承認を取得するための開発推進（治験実施）が必要となる。一方で，小児医薬品等開発を進めていくうえでは，医療施設側の課題として，①新生児から思春期まで含まれる不均一な集団であり，医薬品の剤型や薬物動態など各年代に応じたきめ細かな検討が必要，②小児の臨床開発にかかわる専門家（CRC，DM，生物統計家など）が臨床現場に不足しているため，臨床試験（医師主導治験を含む）を自ら企画・実施することが困難であること，企業側のニーズとして，①小児での開発（とくに希少疾患，難病）を進める際に，どこに患者が存在するのか不明，②採算性が低いため，より安易に開発できる環境が必要，③製造販売後調査にも多大（人的，コスト的）な労力を要する，④学童（通学）も考慮した試験デザインの検討が必要，⑤インフォームドアセントの取得など小児特有の配慮を要するなどの“ ハードル” が存在している。このような問題を解決していくためには，臨床現場での人材育成が必要であると同時に，より効率的，安価に開発（治験）が実施できる環境が必要となる。本稿では，小児領域で取り組んでいる開発推進のための環境整備などについて紹介する。なお，本演題および本稿の内容は，「第18 回CRCと臨床試験のあり方を考える会議2018 in 富山」シンポジウム6 ＜いろんな立場から見た，子どもへの説明と同意～ ICH E11 の改訂を機会に見直そう～＞における「小児医薬品開発推進に向けた取組みについて（ICH-E11 の改訂も含めて）」（演者：栗山猛）の発表内容と一部重複していることご容赦いただきたい。

難病とは，発病の機構が明らかでなく，かつ治療方法が確立していない希少な疾病であって，当該疾病にかかることにより長期にわたり療養を必要とすることとなるものと定義され，アンメット・メディカルニーズの存在する代表的なものである。その治療法開発においては，病態が十分解明されていないこと，疾病の情報が少ないこと，さらにはその希少性から大変な困難が存在する。臨床研究・治験の推進に関する今後の方向性について2019 年版取りまとめ（令和元年12 月6 日）においても，研究開発が進みにくい領域として小児疾病や難病・希少疾患が取り上げられ，臨床研究中核病院の承認要件の見直しについても，神経難病領域を特定領域と想定する議論がなされている。

東京大学医学部附属病院は38 診療科，病床数1178 床を有する特定機能病院である。2010 年11 月に小児治験ネットワークの協力施設（実施可能性調査のみ対応可能な施設）として加盟している。2016年3 月に臨床研究中核病院としても承認を受け，小児疾患や難病などにおいても研究開発を促進していくことが期待されている。

エンドポイントに用いられる患者評価であるアウトカム評価は，評価またはスコア（カテゴリ変数または連続変数）を提供する測定ツールであり，患者の健康状態のある側面を表している。アウトカム評価は，ある疾患または状態に対する治療法を開発するときの有効性のエンドポイントを定義するために用いられる。大部分の有効性のエンドポイントは，患者の特定の臨床評価に基づいている。臨床評価が臨床試験のアウトカムとして用いられる場合は，臨床アウトカム評価（Clinical Outcome Assessments: COA）と呼ばれる。COA には選択，判断または動機に影響を受ける可能性のある評価が含まれる。COA は明確に定義され，治療のベネフィットを（直接的または間接的に）立証する十分な測定特性を保持していなければならない。対照的に，バイオマーカー評価は，患者の動機や評価者の判断にはほとんど影響を受けない評価である。本報告書は「ISPOR（The Professional Society for HealthEconomics and Outcomes Research）臨床アウトカム評価報告書―アウトカム研究のための新たな実施基準タスクフォース」と題する2 つの報告書のうちの1つ目である。本報告書はCOA 測定の原則を理解するために重要で基本的な定義を提供している。本報告書で提供される基盤として，ベネフィットのある効果を立証するとはどういうことか，患者の評価が治療のベネフィットを示すという目的にどのように関係しているか，そしてこれらの評価が臨床試験のエンドポイントでどのように使用されているかが含まれる。さらに，本報告書は測定特性に影響を与えうる患者評価および臨床試験の要因の本質的な属性について解説している。評価を開発するとき，または改良するときにこれらの要因を考慮すべきである。これらの考慮事項は，研究者が試験をデザインする際に，既存の評価を用いるか，それとも新しいアウトカム評価を開発するかを選択するのに役立つだろう。　本報告書は主として臨床試験のエンドポイントを定義するための新たなCOA の開発について記述しているが，これらの原則はもっと一般的に適用される場合がある。COA を吟味，開発するうえでクリティカルな要素は，患者がどのように感じているか，または機能しているかという明確に同定された側面に与える効果として，意図する治療のベネフィットを示すことである。この側面は患者にとって重要であり，また患者の日常生活の一部でなければならない。健康にとって意義のある側面は，直接測定することができ，また，直接評価するのが実際的でない場合，もしくは測定することが難しい場合は間接的に測定することができる。間接的な測定では，関心のある概念（Concept of Interest:COI）を同定することができる。COI は患者がどのように感じているか，または機能しているかに関連している必要がある。次に，COI を測定するための方法を開発する。COA の意図した場面および使用方法（使用場面）において，これらの測定法と患者がどのように感じているか，または機能しているかとの関連性を定義することができる。COA は，エンドポイントに用いる場合にCOA の測定特性に影響を与える同定可能な属性または特徴を有する。これらの特徴の1 つは，判断が測定に影響を与えうるかどうかであり，影響を与える場合には，誰の判断であるかである。この属性はCOAの次の4 つのカテゴリを定義する：患者報告アウトカム，臨床家報告アウトカム，観察者報告アウトカムおよびパフォーマンスアウトカムである。本報告書には，その他の重要なCOA の特徴の解説と，詳細な説明が含まれている。本報告書の情報はCOA の開発，改良および標準化を支援し，最終的には測定特性を改善させるものである。

Background and Objectives　A long-term post-marketing prospective study was conducted to evaluate the safety and efficacy of anagliptin（brand name: SUINY®）in combination therapy with rapid-acting insulin secretagogues, insulin, SGLT2 inhibitors or GLP-1 receptor agonists in real-world clinical practice. Methods　The study included patients with type 2 diabetes who had not previously used anagliptin and who were taking either a rapid︱acting insulin secretagogue, insulin, an SGLT2 inhibitor or a GLP-1 receptor agonist. Adverse events and efficacy endpoints and others were investigated using a central registry system. The observation period was 1 year from the start of anagliptin treatment. Results　According to the safety analysis set（1473 patients）, the incidence of adverse drug reactions was 7.40％（109 patients）, including hypoglycaemia（2.44％）, weight increased （0.34％）, constipation and blood triglycerides increased（0.27％ each）, hepatic function abnormal and renal impairment（0.20％ each）. The incidence of serious adverse drug reactions was 1.36％（20 patients）, including gastric cancer, hepatocellular carcinoma and hypoglycaemia （0.14％ each）. The efficacy of anagliptin was maintained up to 1 year, with a mean change in HbA1c of －0.59±1.49（SD）％ at the last assessment. Conclusions　After one year of use, no new safety or efficacy issues were identified, suggesting that anagliptin may be a useful treatment option for combination therapy in patients with type 2 diabetes.

Objectives　To investigate the real-world safety and efficacy of epinastine hydrochloride ophthalmic solution 0.1％ for pediatric patients with allergic conjunctivitis. Methods　The safety, efficacy and patientsʼ satisfaction of epinastine hydrochloride ophthalmic solution 0.1％ in pediatric allergic conjunctivitis patients under 12 years old were evaluated. Results　No adverse drug reactions were observed in the 329 patients. Significant decrease were observed in subjective symptom score and objective findings score, which were indices of efficacy, by treating with epinastine. In terms of“usability”and“efficacy”in patientsʼ satisfaction, more than 90％ of patients were“satisfied”or“bit satisfied”with both“usability”and “efficacy”after treatment with epinastine. Conclusions　Epinastine hydrochloride ophthalmic solution 0.1％ showed well benefit-risk balance and a high level of patientsʼ satisfaction for the treatment of pediatric allergic conjunctivitis, which suggest that this drug is a useful anti-allergic ophthalmic solution.

Objectives　The Eucommia bark extract is used as an antihypertensive medicine in China and Japan. The Eucommia leaf extract is also used as a health food for the purpose of antihypertensive treatment in Japan. Both extracts contain geniposidic acid as one of the common main constituents. The only difference between the two extracts is that the Eucommia bark extract contains pinoresinol diglucoside as one of the main constituents in addition to geniposidic acid. 　It was recently revealed that the oral administration of geniposidic acid to spontaneously hypertensive rats （SHR）acted as a GLP︱1R agonist to the atrium and increased atrial natriuretic peptide（ANP）secretion in blood vessels, which caused relaxation of the vascular smooth muscle. 　　There is a previous study in humans that only the Eucommia bark extract might show the antihypertensive effect by ANP secretion. So, the differences of the antihypertensive effects of Eucommia bark extract and Eucommia leaf extract in humans were considered. Methods　Guinea pigs were used to prepare a specimen for the right atrium. The heart rate and contractility were measured. 　　Rabbits were used to measure the blood pressure. Geniposidic acid was infused through the ear vein. Results　The Guinea pig experiment supported the results of the previous studies that the antihypertensive effect of Eucommia leaf extract in rodent SHR depends on ANP secretion by geniposidic acid. Geniposidic acid did not show the antihypertensive effect in non-rodents, rabbits, indicating no ANP secretion. 　　The difference of antihypertensive by ANP secretion between Eucommia bark extract and Eucommia leaf extract in humans might depend on the difference of the action of extract containing geniposidic acid against Epac 2 activity of the atrium, which is similar to the difference found between the rodent and non-rodent. Conclusions　In order to show the antihypertensive effect of the Eucommia extract by ANP secretion in humans, it was suggested that the coexistence of high cAMP-PDE inhibitor like pinoresinol diglucoside in addition to geniposidic acid might be necessary as observed in Eucommia bark extract. Therefore, it was concluded that the Eucommia leaf extract does not offer antihypertentive effect by ANP secretion in humans.

Objective　We evaluated the physiological function and QOL improvement effect related to nocturia in men when α-mangostin derived from mangosteen peel was ingested for 8 weeks. Methods　This study was a randomized, double-blind, placebo -controlled, parallel-group study. Healthy men aged 40 to 70 years who are dissatisfied with frequent daytime pollakiuria, nocturia, and sleep quality ingested 40 mg（L group）or 80 mg（H group）of α-mangostin or placebo（P group）daily for 8 weeks. We evaluated the physiological functions related to urination at night and QOL using the urination-related indicators N-QOL, OAB-q, and urination diary as the primary endpoints, and the sleep-related indicators Pittsburgh sleep questionnaire and OSA sleep questionnaire as secondary endpoints. Results　In the group that ingested α-mangostin, it was significantly improved in the urination-related item N-QOL question 12 compared to the P group at the 8th week of ingestion. Furthermore, in the H group, PSQIG was significantly improved at 8 weeks after ingestion as compared with the P group. In addition, when a subgroup analysis was performed on subjects with a PSQIG score of 5 or higher, in the H group, in addition to N-QOL question 12 and PSQIG at the 8th week of intake, the number of nighttime urination was also significantly improved than that of the P group. Conclusion　It was suggested that the intake of α-mangostin improves the physiological function related to nighttime urination in healthy men, and has the effect of improving the annoyance related to nighttime urination and the accompanying sleep quality.

Objectives　The aim of the present study was to investigate the effect of chocolate containing fructooligosaccharides on postprandial blood glucose levels in healthy human. Methods　A Randomized, placebo-controlled, single-blind, crossover study was conducted. 18 subjects（aged 43.8±8.7 years）ingested chocolate with（test diet）or without（control diet）fructooligosaccharides. Blood glucose levels and plasma insulin levels were measured before and 15, 30, 45, 60, 90, and 120 minutes after ingestion. Results　The incremental area under the curve（ΔAUC）of blood glucose levels for 0-120 minutes following ingestion of the test diet was significantly lower than that of the control diet. Blood glucose levels at 15, 30 and 45 minutes after ingestion of the test diet were also significantly lower than those of the control diet. Moreover, plasma insulin levels at 30, 45, 60, 90 and 120 minutes after ingestion of the test diet were significantly lower than those of the control diet. ΔAUC of plasma insulin levels following ingestion of the test diet was also significantly lower than that of the control diet. No adverse events related to the test or control diet were observed. Conclusions　The results of this study suggest that ingestion of chocolate with fructooligosaccharides has significantly lower blood glucose levels and plasma insulin levels than ingestion of chocolate without fructooligosaccharides. （UMIN ID: UMIN000041574）

Objectives　In this study, we investigated the anti-obesity effect of Lacticaseibacillus paracasei（formerly designated as Lactobacillus paracasei: L. paracasei）K71 intake in humans. Methods　This randomized, double-blind, placebo-controlled, parallel-group trial selected 66 healthy male╱female subjects with body mass index（BMI）≥23 and＜30 and randomly allocated them to two groups, a test food group and a placebo group. Subjects ingested either a test food containing 50 mg（approximately 1⊠1011 bacteria）of L. paracasei K71 or a placebo food for 12 weeks. Visceral fat area, waist circumference, body weight, BMI, total cholesterol, triglyceride（TG）, high-density lipoprotein（HDL）-cholesterol, low-density lipoprotein（LDL）-cholesterol, body fat percentage, muscle mass, abdominal computed tomography（CT）, body part circumference, and subcutaneous fat thickness were evaluated. Results　Compared with the placebo group, the test food group showed significantly decreased body weight, BMI, body fat percentage, and TG level, and significantly increased HDL-cholesterol level from that before ingestion. No adverse events due to the test food were observed during the test period. Conclusion　These results suggest that the continuous intake of L. paracasei K71 has an anti-obesity effect on healthy subjects. UMIN-CR ID: UMIN000041194

Objective　This study aimed to evaluate both the effects on the reduction of eye and nasal discomfort, and the safety profile by ingesting dried powdered Ecklonia stolonifera from Nishinoshima Town. Methods　A randomized, double-blind, placebo-controlled, parallel-group comparison study was conducted on 60 healthy individuals who complained of eye and nasal discomfort but were neither consulting an otolaryngologists, nor on medication. The participants were divided into two groups, namely, a test food group and a placebo food group. The test food group ingested 340 mg of dried powdered of E. stolonifera containing 37.4 mg of phlorotannin, whereas the placebo food group ingested 250 mg of maltodextrin for 4 weeks. Allergic rhinitis╱conjunctivitis quality of life（QOL）survey and blood biomarkers were evaluated for eye and nasal discomfort, and safety. Results　In participants with medium and severe eye and nasal symptoms, regular ingestion of dried powdered of E. stolonifera was found to reduce eye and nasal discomfort, and improve the QOL of both daily, and social life compared to placebo food group. These results were obtained upon evaluation by the QOL survey, Japanese allergic conjunctival diseases Quality of Life Questionnaire（JACQLQ）. In addition, no adverse effects attributable to the ingestion of dried powdered of E. stolonifera were observed during the experimental period. Conclusion　Dry powder of the phlorotannin-containing brown alga, E. stolonifera, from Nishinoshima Town is both effective and safe for use in improving eye and nasal discomfort, and the accompanying QOL. （UMIN-ID: UMIN000043543）

Objectives　This randomized, double-blinded, placebo-controlled, parallel-group study aimed to evaluate the effects of Kaempferia parviflora extract on quality of life （QOL）. Methods　Fifty healthy participants were enrolled in this study and were randomly assorted into a test food group and a placebo group. Participants consumed either test food containing K. parviflora extract（containing 0.49 mg╱day of tetramethylluteolin）, or received a placebo for 4 weeks. QOL was evaluated using questionnaires（VAS, SF-36）. Results　The test food group displayed a significant decrease in VAS scores for“fatigue”and “complexion”（P＜0.05）relative to the placebo food group. The test food group also displayed a significant increase in SF-36 scores for“role physical”“, general health”and“social functioning”（P＜0.05）relative to the placebo food group. During the study period, no adverse events attributable to the test foods were observed. Conclusions　Overall, these findings indicate that foods containing K. parviflora extract can improve QOL in healthy individuals. （UMIN-CTR ID: UMIN000044186）

Objective　This study investigated the effect of Lactobacillus paracasei subsp. paracasei NY1301-containing beverage on fatigue and quality of sleep. Methods　In this study, 154 healthy Japanese subjects with a feeling of tiredness were enrolled. The subjects were randomly assigned into either the intervention or placebo group （n＝77 each）. Each group received either NY1301-containing test beverage or placebo beverage for 12 weeks. The primary endpoint was subjective fatigue（visual analog scale）, and the secondary endpoints were subjective quality of sleep（visual analog scale）, Profile of Mod States 2nd edition（POMS2）, Oguri-Shirakawa-Azumi sleep inventory MA version（OSA-MA）, intestinal flora（amplicon sequence analysis）, fecal IgA and plasma catecholamines 3 fractions were assessed. Results A significant difference between the intervention group and the placebo group was observed for the VAS score for fatigue and quality of sleep. The VAS score for fatigue was significantly decreased after 12 weeks of test beverage intake in comparison to placebo intake. The difference of the VAS score for quality of sleep before and after the test beverage intake was significantly decreased in comparison to placebo intake. The fecal flora analysis showed that Lactobacillus sp. were significantly increased after intake of test beverage. Furthermore, no adverse effects were observed. Conclusion　This study demonstrated that the intake of NY1301-containing beverage decreased fatigue and improved quality of sleep. （UMIN ID: UMIN000042933）

Objective　The absorption of piceatannol, polyphenol with various physiological functions, was compared between passion fruit seed extract and passion fruit. Methods　An open-label crossover study was conducted in healthy subjects. The subjects ingested beverage containing passion fruit seed extract or passion fruits. Plasma piceatannol concentration and area under the curve（AUC）were assessed by collecting blood samples from 0 to 180 minutes after ingestion of the test food. Results　The maximum plasma piceatannol concentration and AUC of 8 subjects were significantly higher in passion fruit seed extract group than in passion fruit group. Conclusion　In healthy adults, the intake of passion fruit seed extract showed higher absorption of piceatannol compared to passion fruit. （UMIN ID: UMIN000045597）

Objectives　Evidence suggests that the prevention and improvement of fatigue are important issues in modern society; however, intervention studies on the intake of nutritional food containing multiple vitamins and minerals with effect on fatigue are limited. This study aimed to evaluate the effect of continuous intake of nutritional jelly（containing eleven vitamins and four minerals）on fatigue, among subjects with the feeling of fatigue and unbalanced dietary habit, in a randomized double-blind placebo-controlled parallel-group comparative study. Methods　Subjects were randomly assigned to either nutritional jelly or placebo group. Each subject in the nutritional jelly group ingested 150 g of jelly drink, daily, for 8 weeks, while subjects in the placebo group ingested placebo jelly drink. The primary outcome assessed was the Chalder Fatigue Scale score. The secondary outcomes were questionnaire assessed physical condition score, mental fatigue assessed by visual analog scale, salivary chromogranin A, Profile of Mood States 2nd Edition, low frequency［LF］╱high frequency［HF］ratio, serum cortisol, nutritional profiles, iron metabolism, oxidative marker, serum vitamin and mineral levels, and food frequency questionnaire. Results　The Chalder Fatigue Scale score was not improved by the intake of nutritional jelly. However, nutritional jelly increased vitamin B6 and folic acid compared to the placebo group levels. Furthermore, nutritional jelly intake improved the questionnaire assessed physical condition score, albumin╱globulin ratio, unsaturated iron binding capacity, and total iron binding capacity. Conclusions　These results suggested that the intake of nutritional jelly improved mental and physical fatigue, and it might also improve the nutritional status and anemia by vitamins and minerals supplementation.

Objectives　The constipation relieving effect of jelly supplemented with yuzu juice and β-glucan was evaluated in healthy subjects with a constipation tendency. Furthermore, the safety of overdosing at three times the recommended dose was analyzed. Methods　A double-blind randomized controlled trial was conducted by setting up a test group that was administered jelly supplemented with yuzu juice and β-1,3-1,6-glucan and a control group that was administered placebo jelly. The recommended regimen was 2 packets╱day for 12 weeks. Questionnaire-based surveys were performed to evaluate the alleviation of symptoms daily for 2 weeks before and 4 weeks after treatment initiation. The primary endpoints were defecation frequency and volume, stool shape, hardness, color, odor, and sensation after defecation. An overdose study was conducted wherein 6 packets╱day of test jelly were administered for 4 weeks. Clinical assessment and blood tests were performed before as well as 2 and 4 weeks after treatment initiation. Results　The frequency and volume of defecation increased significantly in both groups compared to those before treatment initiation. The test group reported a significantly higher stool volume than the control group in the 2nd and 4th week. The sensation after defecation significantly improved in the test group in the 2nd week after treatment initiation. Clinical evaluation and blood parameters were normal 2 and 4 weeks after initiation of the overdose regimen. Conclusions　Jelly supplemented with yuzu juice and β-glucan can relieve constipation. Additionally, overdosing at three times the recommended dose does not cause adverse effects. UMIN ID: UMIN000031641 & UMIN000035164

Objectives　We investigated the effects of bovine lactoferrin（LF）on subjective gastrointestinal symptoms. Methods　A randomized, double-blind, placebo-controlled trial was performed. Healthy subjects at Matsumoto University ingested placebo or bovine LF（200 mg╱day）for 4 weeks. The primary endpoint was subjective gastrointestinal symptoms related to physical conditions. The secondary endpoints were the activities of plasmacytoid dendritic cells（pDCs）in the peripheral blood. In addition, in vitro, pDCs were incubated with Toll-like receptor（TLR）-7╱8 agonist in the presence or absence of LF, and the production of interferon（IFN）-α/β was quantified. Results　A total of 80 subjects were randomized（placebo, n＝40; LF, n＝40）, among whom three subjects withdrew consent. The remaining 77 subjects were included in the full analysis set and analyzed（placebo, n＝39; LF, n＝38）. The cumulative incidence days of abdominal pain and diarrhea during the intervention were significantly lower in the LF group than in the placebo group. The expression of CD86（a co-stimulatory molecule）on pDCs and the production of IFN-α in pDCs upon TLR-7╱8 stimulation were significantly greater in the LF group than in the placebo group at 4 weeks. Adverse events were similar between the groups, and no adverse drug reactions were observed. Also in vitro, LF enhanced IFN-α/β production by pDCs. Conclusions　These results suggest that orally ingested LF supports normal immune systems via activation of pDCs and maintains physical conditions in healthy subjects. Trial registration　UMIN000043726 Funding　Morinaga Milk Industry Co., Ltd.

Objectives　In the study, we investigated the efficacy of S-allylcysteine（SAC）-enriched garlic extract（SGE）supplementation to mitigate fatigue sensation and the exacerbation of psychological feelings related to mental fatigue. Methods　Twenty-two eligible healthy adults who felt fatigue in everyday life were assigned to either a test food（SGE）group or a placebo group for the randomized, double-blind, placebo-controlled, parallel, comparative clinical study. At the beginning of the study, two and four weeks after administration of either foods containing SGE or placebo, the subjective fatigue sensation and psychological feelings were examined using a visual analogue scale （VAS）before and after mental load. Results　The change of VAS values between mental load for subjective fatigue sensation at 4-weeks since taking SGE supplementation, the primary endpoint, lowered by 12.5 mm vs. placebo through intake of SGE significantly（P＝0.03）. The change of VAS values between mental load for feeling of mental fatigue and feeling of stress were lowered after 2-weeks since taking SGE supplementation significantly（P＝0.04 and 0.01, respectively）. Moreover, the SGE group demonstrated significant differences in feeling about getting more focused（P＝0.02）and showed a tendency to reduce the VAS values for feeling having a clear head and feeling motivated after 4-weeks post-intervention（P＝0.06 and 0.07, respectively）. No obvious adverse events related to test food and placebo intake were observed, based on subjective symptom, physiological and hematological examination, biochemical tests of the blood and urine testing. Conclusions　Supplementation of SGE can mitigate fatigue sensation and the exacerbation of psychological feelings related to mental fatigue.（ UMIN ID: UMIN000043492）

統計解析を行う前に，データをいろいろ変換することがあります。対数変換（Logarithmic transformation）がもっとも身近かもしれません。臨床薬理を専門とする方などはよく見かけることでしょう。化学で出てくる（ペーハー）もそうです。ご存じのとおり，酸アルカリの指標である「pH ＝－ log10（H＋）」（H＋は水素イオン濃度）は対数で定義されます。データ変換というのは大変広いです。たとえば，BMI30 以上を肥満と定義するのもその一つです。ここではそうしたグループ化は扱いません。また，ノンパラメトリック手法では順位変換（Rank transformation）をよく用いますが，これも扱わないことにします。いわゆる関数を使ったデータ変換のみを扱うことにします。