Normal Curves: Sexy Science, Serious Statistics

• Sugar Sag: Is Your Diet Aging You?

  Wrinkles and sagging skin—just normal aging, or can you blame your sweet tooth? We dive into “sugar sag,” exploring how sugar, processed foods, and even your crispy breakfast toast might be making you look older than if you’d said no to chocolate cake and yes to broccoli. Along the way, we encounter statistical adjustment, training and test data sets, what we call “references to nowhere,” plus some cadavers and collagen. Ever heard of an AGE reader? Find out how this tool might offer a sneak peek at your date’s age—and maybe even a clue about his… um… “performance.”Statistical topics Training and test setsStatistical adjustmentOverfitting PlagiarismProper citing practicesReferences to nowhereMethodologic morals“When you plagiarize, you steal the errors too.”“Overdone statistical adjustment is like overdone photo filters–at a certain point it’s just laughable.”CitationsCollagen turnover: Verzijl N, DeGroot J, Thorpe SR, et al.Effect of Collagen Turnover on the Accumulation of Advanced Glycation End Products. JBC. 2000;275:39027-31.Cadaver study:Hamlin CR, Kohn RR, Luschin JH. Apparent Accelerated Aging of Human Collagen in Diabetes Mellitus. Diabetes. 1975; 24: 902–904.AGE ReaderStudies of AGEs and diabetes and health:Monnier VM, Cerami A. Nonenzymatic browning in vivo: possible process for aging of long-lived proteins. Science. 1981;211:491-3. Brownlee M, Vlassara H, Cerami A. Nonenzymatic glycosylation and the pathogenesis of diabetic complications. Ann Intern Med. 1984;101:527-37. Monnier VM, Vishwanath V, Frank KE, et al. Relation between Complications of Type I Diabetes Mellitus and Collagen-Linked Fluorescence. N Engl J Med. 1986;314:403-408.Monnier VM, Sell DR, Abdul-Karim FW, et al. Collagen browning and cross-linking are increased in chronic experimental hyperglycemia. Relevance to diabetes and aging. Diabetes. 1988;37:867-72. Monnier VM, Bautista O, Kenny D, et al. Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. Diabetes 1999; 48: 870–80.Genuth S, Sun W, Cleary P, et al. Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes. 2005;54:3103-11. van Waateringe RP, Slagter SN, van Beek AP, et al. Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is associated with the metabolic syndrome and its individual components. Diabetol Metab Syndr. 2017;9:42. Kouidrat Y, Zaitouni A, Amad A, et al. Skin autofluorescence (a marker for advanced glycation end products) and erectile dysfunction in diabetes. J Diabetes Complications. 2017;3:108-113. Fujita N, Ishida M, Iwane T, et al. Association between Advanced Glycation End-Products, Carotenoids, and Severe Erectile Dysfunction. World J Mens Health. 2023;41:701-11. Uruska A, Gandecka A, Araszkiewicz A, et al. Accumulation of advanced glycation end products in the skin is accelerated in relation to insulin resistance in people with Type 1 diabetes mellitus. Diabet Med. 2019;36:620-625. Boersma HE, Smit AJ, Paterson AD, et al. Skin autofluorescence and cause-specific mortality in a population-based cohort. Sci Rep 2024;14:19967.Review article with conflicts of interest: Draelos ZD. Sugar Sag: What Is Skin Glycation and How Do You Combat It? J Drugs Dermatol. 2024; 23:s5-10.Clinical study on AGE interrupter cream:Draelos ZD, Yatskayer M, Raab S, Oresajo C. An evaluation of the effect of a topical product containing C-xyloside and blueberry extract on the appearance of type II diabetic skin. J Cosmet Dermatol. 2009;8:147-51. The citation trail:2023 review article: Zgutka K, Tkacz M, Tomasiak, et al. A Role for Advanced Glycation End Products in Molecular Ageing. Int J Mol Sci. 2023; 24: 9881. Sentence: “Interestingly, strict control of blood sugar for 4 months reduced the production of glycosylated collagen by 25%, and low-sugar food prepared by boiling could also reduce the production of AGEs [152].”Reference 152 is a review article: Cao C, Xiao Z, Wu Y, et al. Diet and Skin Aging-From the Perspective of Food Nutrition. Nutrients. 2020;12:870. Sentence: “However, strict control of blood sugar for four months can reduce the production of glycosylated collagen by 25%, and low-sugar food prepared by boiling can also reduce the production of AGEs [93–95].”Reference 93 is a review article: Nguyen HP, Katta R. Sugar sag: Glycation and the role of diet in aging skin. Skin Ther Lett. 2015; 20: 1–5. Sentence: “Tight glycemic control over a 4-month period can result in a reduction of glycated collagen formation by 25%.37,38”Reference 94 and 38 is a review article: Draelos ZD. Aging skin: the role of diet: facts and controversies. Clin Dermatol. 2013;31:701-6. Sentence: “Tighter glycemic control can reduce glycated collagen by 25% in 4 months.” No citation given.Reference 95 and 37 is a review article: Danby FW. Nutrition and aging skin: Sugar and glycation. Clin. Dermatol. 2010;28: 409–11. Sentence: “...tight glycemic control can drop glycated collagen formation by 25% in 4 months.” No citation given.The origi...

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  1:08:27
• Hookworms: Can parasites improve your health?

  What if you could treat your prediabetes with . . . worms? Regina and Kristin dive into a surprising early-phase clinical trial on hookworm therapy—that’s right, intentionally infecting yourself with parasitic worms—to treat metabolic conditions. They dig into the biological rationale (inflammation, abdominal fat, and gut immunology), the clever study design (hello, Tabasco sauce!), and the statistical chops behind this phase 1B trial (block randomization, missing data, and nonparametric hypothesis tests).  Along the way, expect self-experimenting scientists, worm sex, poop analysis, and the world’s nerdiest aphrodisiac: a well-documented protocol. Statistical topicsRandomized controlled trial (RCT)Primary and secondary outcomesPlacebos, placebo effect, and nocebo effectBlock randomizationSample sizeDouble-blindingMissing data protocolsReproducible researchNonparametric hypothesis testingKruskal-Wallis testMethodological morals“Walk before you can run. Invest in simple but high-quality Phase I clinical trials.”“When faced with small samples, you better rank and sum, baby.”ReferencesPierce DR, McDonald M, Merone L, et al. Effect of experimental hookworm infection on insulin resistance in people at risk of type 2 diabetes. Nat Commun. 2023;14(1):4503. doi:10.1038/s41467-023-40263-4Nuzzo, R. What Happens When Scientists Experiment on Themselves? Reader’s Digest. Updated April 16, 2016.Ethics of self-experimentation Helminthic Therapy Wiki Pritchard D. Worming your way to good health [video online]. TEDx Talks. Published November 19, 2013. https://www.youtube.com/watch?v=sm5DcdZbnGAChapman PR, Giacomin P, Loukas A, McCarthy JS. Experimental human hookworm infection: a narrative historical review. PLoS Negl Trop Dis. 2021;15(12):e0009908. doi:10.1371/journal.pntd.0009908Sobotková K, Parker W, Levá J, Růžková J, Lukeš J, Jirků Pomajbíková K. Helminth Therapy - From the Parasite Perspective. Trends Parasitol. 2019;35(7):501-515. doi:10.1016/j.pt.2019.04.009Zatterale F, Longo M, Naderi J, et al. Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Front Physiol. 2020;10:1607. Published 2020 Jan 29. doi:10.3389/fphys.2019.01607Kristin and Regina’s online coursesDemystifying Data: A Modern Approach to Statistical Understanding  Clinical Trials: Design, Strategy, and Analysis Medical Statistics Certificate Program  Writing in the Sciences Epidemiology and Clinical Research Graduate Certificate Program Program we teach in:Epidemiology and Clinical Research Graduate Certificate Program Find us on:Kristin -  LinkedIn & Twitter/XRegina - LinkedIn & ReginaNuzzo.com(02:44) - What happens when scientists experiment on themselves (06:56) - Mail-order DIY helminthic therapy (09:26) - Hookworm biology (15:53) - Inflammation, abdominal fat, immune system, and hookworms (21:29) - Hookworm therapy clinical trial design (26:00) - Clinical trial phases deep dive (31:24) - Interesting placebos (sham surgeries and psychedelics) (37:33) - Excitement over hookworm trial open data and data protocols (44:45) - Hookworm trial results (48:48) - Mood and well-being with hookworms (53:26) - Effects of hookworms on weight (56:09) - Nonparametric tests and how they work (01:02:56) - What the participants did after the study (01:04:53) - Wrap-up

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  1:08:00
• Alcohol: Are happy hours good for your heart?

  Does a daily glass of wine really keep the cardiologist away? It’s a claim we’ve all heard: light to moderate drinking is good for your heart. But is it science or just a convenient excuse for happy hour? In this episode, we dive into the history behind this claim, discuss the challenges of observational studies and statistical adjustment, and explore attempts at randomized trials and natural experiments to get to the bottom of this boozy debate. Grab your drink—or maybe don’t—and join us! Statistical topicsStatistical AdjustmentRegressionResidual and Unmeasured ConfoundingRandomized TrialsMultiple TestingOutcome SwitchingMendelian Randomization Methodological morals“Statistical adjustment cannot erase all confounding.”“When you can’t experiment on people, let Nature experiment on people.”CitationsAlcohol and Drinking. Gallup Poll. 2024. Canada’s Guidance on Alcohol and Health. Canadian Centre on Substance Use and Addiction. 2023.  U.S. Department of Agriculture and U.S. Department of Health and Human Services. 2020 – 2025 Dietary Guidelines for Americans. 2020.U.S. Department of Agriculture and U.S. Department of Health and Human Services. Alcohol and Cancer Risk: The US Surgeon General's Advisory. 2025.Mezue K, Osborne MT, Abohashem S, et al. Reduced stress-related neural network activity mediates the effect of alcohol on cardiovascular risk. JACC. 2023;81:2315-25.McPhillips D, Goodman B. Small amounts of alcohol may turn down stress in the brain, benefiting the heart, new study finds. CNN. June 12, 2023.Friedman GD, Klatsky AL. Is alcohol good for your health? NEJM. 1993;329:1882-3.Sainani K. Alcohol and Weight. Allure. July 14, 2010.Wang LU, Lee IM, Manson JE, et al. Alcohol consumption, weight gain, and risk of becoming overweight in middle-aged and older women. Arch Intern Med. 2010;170:453-61.Sainani K. Drinking and Weight. Allure. Oct 31, 2008.Tolstrup JS, Halkjær J, Heitmann BL, et al. Alcohol drinking frequency in relation to subsequent changes in waist circumference. Am J Clin Nutr. 2008;87:957-63.Rabin RC. Major Study on Drinking Will be Shut Down. New York Times. June 15, 2018.Mitchell G, Lesch M, McCambridge J. Alcohol industry involvement in the moderate alcohol and cardiovascular health trial. AJPH. 2020;110:485-8.Gepner Y, Golan R, Harman-Boehm I, et al. Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes: A 2-Year Randomized, Controlled Trial. Ann Intern Med. 2015;163:569-79.Slade E, Drysdale H, Goldacre B, et al. Discrepancies between prespecified and reported outcomes. Ann Intern Med. 2016;164:374.Biddinger KJ, Emdin CA, Haas ME, et al. Association of habitual alcohol intake with risk of cardiovascular disease. JAMA Netw Open. 2022;5:e223849.Page with more details on the CASCADE trial Kristin and Regina’s online courses: Demystifying Data: A Modern Approach to Statistical Understanding  Clinical Trials: Design, Strategy, and Analysis Medical Statistics Certificate Program  Writing in the Sciences Epidemiology and Clinical Research Graduate Certificate Program Program that we teach in:Epidemiology and Clinical Research Graduate Certificate Program Find us on:Kristin -  LinkedIn & Twitter/XRegina - LinkedIn & ReginaNuzzo.com(00:00) - Introduction (03:00) - Drinking habits in America (04:13) - New Canadian drinking guidelines (07:51) - Definition of light-to-moderate drinking (08:43) - Risks and benefits of light-to-moderate drinking (11:37) - History of the heart health claim (18:34) - Problems with observational studies (22:40) - Statistical adjustment (25:39) - Residual and unmeasured confounding (31:19) - Overconfidence in observational studies (35:16) - Randomized trials of alcohol (36:32) - Canceled NIH randomized trial of alcohol (41:42) - The CASCADE randomized trial of wine (43:18) - The problem of multiple testing (47:56) - Outcome switching (49:32) - Mendelian randomization (59:04) - Mendelian randomization studies of alcohol and heart disease (01:03:09) - Wrap-up

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  1:05:31
• The Red Dress Effect: Are women in red sexier?

  Wear red and drive men wild with lust – or so says scientific research on color’s role in human mating. But can a simple color swap really boost a woman’s hotness score? In this episode, we delve into the evidence behind the Red Dress Effect, from a controversial first study in college men to what the latest research says about who this trick might work for (and who it might not). Along the way we encounter red monkey butts, old-Internet websites, the Winner’s Curse in scientific research, adversarial collaborations, and why size (ahem, sample size) really does matter. Statistical topicsReproducibility crisis in psychologySample sizeSelection biasWinner’s curseCohen’s d standardized effect sizeAdversarial collaborationMeta-analysisPreregistrationPublication biasStatistical moderatorsMethodological morals“The smaller the sample, the flashier the result, the less you should trust it.”“Good scientists learn from their statistical mistakes and fix them.”ReferencesClarke, G. How to Be Sexy: 7 Weird (But True) Rules of Attraction. Allure. January 23, 2013.Nuzzo, R. Vying for a soul mate? Psych out the competition with science. Los Angeles Times. December 8, 2008. Vying for a Soul Mate on the Today Show, December 30, 2008.Elliot, A.J. and Niesta, D. Romantic red: red enhances men's attraction to women.  Journal of personality and social psychology. 2008; 95: 1150 – 1164. Lehrer, J. The Truth Wears Off. The New Yorker, December 5, 2010. MacMahon, B., Yen, S., Trichopoulos, D., Warren, K. and Nardi, G. Coffee and cancer of the pancreas. New England Journal of Medicine. 1981; 304: 630-633.Ioannidis, J.P. Why most published research findings are false. PLoS medicine. 2005; 2(8), e124 Lehmann, G.K., Elliot, A.J. and Calin-Jageman, R.J. Meta-analysis of the effect of red on perceived attractiveness. Evolutionary Psychology. 2018; 16: 1474704918802412. Pazda, A.D., Thorstenson, C.A. and Elliot, A.J. The effect of red on attractiveness for highly attractive women. Curr Psychol. 2023; 42: 8066–8073Kristin and Regina’s online courses: Demystifying Data: A Modern Approach to Statistical Understanding  Clinical Trials: Design, Strategy, and Analysis Medical Statistics Certificate Program  Writing in the Sciences Epidemiology and Clinical Research Graduate Certificate Program Chapters(00:00) - Introduction (06:04) - Red Dress Effect on TV (10:01) - Red Monkey Butts (12:56) - 2008 Study on Romantic Red (16:04) - HotOrNot.com (20:10) - 2008 Study Results (25:10) - Cohen’s d Standardized Effect Size (30:52) - Problems with Small Sample Sizes (34:12) - Winner’s Curse and Publication Bias (38:40) - Reproducibility Crisis (44:03) - Adversarial Collaboration (49:01) - Meta-Analysis and Pre-Registration (55:23) - Adversarial Discussion Sections and Updates (01:02:55) - Latest Red Study (01:06:26) - Wrap-Up

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  1:08:45
• Vitamin D Part 2: Good for more than just your bones?

  Can you really sit on your couch, pop vitamin D pills, and shave seconds off your 5k? Touted as a miracle cure-all, vitamin D is claimed to slash cancer and infection risks while boosting mood, cognition, and athletic performance. But does upping your vitamin D really make you healthier and happier? In this episode, we’ll follow the epidemiologic evidence—from clues in petri dishes through randomized trials. Along our journey, we’ll encounter chocolate-fueled Nobel Prizes, rock stars, pasty Brits, and a tangled mess of promiscuous variables.Statistical topicsecological studiesecological fallacycorrelation is not causationobservational studiesstatistical adjustmentconfoundingrandomized trialsfactorial designpost-hoc analysessubgroup analysesMethodologic morals“Variables with too many entanglements make observational studies a fool’s game.”“If your intervention works only when you torture your data, it’s probably a false confession.”CitationsGarland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 1980;9:227-31.Messerli FH. Chocolate consumption, cognitive function, and Nobel laureates. N Engl J Med. 2012;367:1562-64.Holick, MF. The Vitamin D Solution: A 3-Step Strategy to Cure Our Most Common Health Problems. Penguin Publishing Group, 2011. McMillan A. Can vitamin D boost your fitness routine? Dec 18, 2018.Marawan A, Kurbanova N, Qayyum R. Association between serum vitamin D levels and cardiorespiratory fitness in the adult population of the USA. Eur J Prev Cardiol. 2019;26:750-55.Vitamin D levels in the blood linked to cardiorespiratory fitness. European Society of Cardiology. Oct 30, 2018.Jones AM, Kirby BS, Clark IE, et al. Physiological demands of running at 2-hour marathon race pace. J Appl Physiol. 2021;130:369-79.Manson JE, Bassuk SS, Lee IM, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33:159-71.Manson JE, Cook NR, Lee IM, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. NEJM. 2019;380:33-44.Lee KL, McNeer JF, Starmer CF, et al. Clinical judgment and statistics: lessons from a simulated randomized trial in coronary artery disease. Circulation. 1980; 61:508-15.Wood S. VITAL: No Benefits to Vitamin D and Omega-3s in Reducing Major CV Events, Cancer. TCTMD.com. Nov 10, 2018.Neale RE, Baxter C, Romero BD, et al. The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality. Lancet Diabetes Endocrinol. 2022;10:120-28.Okereke OI, Reynolds CF, Mischoulon D, et al. Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial. JAMA. 2020;324:471-80.LeBoff MS, Murata EM, Cook NR, et al. VITamin D and OmegA-3 TriaL (VITAL): Effects of Vitamin D Supplements on Risk of Falls in the US Population. J Clin Endocrinol Metab. 2020;105:2929-38.Albert CM, Cook NR, Pester J, et al. Effect of Marine Omega-3 Fatty Acid and Vitamin D Supplementation on Incident Atrial Fibrillation: A Randomized Clinical Trial. JAMA. 2021;325:1061-73.Rist PM, Buring JE, Cook NR, et al. Effect of Vitamin D and/or Marine n-3 Fatty Acid Supplementation on Changes in Migraine Frequency and Severity. Am J Med. 2021;134:756-62.Christen WG, Cook NR, Manson JE, et al. Effect of Vitamin D and ω-3 Fatty Acid Supplementation on Risk of Age-Related Macular Degeneration: An Ancillary Study of the VITAL Randomized Clinical Trial. JAMA Ophthalmol. 2020;138:1280-89.MacFarlane LA, Cook NR, Kim E, et al. The Effects of Vitamin D and Marine Omega-3 Fatty Acid Supplementation on Chronic Knee Pain in Older US Adults: Results From a Randomized Trial. Arthritis Rheumatol. 2020 Nov;72(11):1836-1844.Chou SH, Murata EM, Yu C, et al. Effects of Vitamin D3 Supplementation on Body Composition in the VITamin D and OmegA-3 TriaL (VITAL). J Clin Endocrinol Metab. 2021;106:1377-88.Kang JH, Vyas CM, Okereke OI, et al. Effect of vitamin D on cognitive decline: results from two ancillary studies of the VITAL randomized trial. Sci Rep. 2021;11:23253.Rist PM, Buring JE, Cook NR, et al. Effect of vitamin D and/or omega‐3 fatty acid supplementation on stroke outcomes: A randomized trial. Eur J Neurol. 2021;28:809-15.Hahn J, Cook NR, Alexander EK, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ. 2022;376:e066452LeBoff MS, Chou SH, Murata EM, et al. Effects of Supplemental Vitamin D on Bone Health Outcomes in Women and Men in the VITamin D and OmegA-3 TriaL (VITAL). J Bone Miner Res. 2020;35:883-93.LeBoff MS, Chou SH, Ratliff KA, et al. Supplemental vitamin D and incident fractures in midlife and older adults. NEJM. 2022;387:299-309.Kolata G. Study finds another condition that vitamin D pills do not help. The New York Times. July 27, 2022Jolliffe DA, Holt H, Greenig M, et al. Effect of a test-and-treat approach to vitamin D supplementa...

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